bluuebunny/crossref_metadata_2025 huggingface dataset:
Bortezomib Inhibits PKR-Like Endoplasmic Reticulum (ER) Kinase and Induces Apoptosis via ER Stress in Human Pancreatic Cancer Cells
Authors: Nawrocki Steffan T. , Carew Jennifer S. , Dunner Kenneth , Boise Lawrence H. , Chiao Paul J. , Huang Peng , Abbruzzese James L. , McConkey David J.
Published: December 2005

Bortezomib (Velcade, formerly known as PS-341) is a boronic acid dipeptide derivative that is a selective and potent inhibitor of the proteasome. We hypothesized that proteasome inhibition would lead to an accumulation of misfolded proteins in the cell resulting in endoplasmic reticulum (ER) stress. The ability of bortezomib to induce ER stress and the unfolded protein response was investigated in a human pancreatic cancer cell line, L3.6pl. Bortezomib increased expression of ER stress markers, CHOP and BiP, but inhibited PKR-like ER kinase and subsequent phosphorylation of eukaryotic initiation factor 2α (eif2α), both of which are key events in translational suppression. These effects resulted in an accumulation of ubiquitylated proteins leading to protein aggregation and proteotoxicity. Peptide inhibitor or small interfering RNA targeting ER-resident caspase-4 blocked DNA fragmentation, establishing a central role for caspase-4 in bortezomib-induced cell death. The translation inhibitor cycloheximide abrogated bortezomib-induced protein aggregation, caspase-4 processing, and all other characteristics of apoptosis. Because malignant cells have higher protein synthesis rates than normal cells, they may be more prone to protein aggregation and proteotoxicity and possess increased sensitivity to bortezomib-induced apoptosis. Taken together, the results show that bortezomib induces a unique type of ER stress compared with other ER stress agents characterized by an absence of eif2α phosphorylation, ubiquitylated protein accumulation, and proteotoxicity. (Cancer Res 2005; 65(24): 11510-9)
Tumor Cell Plasticity in Ewing Sarcoma, an Alternative Circulatory System Stimulated by Hypoxia
Authors: van der Schaft Daisy W.J. , Hillen Femke , Pauwels Patrick , Kirschmann Dawn A. , Castermans Karolien , oude Egbrink Mirjam G.A. , Tran Maxine G.B. , Sciot Rafael , Hauben Esther , Hogendoorn Pancras C.W. , Delattre Olivier , Maxwell Patrick H. , Hendrix Mary J.C. , Griffioen Arjan W.
Published: December 2005

A striking feature of Ewing sarcoma is the presence of blood lakes lined by tumor cells. The significance of these structures, if any, is unknown. Here, we report that the extent of blood lakes correlates with poor clinical outcomes, whereas variables of angiogenesis do not. We also show that Ewing sarcoma cells form vessel-like tubes in vitro and express genes associated with vasculogenic mimicry. In tumor models, we show that there is blood flow through the blood lakes, suggesting that these structures in Ewing sarcoma contribute to the circulation. Furthermore, we present evidence that reduced oxygen tension may be instrumental in tube formation by plastic tumor cells. The abundant presence of these vasculogenic structures, in contrast to other tumor types, makes Ewing sarcoma the ideal model system to study these phenomena. The results suggest that optimal tumor treatment may require targeting of these structures in combination with prevention of angiogenesis. (Cancer Res 2005; 65(24): 11520-8)
Identification of GATA3 as a Breast Cancer Prognostic Marker by Global Gene Expression Meta-analysis
Authors: Mehra Rohit , Varambally Sooryanarayana , Ding Lei , Shen Ronglai , Sabel Michael S. , Ghosh Debashis , Chinnaiyan Arul M. , Kleer Celina G.
Published: December 2005

GATA binding protein 3 (GATA3) is a transcriptional activator highly expressed by the luminal epithelial cells in the breast. Here we did a meta-analysis of the available breast cancer cDNA data sets on a cohort of 305 patients and found that GATA3 was one of the top genes with low expression in invasive carcinomas with poor clinical outcome. To validate its prognostic utility, we did a tissue microarray analysis on a cohort of 139 consecutive invasive carcinomas (n = 417 tissue samples) immunostained with a monoclonal antibody against GATA3. Low GATA3 expression was associated with higher histologic grade (P < 0.001), positive nodes (P = 0.002), larger tumor size (P = 0.03), negative estrogen receptor and progesterone receptor (P < 0.001 for both), and HER2-neu overexpression (P = 0.03). Patients whose tumors expressed low GATA3 had significantly shorter overall and disease-free survival when compared with those whose tumors had high GATA3 levels. The hazard ratio of metastasis or recurrence according to the GATA3 status was 0.31 (95% confidence interval, 0.13-0.74; P = 0.009). Cox multivariate analysis showed that GATA3 had independent prognostic significance above and beyond conventional variables. Our data suggest that immunohistochemical analysis of GATA3 may be the basis for a new clinically applicable test to predict tumor recurrence early in the progression of breast cancer. (Cancer Res 2005; 65(24): 11259-64)
CDC4 Mutations Occur in a Subset of Colorectal Cancers but Are Not Predicted to Cause Loss of Function and Are Not Associated with Chromosomal Instability
Authors: Kemp Zoe , Rowan Andrew , Chambers William , Wortham Noel , Halford Sarah , Sieber Oliver , Mortensen Neil , von Herbay Axel , Gunther Thomas , Ilyas Mohammad , Tomlinson Ian
Published: December 2005

CDC4/FBXW7 is part of a ubiquitin ligase complex which targets molecules such as cyclin E, c-myc, and c-jun for destruction. CDC4 mutations occur in several cancer types and are best described in colorectal tumors. Knockout of CDC4 in vitro in colorectal cancer cells causes changes suggestive of chromosomal instability (CIN). In p53+/− mice, radiation-induced lymphomas show deletion or mutation of one copy of CDC4 and knockdown of CDC4 leads to increased aneuploidy in mouse fibroblasts. We screened 244 colorectal tumors and 40 cell lines for CDC4 mutations and allelic loss. Six percent (18 of 284) of tumors, including near-diploid (CIN−) lesions, harbored CDC4 mutations and there was no association between mutation and CIN (polyploidy). The CDC4 mutation spectrum in colorectal tumors was heavily biased towards C:G>T:A changes, either missense mutations at critical arginine residues or nonsense changes in the 5′ half of the gene. The reasons for this odd mutation spectrum were unclear but C:G>T:A changes were not found more often than expected at APC, K-ras, or p53 in the same tumors and we found no specific defects in DNA repair to account for the observations. No colorectal tumor was found to carry two CDC4 mutations predicted to abolish protein function; partial loss of CDC4 function may therefore cause tumorigenesis. The in vitro studies, therefore, did not assess the functional effects of mutant alleles which are found in vivo. CDC4 mutations may be selected primarily to drive progression through the cell cycle although CIN might be an important secondary effect in some cancers. (Cancer Res 2005; 65(24): 11361-6)
The Shed Ectodomain of Nr-CAM Stimulates Cell Proliferation and Motility, and Confers Cell Transformation
Authors: Conacci-Sorrell Maralice , Kaplan Anna , Raveh Shani , Gavert Nancy , Sakurai Takeshi , Ben-Ze'ev Avri
Published: December 2005

Nr-CAM, a cell-cell adhesion molecule of the immunoglobulin-like cell adhesion molecule family, known for its function in neuronal outgrowth and guidance, was recently identified as a target gene of β-catenin signaling in human melanoma and colon carcinoma cells and tissue. Retrovirally mediated transduction of Nr-CAM into fibroblasts induces cell motility and tumorigenesis. We investigated the mechanisms by which Nr-CAM can confer properties related to tumor cell behavior and found that Nr-CAM expression in NIH3T3 cells protects cells from apoptosis in the absence of serum by constitutively activating the extracellular signal-regulated kinase and AKT signaling pathways. We detected a metalloprotease-mediated shedding of Nr-CAM into the culture medium of cells transfected with Nr-CAM, and of endogenous Nr-CAM in B16 melanoma cells. Conditioned medium and purified Nr-CAM-Fc fusion protein both enhanced cell motility, proliferation, and extracellular signal-regulated kinase and AKT activation. Moreover, Nr-CAM was found in complex with α4β1 integrins in melanoma cells, indicating that it can mediate, in addition to homophilic cell-cell adhesion, heterophilic adhesion with extracellular matrix receptors. Suppression of Nr-CAM levels by small interfering RNA in B16 melanoma inhibited the adhesive and tumorigenic capacities of these cells. Stable expression of the Nr-CAM ectodomain in NIH3T3 cells conferred cell transformation and tumorigenesis in mice, suggesting that the metalloprotease-mediated shedding of Nr-CAM is a principal route for promoting oncogenesis by Nr-CAM. (Cancer Res 2005; 65(24): 11605-12)
Papillomavirus E2 Protein Induces Expression of the Matrix Metalloproteinase-9 via the Extracellular Signal-Regulated Kinase/Activator Protein-1 Signaling Pathway
Authors: Behren Andreas , Simon Christian , Schwab Roxana Michaela , Loetzsch Ekaterina , Brodbeck Stephan , Huber Evamaria , Stubenrauch Frank , Zenner Hans Peter , Iftner Thomas
Published: December 2005

Papillomaviruses are involved in the development of cancers of the female cervix, head and neck, and skin. An excellent model to study papillomavirus-induced tumor induction and progression is the New Zealand White rabbit, where the skin is infected with the cottontail rabbit papillomavirus (CRPV). This leads to the formation of benign tumors that progress into invasive and metastasizing carcinomas without the need for cofactors. We have shown previously that specific mutations in the transactivation domain of the transcription/replication factor E2 cause a dramatic loss in the tumor induction efficiency of the viral genome and a major deficiency in tumor progression as we show now. By comparing wild-type (WT) and mutant E2-induced skin tumors, we found high levels of matrix metalloproteinase-9 (MMP-9) protein and transcripts in WT CRPV-E2–induced tumors in contrast to certain mutant CRPV-E2–induced papillomas and normal uninfected skin. Stable cell lines and reporter assays revealed that E2 from different papillomavirus types is able to transactivate the MMP-9 promoter via the promoter-proximal activator protein-1 (AP-1) site as shown in reporter gene assays with mutant MMP-9 promoter constructs. Furthermore, WT E2 but not mutant E2 strongly transactivated a minimal promoter reporter construct with multiple AP-1 sites. The MMP-9 protein induced in cells expressing E2 degrades collagen matrices as measured in Matrigel-based invasion/mobility assays. E2-induced MMP-9 expression can be blocked by a chemical inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase 1 (PD 098059), suggesting that E2 activates the MAPK/ERK signaling pathway, which is further supported by the induction of ERK1 in CRPV-E2–transfected cells. (Cancer Res 2005; 65(24): 11613-21)
Sphingosine Kinase-1 as a Chemotherapy Sensor in Prostate Adenocarcinoma Cell and Mouse Models
Authors: Pchejetski Dimitri , Golzio Muriel , Bonhoure Elisabeth , Calvet Cyril , Doumerc Nicolas , Garcia Virginie , Mazerolles Catherine , Rischmann Pascal , Teissié Justin , Malavaud Bernard , Cuvillier Olivier
Published: December 2005

Systemic chemotherapy was considered of modest efficacy in prostate cancer until the recent introduction of taxanes. We took advantage of the known differential effect of camptothecin and docetaxel on human PC-3 and LNCaP prostate cancer cells to determine their effect on sphingosine kinase-1 (SphK1) activity and subsequent ceramide/sphingosine 1-phosphate (S1P) balance in relation with cell survival. In vitro, docetaxel and camptothecin induced strong inhibition of SphK1 and elevation of the ceramide/S1P ratio only in cell lines sensitive to these drugs. SphK1 overexpression in both cell lines impaired the efficacy of chemotherapy by decreasing the ceramide/S1P ratio. Alternatively, silencing SphK1 by RNA interference or pharmacologic inhibition induced apoptosis coupled with ceramide elevation and loss of S1P. The differential effect of both chemotherapeutics was confirmed in an orthotopic PC-3/green fluorescent protein model established in nude mice. Docetaxel induced a stronger SphK1 inhibition and ceramide/S1P ratio elevation than camptothecin. This was accompanied by a smaller tumor volume and the reduced occurrence and number of metastases. SphK1-overexpressing PC-3 cells implanted in animals developed remarkably larger tumors and resistance to docetaxel treatment. These results provide the first in vivo demonstration of SphK1 as a sensor of chemotherapy. (Cancer Res 2005; 65(24): 11667-75)
Modeling Human Cancer: Report on the Eighth Beatson International Cancer Conference
Authors: Olson Michael F.
Published: December 2005

One of the major challenges facing cancer researchers is the necessity to adequately model the human disease. This need is driven by goals, including validating/determining the contribution of a gene to cancer, establishing systems for drug discovery and validation, and discovering additional factors that modify the oncogenic process. Recent advances in cancer modeling were discussed at the Eighth Beatson International Cancer Conference on June 19 to 22, 2005 in Glasgow, United Kingdom. The conference was attended by 250 scientists with >130 oral and poster presentations. The research presented made use of systems ranging from two-dimensional and three-dimensional cell culture to nonmammalian and mammalian in vivo models. In addition to basic research on the fundamental processes involved in cancer, novel developments in cancer treatment were presented. (Cancer Res 2005; 65(24): 11247-50)
Apoptotic Cells Initiate Endothelial Cell Sprouting via Electrostatic Signaling
Authors: Weihua Zhang , Tsan Rachel , Schroit Alan J. , Fidler Isaiah J.
Published: December 2005

Angiogenesis, the development of new blood vessels from preexisting vessels, is crucial to tissue growth, repair, and maintenance. This process begins with the formation of endothelial cell sprouts followed by the proliferation and migration of neighboring endothelial cells along the preformed extensions. The initiating event and mechanism of sprouting is not known. We show that the phenotypic expression of negatively charged membrane surface in apoptotic cells initiates the formation of directional endothelial cell sprouts that extend toward the dying cells by a mechanism that involves endothelial cell membrane hyperpolarization and cytoskeleton reorganization but is independent of diffusible molecules. (Cancer Res 2005; 65(24): 11529-35)
Aromatase Inhibitors in Human Lung Cancer Therapy
Authors: Weinberg Olga K. , Marquez-Garban Diana C. , Fishbein Michael C. , Goodglick Lee , Garban Hermes J. , Dubinett Steven M. , Pietras Richard J.
Published: December 2005

Lung cancer is the most common cancer in the world. It is a highly lethal disease in women and men, and new treatments are urgently needed. Previous studies implicated a role of estrogens and estrogen receptors in lung cancer progression, and this steroidal growth-stimulatory pathway may be promoted by tumor expression and activity of aromatase, an estrogen synthase. We found expression of aromatase transcripts and protein in human non–small cell lung cancer (NSCLC) cells using reverse transcription-PCR and Western immunoblots, respectively. Aromatase staining by immunohistochemistry was detected in 86% of archival NSCLC tumor specimens from the clinic. Further, biological activity of aromatase was determined in NSCLC tumors using radiolabeled substrate assays as well as measure of estradiol product using ELISA. Significant activity of aromatase occurred in human NSCLC tumors, with enhanced levels in tumor cells compared with that in nearby normal cells. Lung tumor aromatase activity was inhibited by anastrozole, an aromatase inhibitor, and treatment of tumor cells in vitro with anastrozole led to significant suppression of tumor cell growth. Similarly, among ovariectomized nude mice with A549 lung tumor xenografts, administration of anastrozole by p.o. gavage for 21 days elicited pronounced inhibition of tumor growth in vivo. These findings show that aromatase is present and biologically active in human NSCLCs and that tumor growth can be down-regulated by specific inhibition of aromatase. This work may lead to development of new treatment options for patients afflicted with NSCLC. (Cancer Res 2005; 65(24): 11287-91)
Motexafin Gadolinium and Zinc Induce Oxidative Stress Responses and Apoptosis in B-Cell Lymphoma Lines
Authors: Lecane Philip S. , Karaman Mazen W. , Sirisawad Mint , Naumovski Louie , Miller Richard A. , Hacia Joseph G. , Magda Darren
Published: December 2005

There is an emerging appreciation of the importance of zinc in regulating cancer cell growth and proliferation. Recently, we showed that the anticancer agent motexafin gadolinium (MGd) disrupted zinc metabolism in A549 lung cancer cells, leading, in the presence of exogenous zinc, to cell death. Here, we report the effect of MGd and exogenous zinc on intracellular levels of free zinc, oxidative stress, proliferation, and cell death in exponential phase human B-cell lymphoma and other hematologic cell lines. We find that increased levels of oxidative stress and intracellular free zinc precede and correlate with cell cycle arrest and apoptosis. To better understand the molecular basis of these cellular responses, gene expression profiling analyses were conducted on Ramos cell cultures treated with MGd and/or zinc acetate. Cultures treated with MGd or zinc acetate alone elicited transcriptional responses characterized by induction of metal response element–binding transcription factor-1 (MTF-1)–regulated and hypoxia-inducible transcription factor-1 (HIF-1)–regulated genes. Cultures cotreated with MGd and zinc acetate displayed further increases in the levels of MTF-1– and HIF-1–regulated transcripts as well as additional transcripts regulated by NF-E2–related transcription factor 2. These data provide insights into the molecular changes that accompany the disruption of intracellular zinc homeostasis and support a role for MGd in treatment of B-cell hematologic malignancies. (Cancer Res 2005; 65(24): 11676-88)
Anoikis and Survival Connections in the Tumor Microenvironment: Is There a Role in Prostate Cancer Metastasis?
Authors: Rennebeck Gabriela , Martelli Matthew , Kyprianou Natasha
Published: December 2005

Overcoming the androgen independence of prostate tumors is considered the most critical therapeutic end point for improving survival in patients with metastatic prostate cancer. Normal epithelial and endothelial cells can undergo apoptosis when detached from the extracellular matrix (ECM), via the anoikis phenomenon. In contrast, tumor cells upon detachment from the ECM are capable of evading anoikis and metastasizing to different distant organs. Is the biological repertoire of the epithelial and endothelial cells sufficient to account for the events associated with the process of anoikis during prostate cancer metastasis? Although there is no clear answer to this question, what has become increasingly evident from the existing evidence is that molecules that induce anoikis in tumor epithelial and endothelial cells provide exciting new leads into effective therapeutic targeting as well as markers of prostate cancer progression and prediction of therapeutic resistance. This review analyzes recent findings on anoikis regulators and discusses the relevance of this unique apoptosis mode in the development of metastatic prostate cancer and identification of molecular signatures for treatment of advanced disease. (Cancer Res 2005; 65(24): 11230-5)
Coactivation of Liver Receptor Homologue-1 by Peroxisome Proliferator-Activated Receptor γ Coactivator-1α on Aromatase Promoter II and Its Inhibition by Activated Retinoid X Receptor Suggest a Novel Target for Breast-Specific Antiestrogen Therapy
Authors: Safi Rachid , Kovacic Agnes , Gaillard Stéphanie , Murata Yoko , Simpson Evan R. , McDonnell Donald P. , Clyne Colin D.
Published: December 2005

Aromatase inhibitors target the production of estrogen in breast adipose tissue, but in doing so, also decrease estrogen formation in bone and other sites, giving rise to deleterious side effects, such as bone loss and arthralgia. Thus, it would be clinically useful to selectively inhibit aromatase production in breast. In this regard, we have determined that the orphan nuclear receptor liver receptor homologue-1 (LRH-1) is a specific transcriptional activator of aromatase gene expression in human breast preadipocytes but not in other tissues of postmenopausal women. In this study, we show that the coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a physiologically relevant modulator of LRH-1, and that its transcriptional activity can be inhibited effectively using receptor-interacting peptide antagonists that prevent PGC-1α recruitment. Interestingly, we note that all of these peptides also interact in an agonist-dependent manner with retinoid X receptor α (RXRα), suggesting that these two receptors may compete for limiting cofactors within target cells. In support of this hypothesis, we show that 9-cis-retinoic acid, acting through RXR, inhibits both the basal and PGC-1α–induced transcriptional activity of LRH-1. The importance of this finding was confirmed by showing that LRH-1–dependent, PGC-1α–stimulated regulation of aromatase gene expression in primary human breast preadipocytes was effectively suppressed by RXR agonists. We infer from these data that LRH-1 is a bona fide target whose inhibition would selectively block aromatase expression in breast, while sparing other sites of expression. (Cancer Res 2005; 65(24): 11762-70)
Para to Ortho Repositioning of the Arsenical Moiety of the Angiogenesis Inhibitor 4-(N-(S-Glutathionylacetyl)Amino)Phenylarsenoxide Results in a Markedly Increased Cellular Accumulation and Antiproliferative Activity
Authors: Dilda Pierre J. , Decollogne Stephanie , Rossiter-Thornton Michael , Hogg Philip J.
Published: December 2005

The synthetic tripeptide arsenical 4-(N-(S-glutathionylacetyl)amino)p-phenylarsenoxide (p-GSAO) is an angiogenesis inhibitor that inactivates mitochondrial adenine nucleotide translocase (ANT) by cross-linking a pair of matrix-facing cysteine residues. This causes an increase in superoxide levels and proliferation arrest of endothelial cells followed by mitochondrial depolarization and apoptosis. p-GSAO induces proliferation arrest in endothelial cells and is a selective inhibitor of endothelial cells compared with tumor cells. An analogue of p-GSAO has been made in which the arsenical moiety is at the ortho instead of the para position on the phenyl ring. o-GSAO, like p-GSAO, bound to ANT in a dithiol-dependent manner but was ∼8-fold more efficient than p-GSAO at triggering the mitochondria permeability transition in isolated mitochondria. o-GSAO was an ∼50-fold more potent inhibitor of endothelial and tumor cell proliferation than p-GSAO. The mechanism of this effect was a consequence of ∼300-fold faster rate of accumulation of o-GSAO in the cells, which is due, at least in part, to impaired export by the multidrug resistance–associated protein 1. Administration of o-GSAO to tumor-bearing mice delayed tumor growth by inhibiting tumor angiogenesis but there were side effects not observed with p-GSAO administration. (Cancer Res 2005; 65(24): 11729-34)
The G691S RET Polymorphism Increases Glial Cell Line–Derived Neurotrophic Factor–Induced Pancreatic Cancer Cell Invasion by Amplifying Mitogen-Activated Protein Kinase Signaling
Authors: Sawai Hirozumi , Okada Yuji , Kazanjian Kevork , Kim Joseph , Hasan Sascha , Hines Oscar J. , Reber Howard A. , Hoon Dave S.B. , Eibl Guido
Published: December 2005

Mutations of the RET proto-oncogene are responsible for several inherited human diseases and may function as genetic modifiers of the disease. However, the role of RET mutations in pancreatic cancer has not been studied. Expression of the glial cell line–derived neurotrophic factor (GDNF) receptors RET and GDNF family receptor α1 (GFRα1) in human pancreatic cancer cells was determined by Western blot, immunofluorescence, and flow cytometry. The effect of GDNF on cell proliferation and invasion was assessed. Small interfering RNA and antibodies were used to evaluate the involvement of RET. The G691S RET polymorphism was analyzed by sequencing and restriction analysis. The modifying effect of G691S RET on GDNF-induced invasion and mitogen-activated protein kinase (MAPK) signaling was evaluated. Transfection studies with wild-type and mutated RET determined the functional role of the G691S polymorphism. Pancreatic cancer specimens and matched tissues were analyzed for the presence of the G691S RET polymorphism. GDNF receptors were found on all cell lines. GDNF increased pancreatic cancer cell proliferation and invasion, which was mediated by RET. The effect of GDNF was more profound in cells with the G691S RET polymorphism (P < 0.01). G691S RET correlated with an enhanced activation of the downstream extracellular signal-regulated kinase pathway. Overexpression of G691S RET increased pancreatic cancer cell invasion. The G691S RET polymorphism was also detected in human pancreatic tumors and represented a somatic mutation in some patients. These findings indicate that the G691S RET single nucleotide polymorphism may directly correlate with the aggressive growth of pancreatic cancers and may function as a genetic modifier or even low-penetrance gene. (Cancer Res 2005; 65(24): 11536-44)
Dentin Matrix Protein 1 Enhances Invasion Potential of Colon Cancer Cells by Bridging Matrix Metalloproteinase-9 to Integrins and CD44
Authors: Karadag Abdullah , Fedarko Neal S. , Fisher Larry W.
Published: December 2005

The up-regulation of various matrix metalloproteinases (MMP), certain cell receptors such as integrins and CD44, and the SIBLING family of integrin-binding glycophosphoproteins have been reported separately and in various combinations for many types of tumors. The mechanisms by which these different proteins may be interacting and enhancing the ability of a cancer cell to survive and metastasize have become an interesting issue in cancer biology. Dentin matrix protein 1 (DMP1) has been known for a number of years to bind to CD44 and ArgGlyAsp sequence–dependent integrins. This SIBLING was recently shown to be able to specifically bind and activate proMMP-9 and to make MMP-9 much less sensitive to inhibition by tissue inhibitors of metalloproteinases and synthetic inhibitors. In this study, we used a modified Boyden chamber assay to show that DMP1 enhanced the invasiveness of the MMP-9 expressing colon cancer cell line, SW480, through Matrigel in a dose-dependant manner. DMP1 (100 nmol/L) increased invasion 4-fold over controls (86.1 ± 13.9 versus 22.3 ± 9.8, P < 0.001). The enhanced invasive potential required the presence of MMP-9 and at least one of the cell surface receptors, CD44, αvβ3, or αvβ5 integrin. The bridging of MMP-9 to the cell surface receptors was shown by both pull-down and fluorescence activated cell sorting experiments. Because all of these proteins were also shown by immunohistochemistry to be expressed in serial sections of a colon adenocarcinoma, we have hypothesized that the MMP-9/DMP1/cell surface complexes observed to enhance cell invasion in vitro may be aiding metastatic events in vivo. (Cancer Res 2005; 65(24): 11545-52)
Gold(III) Porphyrin 1a Induced Apoptosis by Mitochondrial Death Pathways Related to Reactive Oxygen Species
Authors: Wang Ying , He Qing-Yu , Sun Raymond Wai-Yin , Che Chi-Ming , Chiu Jen-Fu
Published: December 2005

Apoptosis is a tightly controlled multistep mechanism of cell death, and mitochondria are considered to play a central role in this process. Mitochondria initiate two distinct apoptosis pathways, one caspase-dependent and the other caspase-independent. In addition, mitochondrial production of reactive oxygen species (ROS) seems to play a role in cell death. Most chemotherapeutic agents induce apoptosis through at least one of these pathways. The post-initiation mechanisms of gold(III) porphyrin 1a were investigated in this study. HONE1 cells exposed to gold(III) porphyrin 1a underwent apoptosis after 24 hours. Functional proteomic studies revealed the alteration of several cytoplasmic protein expressions in HONE1 cells after treatment with the drug. These proteins include enzymes participating in energy production and proteins involved in cellular redox balance. There was a quick attenuation of mitochondrial membrane potential (ΔΨm) with the alterations of Bcl-2 family proteins, the release of cytochrome c, and apoptosis-inducing factor (AIF) following gold(III) porphyrin 1a treatment. Cytochrome c in turn activated caspase-9 and caspase-3. Cotreatment with caspase inhibitor (zVAD-fmk) showed that the activated caspases worked in conjunction with AIF-initiated apoptosis pathways. Further study showed that ROS played a part in gold(III) porphyrin 1a–induced apoptosis by regulating ΔΨm. In summary, gold(III) porphyrin 1a induced apoptosis through both caspase-dependent and caspase-independent mitochondrial pathways, and intracellular oxidation affected gold(III) porphyrin 1a–induced apoptosis. These results support a role for gold(III) porphyrin 1a as a promising anticancer drug lead and as a possible novel therapeutic agent directed toward the mitochondria. (Cancer Res 2005; 65(24): 11553-64)
Organ-Specific Increase in Mutation Accumulation and Apoptosis Rate in CuZn-Superoxide Dismutase–Deficient Mice
Authors: Busuttil Rita A. , Garcia Ana Maria , Cabrera Carlos , Rodriguez Armando , Suh Yousin , Kim Woo Ho , Huang Ting-Ting , Vijg Jan
Published: December 2005

Reactive oxygen species have been implicated as a cause of cancer and aging in mammals. Mice deficient for the antioxidant enzyme CuZn-superoxide dismutase (Sod1) have a decreased life span and an elevated incidence of liver cancer. To test the hypothesis that the cancer-prone phenotype in such mice is due to accelerated spontaneous mutation accumulation, we crossed these mutants with mice harboring a neutral lacZ mutation reporter gene. At 2 months of age, the lacZ mutation frequency in the liver of the hybrid animals was already twice as high as in littermate controls of the same age. This difference in mutation frequency increased to >3-fold at 6 months of age, after which it did not increase any further. Characterization of the mutation spectra in liver of the Sod1-null mice indicated mainly GC-to-TA transversions and GC-to-AT transitions, signature mutations of oxidative stress. The accelerated mutation accumulation in liver was accompanied by an increased frequency of apoptotic cells, as indicated by an increase in both terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling– and caspase 3–stained cells at 6 and 12 months of age. In kidney, an elevated mutation frequency above controls of ∼2.5-fold was found not earlier than at 6 months. No increased mutation accumulation was observed in brain or spleen. These results support the hypothesis, that oxidative stress is an important causal factor of cancer in mammals. (Cancer Res 2005; 65(24): 11271-5)
Context-Dependent Hormone-Refractory Progression Revealed through Characterization of a Novel Murine Prostate Cancer Cell Line
Authors: Watson Philip A. , Ellwood-Yen Katharine , King Jennifer C. , Wongvipat John , LeBeau Michelle M. , Sawyers Charles L.
Published: December 2005

Insights into the molecular basis of hormone-refractory prostate cancer have principally relied on human prostate cancer cell lines, all of which were derived from patients who had already failed hormonal therapy. Recent progress in developing genetically engineered mouse prostate cancer models provides an opportunity to isolate novel cell lines from animals never exposed to hormone ablation, avoiding any potential bias conferred by the selective pressure of the castrate environment. Here we report the isolation of such a cell line (Myc-CaP) from a c-myc transgenic mouse with prostate cancer. Myc-CaP cells have an amplified androgen receptor gene despite no prior exposure to androgen withdrawal and they retain androgen-dependent transgene expression as well as androgen-dependent growth in soft agar and in mice. Reexpression of c-Myc from a hormone-independent promoter rescues growth in androgen-depleted agar but not in castrated mice, showing a clear distinction between the molecular requirements for hormone-refractory growth in vitro versus in vivo. Myc-CaP cells represent a unique reagent for dissecting discreet steps in hormone-refractory prostate cancer progression and show the general utility of using genetically engineered mouse models for establishing new prostate cancer cell lines. (Cancer Res 2005; 65(24): 11565-71)
A Blueprint for a Human Epigenome Project: The AACR Human Epigenome Workshop
Authors: Jones Peter A. , Martienssen Robert
Published: December 2005

Epigenetic processes control the packaging and function of the human genome and contribute to normal and pathologic states, including cancer. The time is ripe to undertake an international effort to identify all the chemical changes and relationships between chromatin constituents that provide function to the genetic code. A timely workshop of leading experts, convened by the American Association for Cancer Research (AACR), confirmed that the technology is at hand to begin defining human epigenomes at high resolution. (Cancer Res 2005; 65(24): 11241-6)
The Sensitivity of Diel CO2 and H2O Vapor Exchange of a Tropical Transitional Forest to Seasonal Variation in Meteorology and Water Availability
Authors: Vourlitis George L. , de Souza Nogueira José , Filho Nicolau Priante , Hoeger Wander , Raiter Fernando , Biudes Marcelo Sacardi , Arruda Jose Carlos , Capistrano Vinicius Buscioli , Brito de Faria Jorge Luiz , de Almeida Lobo Francisco
Published: December 2005

Measurements of ecosystem gas exchange, meteorology, and hydrology (rainfall and soil moisture) were used to assess the seasonal patterns of, and controls on, average diel (24 h) net ecosystem CO2 exchange (NEE), evapotranspiration (E), and bulk canopy water vapor conductance (Gc) of a tropical transitional (ecotonal) forest in the Brazilian Amazon. Diel trends in E and NEE were almost completely explained by the diel variation in photosynthetic photon flux density (QPPFD), and while the QPPFD response of E varied little over the annual cycle, the QPPFD response of NEE declined substantially during the dry season, and the magnitude of hysteresis in the NEE–QPPFD response increased as well. The magnitude of the residuals for the QPPFD versus NEE response was significantly negatively correlated with total monthly rainfall and surface soil moisture and positively correlated with the maximum daily temperature and atmospheric vapor pressure deficit (V). Average daily Gc was also significantly correlated with average daily V (r = −0.72) and soil moisture (r = 0.62), suggesting strong stomatal control of NEE during drought. However, drought reduced ecosystem CO2 efflux relatively more than CO2 assimilation, suggesting that the seasonal variation in NEE was largely driven by seasonal variation in respiration. When compared with other tropical forests, seasonality in NEE was negatively correlated with annual rainfall and positively correlated with dry-season length. The relatively high sensitivity of NEE to seasonal variation in climate and water availability has profound implications for C cycling dynamics under novel climates resulting from climate and/or land-use change in the Amazon basin.
The Significance of the 1976 Pacific Climate Shift in the Climatology of Alaska
Authors: Hartmann Brian , Wendler Gerd
Published: December 2005

The 1976 Pacific climate shift is examined, and its manifestations and significance in Alaskan climatology during the last half-century are demonstrated. The Pacific Decadal Oscillation index shifted in 1976 from dominantly negative values for the 25-yr time period 1951–75 to dominantly positive values for the period 1977–2001.

Mean annual and seasonal temperatures for the positive phase were up to 3.1°C higher than for the negative phase. Likewise, mean cloudiness, wind speeds, and precipitation amounts increased, while mean sea level pressure and geopotential heights decreased. The pressure decrease resulted in a deepening of the Aleutian low in winter and spring. The intensification of the Aleutian low increased the advection of relatively warm and moist air to Alaska and storminess over the state during winter and spring.

The regime shift is also examined for its effect on the long-term temperature trends throughout the state. The trends that have shown climatic warming are strongly biased by the sudden shift in 1976 from the cooler regime to a warmer regime. When analyzing the total time period from 1951 to 2001, warming is observed; however, the 25-yr period trend analyses before 1976 (1951–75) and thereafter (1977–2001) both display cooling, with a few exceptions. In this paper, emphasis is placed on the importance of taking into account the sudden changes that result from abrupt climatic shifts, persistent regimes, and the possibility of cyclic oscillations, such as the PDO, in the analysis of long-term climate change in Alaska.
Global Daytime Distribution of Overlapping Cirrus Cloud from NOAA’s Advanced Very High Resolution Radiometer
Authors: Heidinger Andrew K. , Pavolonis Michael J.
Published: December 2005

Data from the National Oceanic and Atmospheric Administration’s (NOAA’s) Advanced Very High Resolution Radiometer (AVHRR) instrument are used to provide the mean July and January global daytime distributions of multilayer cloud, where multilayer cloud is defined as cirrus overlapping one or more lower layers. The AVHRR data were taken from multiple years that were chosen to provide data with a constant local equator crossing time of 1430–1500 local time. The cloud overlap detection algorithm is used in NOAA’s Extended Clouds from AVHRR (CLAVR-x) processing system. The results between 60°N and 60°S indicated that roughly 20% of all clouds and roughly 40% of all ice clouds were classified as cirrus overlapping lower cloud (cirrus overlap). The results show a strong July–January pattern that is consistent with the seasonal cycle in convection. In some regions, cirrus overlap is found to be the dominant type of cloud observed. The distributions of overlapping cirrus cloud presented here are compared with results from other studies based on rawinsondes and manual surface observations. Comparisons are also made with another satellite-derived study that used coincident infrared and microwave observations over the tropical oceans during a 6-month period
A Near-Global Climatology of Single-Layer and Overlapped Clouds and Their Optical Properties Retrieved from Terra/MODIS Data Using a New Algorithm
Authors: Chang Fu-Lung , Li Zhanqing
Published: December 2005

Cloud overlapping has been a major issue in climate studies owing to a lack of reliable information available over both oceans and land. This study presents the first near-global retrieval and analysis of single-layer and overlapped cloud vertical structures and their optical properties retrieved by applying a new method to the Moderate Resolution Imaging Spectroradiometer (MODIS) data. Taking full advantage of the MODIS multiple channels, the method can differentiate cirrus overlapping lower water clouds from single-layer clouds. Based on newly retrieved cloud products using daytime Terra/MODIS 5-km overcast measurements sampled in January, April, July, and October 2001, global statistics of the frequency of occurrence, cloud-top pressure/temperature (Pc/Tc), visible optical depth (τVIS), and infrared emissivity (ɛ) are presented and discussed. Of all overcast scenes identified over land (ocean), the MODIS data show 61% (52%) high clouds (Pc < 500 hPa), 39% (48%) lower clouds (Pc > 500 hPa), and an extremely low occurrence (<4%) of Pc between 500 and 600 hPa. A distinct bimodal distribution of Pc is found and peaks at ∼275 and ∼725 hPa for high and low clouds, thus leaving a minimum in cloud in the middle troposphere. Out of the 61% (52%) of high clouds identified by MODIS, retrievals reveal that 41% (35%) are thin cirrus clouds (ɛ < 0.85 and Pc < 500 hPa) and the remaining 20% (17%) are thick high clouds (ɛ ≥ 0.85). Out of the 41% (35%) of thin cirrus, 29% (27%) are found to overlap with lower water clouds and 12% (8%) are single-layer cirrus. Total low-cloud amount (single-layer plus overlapped) out of all overcast scenes is thus 68% (39% + 29%) over land and 75% (48% + 27%) over ocean, which is greater than the cloud amounts reported by the MODIS and the International Satellite Cloud Climatology Project (ISCCP). Both retrieved overlapping and nonoverlapping cirrus clouds show similar mean τVIS of ∼1.5 and mean ɛ of ∼0.5. The optical properties of single-layer cirrus and single-layer water clouds agree well with the MODIS standard retrievals. Because the MODIS retrievals do not differentiate between cirrus and lower water clouds in overlap situations, large discrepancies are found for emissivity, cloud-top height, and optical depth for high cirrus overlapping lower water clouds.
Local and Remote Impacts of Aerosol Climate Forcing on Tropical Precipitation*
Authors: Chou Chia , Neelin J. David , Lohmann Ulrike , Feichter Johann
Published: December 2005

Mechanisms that determine the direct and indirect effects of aerosols on the tropical climate involve moist dynamical processes and have local and remote impacts on regional tropical precipitation. These mechanisms are examined in a climate model of intermediate complexity [quasi-equilibrium tropical circulation model (QTCM)] forced by prescribed aerosol forcing, which is obtained from a general circulation model (ECHAM4). The aerosol reflection is the dominant aerosol forcing, while the aerosol absorption has complex but much weaker influences on the regional tropical precipitation based on the ECHAM4 aerosol forcing. The local effect associated with aerosols contributes negative precipitation anomalies over convective regions by affecting the net energy flux into the atmospheric column. This net energy flux is controlled by the radiative forcing at the top of the atmosphere on time scales where surface heat flux is near equilibrium, balancing anomalous solar radiation by evaporation, longwave radiation, and sensible heat. Considering the aerosol absorption effect alone, the associated precipitation anomalies are slightly negative but small when surface heat fluxes are near equilibrium. Two effects found in global warming, the upped-ante mechanism and the anomalous gross moist stability mechanism, occur with opposite sign in the aerosol case. Both act as remote effects via the widespread cold tropospheric temperature anomalies induced by the aerosol forcing. In the upped-ante mechanism in global warming, a warm troposphere increases the low-level moisture “ante” required for convection, creating spatially varying moisture anomalies that disfavor precipitation on those margins of convective zones where the mean flow imports air from nonconvective regions. In the aerosol case here, a cool troposphere preferentially decreases moisture in convective regions, creating positive precipitation anomalies at inflow margins. In the anomalous gross moist stability mechanism for the aerosol case, the decrease in moisture in convective regions acts to enhance the gross moist stability, so convection and the associated precipitation are reduced. The partitioning between the aerosol local and remote effects on regional tropical precipitation differs spatially. Over convective regions that have high aerosol concentration, such as the South American region, the aerosol local effect contributes more negative precipitation anomalies than the anomalous gross moist stability mechanism in the QTCM simulations. On the other hand, the remote effect is more important over convective regions with small aerosol concentrations, such as the western Pacific Maritime Continent. Remote effects of midlatitude aerosol forcing have a substantial contribution to tropical anomalies.
The Monte Carlo Independent Column Approximation’s Conditional Random Noise: Impact on Simulated Climate
Authors: Räisänen P. , Barker H. W. , Cole J. N. S.
Published: December 2005

The Monte Carlo Independent Column Approximation (McICA) method for computing domain-average radiative fluxes is unbiased with respect to the full ICA, but its flux estimates contain conditional random noise. Results for five experiments are used to assess the impact of McICA-related noise on simulations of global climate made by the NCAR Community Atmosphere Model (CAM). The experiment with the least noise (an order of magnitude below that of basic McICA) is taken as the reference. Two additional experiments help demonstrate how the impact of noise depends on the time interval between calls to the radiation code. Each experiment is an ensemble of seven 15-month simulations.

Experiments with very high noise levels feature significant reductions to cloudiness in the lowermost model layer over tropical oceans as well as changes in highly related quantities. This bias appears immediately, stabilizes after a couple of model days, and appears to stem from nonlinear interactions between clouds and radiative heating. Outside the Tropics, insignificant differences prevail. When McICA sampling is confined to cloudy subcolumns and when, on average, 50% more samples, relative to basic McICA, are drawn for selected spectral intervals, McICA noise is much reduced and the results of the simulation are almost statistically indistinguishable from the reference. This is true both for mean fields and for the nature of fluctuations on scales ranging from 1 day to at least 30 days.

While calling the radiation code once every 3 h instead of every hour allows the CAM additional time to incorporate McICA-related noise, the impact of noise is enhanced only slightly. In contrast, changing the radiative time step by itself produces effects that generally exceed the impact of McICA’s noise.
An Update of U.S. Temperature Trends
Authors: Lu Qi Qi , Lund Robert , Seymour Lynne
Published: December 2005

This note updates the temperature trend study of the contiguous 48 United States by Lund et al. for data observed during the 4-yr period 1997–2000. A parsimonious changepoint parameterization is now used, and the methods for handling missing data are improved. The number of stations with useable data has now increased from 359 to 969, thereby improving the accuracy of the reported spatial patterns in the trends. The average record length of the 969 stations is now 103 yr, with the longest record starting in 1812 and the shortest in 1926. The methodological improvements and additional 4 yr of data produce slightly smaller trend estimate standard errors. Warming is found in the Northeast, West, and northern Midwest, with slight cooling in the Southeast; overall, the trends here suggest more warming than those of the Lund et al. study.