bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cyclin D1 Induction through IκB Kinase β/Nuclear Factor-κB Pathway Is Responsible for Arsenite-Induced Increased Cell Cycle G1-S Phase Transition in Human Keratinocytes
Authors: Ouyang Weiming , Ma Qian , Li Jingxia , Zhang Dongyun , Liu Zheng-gang , Rustgi Anil K. , Huang Chuanshu 
Published: October 2005

Abstract
Environmental and occupational exposure to arsenite is associated with an increased risk of human cancers, including skin, urinary bladder, and respiratory tract cancers. Although much evidence suggests that alterations in cell cycle machinery are implicated in the carcinogenic effect of arsenite, the molecular mechanisms underlying the cell cycle alterations are largely unknown. In the present study, we observed that exposure of human keratinocyte HaCat cells to arsenite resulted in the promotion of cell cycle progression, especially G1-S transition. Further studies found that arsenite exposure was able to induce cyclin D1 expression. The induction of cyclin D1 by arsenite required nuclear factor-κB (NF-κB) activation, because the inhibition of IκB phosphorylation by overexpression of the dominant-negative mutant, IKKβ-KM, impaired arsenite-induced cyclin D1 expression and G1-S transition. The requirement of IκB kinase β (IKKβ) for cyclin D1 induction was further confirmed by the findings that arsenite-induced cyclin D1 expression was totally blocked in IKKβ knockout (IKKβ−/−) mouse embryo fibroblasts. In addition, knockdown of cyclin D1 expression using cyclin D1–specific small interference RNA significantly blocked arsenite-induced cell cycle progression in HaCat cells. Taken together, our results show that arsenite-induced cell cycle from G1 to S phase transition is through IKKβ/NF-κB/cyclin D1–dependent pathway.
Regulation of Dendritic Cell Differentiation and Antitumor Immune Response in Cancer by Pharmacologic-Selective Inhibition of the Janus-Activated Kinase 2/Signal Transducers and Activators of Transcription 3 Pathway
Authors: Nefedova Yulia , Nagaraj Srinivas , Rosenbauer Amsler , Muro-Cacho Carlos , Sebti Said M. , Gabrilovich Dmitry I. 
Published: October 2005

AbstractAbnormal dendritic cell differentiation and accumulation of immunosuppressive myeloid cells in cancer is one of the major factors of tumor nonresponsiveness. We have previously shown that hyperactivation of the Janus-activated kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) induced by tumor-derived factors (TDF) is responsible for abnormal dendritic cell differentiation. Here, using a novel selective inhibitor of JAK2/STAT3 JSI-124, we investigated the possibility of pharmacologic regulation of dendritic cell differentiation in cancer. Our experiments in vitro have shown that JSI-124 overcomes the differentiation block induced by TDF and promotes the differentiation of mature dendritic cells and macrophages. JSI-124 significantly reduced the presence of immature myeloid cells in vivo and promoted accumulation of mature dendritic cells. In addition to a direct antitumor effect in several animal models, JSI-124 significantly enhanced the effect of cancer immunotherapy. This indicates that pharmacologic inhibition of the JAK2/STAT3 pathway can be an important new therapeutic strategy to enhance antitumor activity of cancer immunotherapy.
Transactivation of Epidermal Growth Factor Receptor Is Involved in Leptin-Induced Activation of Janus-Activated Kinase 2 and Extracellular Signal–Regulated Kinase 1/2 in Human Gastric Cancer Cells
Authors: Shida Dai , Kitayama Joji , Mori Ken , Watanabe Toshiaki , Nagawa Hirokazu 
Published: October 2005

Abstract
Leptin is known to act as a growth factor through the Janus-activated kinase (JAK)/signal transducer and activator of transcription signaling pathway as well as the mitogen-activated protein kinase pathway. In this study, we showed a novel signal transduction pathway using two human gastric cancer cell lines, MKN28 and MKN74. Both gastric cancer cells expressed leptin and its receptors (Ob-R) at the protein level. We found that leptin, even at as low as 0.1 ng/mL, induced significant tyrosine phosphorylation of epidermal growth factor receptor (EGFR). Time-course experiments revealed that phosphorylation was maximal after 5 minutes of stimulation and declined thereafter. We also revealed that tyrosine phosphorylation of EGFR induced by leptin was significantly attenuated by two inhibitors, an EGFR tyrosine kinase inhibitor, AG1478, and a broad-spectrum matrix metalloproteinase inhibitor, GM6001. This indicates that the pathway of EGFR transactivation induced by leptin is dependent on proteolytically released EGFR ligands. Leptin induced JAK2 activation and extracellular signal–regulated kinase (ERK) 1/2 activation in these gastric cancer cells, both of which occurred after the peak of EGFR transactivation. Pretreatment of gastric cancer cells with AG1478 significantly reduced the degree of phosphorylation of both JAK2 and ERK1/2. These findings indicate the involvement of EGFR transactivation in the activation of JAK2 and ERK1/2. Our results reveal that EGFR transactivation is involved in the leptin signaling pathway in gastric cancer cells, which extends the physiologic action of leptin beyond its central effects in the hypothalamus to regulate body weight.
Insulin Receptor Substrate Is a Mediator of Phosphoinositide 3-Kinase Activation in Quiescent Pancreatic Cancer Cells
Authors: Asano Takayuki , Yao Yixin , Shin Sonyo , McCubrey James , Abbruzzese James L. , Reddy Shrikanth A.G. 
Published: October 2005

Abstract
Phosphoinositide 3-kinase (PI3K) is activated in pancreatic cancer cells and plays a central role in their proliferation, survival, and drug resistance. Although the mechanism is unclear, PI3K activation in these cells could be due to physical interaction between its regulatory subunit (p85) and specific tyrosine kinases or their mediators. Consistent with this possibility, PI3K was precipitated with anti-phosphotyrosine antibodies and Akt phosphorylation was blocked by the tyrosine kinase inhibitors SU6656 and PD158780 in quiescent pancreatic cancer cells. Pull-down assays with a fusion protein (GST-p85NC-SH2), and coimmunoprecipitation studies, indicated that the insulin receptor substrate (IRS), and not the epidermal growth factor and insulin-like growth factor receptors or the Src tyrosine kinase, was physically associated with PI3K in these cells. Our data also indicated that SU6656 and PD158780 inhibited Akt activation in pancreatic cancer cells by interfering with the ability of IRS-1 to recruit PI3K. Furthermore, IRS-1 was phosphorylated on a p85-binding site (Y612), and IRS-specific small interfering RNA potently inhibited activation of PI3K and Akt in transfected cells. Taken together, these observations indicate that IRS is a mediator of PI3K activation in quiescent pancreatic cancer cells.
Decoy Receptor 2 (DcR2) Is a p53 Target Gene and Regulates Chemosensitivity
Authors: Liu Xiangguo , Yue Ping , Khuri Fadlo R. , Sun Shi-Yong 
Published: October 2005

Abstract
Decoy receptor 2 (DcR2) is one of the tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptors and suppresses TRAIL-induced apoptosis. Its expression, like the other three TRAIL receptors (i.e., DR4, DR5, and DcR1), is regulated by p53. Here, we report that DcR2 is a p53 target gene and regulates chemosensitivity. In this study, we identified a p53-binding site (p53BS) in the first intron of the DcR2 gene. This p53BS is almost identical to the ones found in the first introns of other three TRAIL receptor genes. By a chromatin immunoprecipitation assay, we detected that the p53 protein bound to the DcR2 p53BS in intact cells. Subcloning of the DcR2 p53BS into a luciferase reporter vector driven by a SV40 promoter exhibited enhanced luciferase activity when transiently cotransfected with a wild-type (wt) p53 expression vector in p53-null cell lines or stimulated with DNA-damaging agents in cell lines having wt p53. Moreover, when the DcR2 p53BS, together with its own corresponding promoter regions, was subcloned into a basic luciferase vector without a promoter element, its transcriptional activities were strikingly increased by cotransfection of the wt p53 gene. However, when this p53BS was deleted from the construct, wt p53 failed to transactivate this reporter construct. Collectively, we conclude that p53 directly regulates the DcR2 gene expression via an intronic p53BS. In addition, overexpression of DcR2 conferred resistance to TRAIL-mediated apoptosis and attenuated cell response to DNA-damaging agents, whereas silencing of DcR2 expression enhanced chemotherapeutic agent–induced apoptosis. These results suggest that DcR2 regulates chemosensitivity.
Low-Level Expression of Proapoptotic Bcl-2–Interacting Mediator in Leukemic Cells in Patients with Chronic Myeloid Leukemia: Role of BCR/ABL, Characterization of Underlying Signaling Pathways, and Reexpression by Novel Pharmacologic Compounds
Authors: Aichberger Karl J. , Mayerhofer Matthias , Krauth Maria-Theresa , Vales Anja , Kondo Rudin , Derdak Sophia , Pickl Winfried F. , Selzer Edgar , Deininger Michael , Druker Brian J. , Sillaber Christian , Esterbauer Harald , Valent Peter 
Published: October 2005

Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative disease in which BCR/ABL enhances survival of leukemic cells through modulation of proapoptotic and antiapoptotic molecules. Recent data suggest that proapoptotic Bcl-2–interacting mediator (Bim) plays a role as a tumor suppressor in myeloid cells, and that leukemic cells express only low amounts of this cell death activator. We here show that primary CML cells express significantly lower amounts of bim mRNA and Bim protein compared with normal cells. The BCR/ABL inhibitors imatinib and AMN107 were found to promote expression of Bim in CML cells. To provide direct evidence for the role of BCR/ABL in Bim modulation, we employed Ba/F3 cells with doxycycline-inducible expression of BCR/ABL and found that BCR/ABL decreases expression of bim mRNA and Bim protein in these cells. The BCR/ABL-induced decrease in expression of Bim was found to be a posttranscriptional event that depended on signaling through the mitogen-activated protein kinase pathway and was abrogated by the proteasome inhibitor MG132. Interestingly, MG132 up-regulated the expression of bim mRNA and Bim protein and suppressed the growth of Ba/F3 cells containing wild-type BCR/ABL or imatinib-resistant mutants of BCR/ABL. To show functional significance of “Bim reexpression,” a Bim-specific small interfering RNA was applied and found to rescue BCR/ABL-transformed leukemic cells from imatinib-induced cell death. In summary, our data identify BCR/ABL as a Bim suppressor in CML cells and suggest that reexpression of Bim by novel tyrosine kinase inhibitors, proteasome inhibition, or by targeting signaling pathways downstream of BCR/ABL may be an attractive therapeutic approach in imatinib-resistant CML.
In vivo Induction of Resistance to Gemcitabine Results in Increased Expression of Ribonucleotide Reductase Subunit M1 as the Major Determinant
Authors: Bergman Andries M. , Eijk Paul P. , Ruiz van Haperen Veronique W.T. , Smid Kees , Veerman Gijsbert , Hubeek Isabelle , van den IJssel Paul , Ylstra Bauke , Peters Godefridus J. 
Published: October 2005

Abstract
Gemcitabine is a deoxycytidine (dCyd) analogue with activity against several solid cancers. Gemcitabine is activated by dCyd kinase (dCK) and interferes, as its triphosphate dFdCTP, with tumor growth through incorporation into DNA. Alternatively, the metabolite gemcitabine diphosphate (dFdCDP) can interfere with DNA synthesis and thus tumor growth through inhibition of ribonucleotide reductase. Gemcitabine can be inactivated by the enzyme dCyd deaminase (dCDA). In most in vitro models, resistance to gemcitabine was associated with a decreased dCK activity. In all these models, resistance was established using continuous exposure to gemcitabine with increasing concentrations; however, these in vitro models have limited clinical relevance. To develop in vivo resistance to gemcitabine, we treated mice bearing a moderately sensitive tumor Colon 26-A (T/C = 0.25) with a clinically relevant schedule (120 mg/kg every 3 days). By repeated transplant of the most resistant tumor and continuation of gemcitabine treatment for &gt;1 year, the completely resistant tumor Colon 26-G (T/C = 0.96) was created. Initial studies focused on resistance mechanisms known from in vitro studies. In Colon 26-G, dCK activity was 1.7-fold decreased; dCDA and DNA polymerase were not changed; and Colon 26-G accumulated 1.5-fold less dFdCTP, 6 hours after a gemcitabine injection, than the parental tumor. Based on in vitro studies, these relative minor changes were considered insufficient to explain the completely resistant phenotype. Therefore, an expression microarray was done with Colon 26-A versus Colon 26-G. Using independently grown nonresistant and resistant tumors, a striking increase in expression of the RRM1 subunit gene was found in Colon 26-G. The expression of RRM1 mRNA was 25-fold increased in the resistant tumor, as measured by real-time PCR, which was confirmed by Western blotting. In contrast, RRM2 mRNA was 2-fold decreased. However, ribonucleotide reductase enzyme activity was only moderately increased in Colon 26-G. In conclusion, this is the first model with in vivo induced resistance to gemcitabine. In contrast to most in vitro studies, dCK activity was not the most important determinant of gemcitabine resistance. Expression microarray identified RRM1 as the gene with the highest increase in expression in the Colon 26-G, which might clarify its complete gemcitabine-resistant phenotype. This study is the first in vivo evidence for a key role for RRM1 in acquired gemcitabine resistance.
Multiple Roles for the Receptor Tyrosine Kinase Axl in Tumor Formation
Authors: Holland Sacha J. , Powell Mark J. , Franci Christian , Chan Emily W. , Friera Annabelle M. , Atchison Robert E. , McLaughlin John , Swift Susan E. , Pali Erlina S. , Yam George , Wong Stephen , Lasaga Joe , Shen Mary R. , Yu Simon , Xu Weiduan , Hitoshi Yasumichi , Bogenberger Jakob , Nör Jacques E. , Payan Donald G. , Lorens James B. 
Published: October 2005

AbstractA focus of contemporary cancer therapeutic development is the targeting of both the transformed cell and the supporting cellular microenvironment. Cell migration is a fundamental cellular behavior required for the complex interplay between multiple cell types necessary for tumor development. We therefore developed a novel retroviral-based screening technology in primary human endothelial cells to discover genes that control cell migration. We identified the receptor tyrosine kinase Axl as a novel regulator of endothelial cell haptotactic migration towards the matrix factor vitronectin. Using small interfering RNA–mediated silencing and overexpression of wild-type or mutated receptor proteins, we show that Axl is a key regulator of multiple angiogenic behaviors including endothelial cell migration, proliferation, and tube formation in vitro. Moreover, using sustained, retrovirally delivered short hairpin RNA (shRNA) Axl knockdown, we show that Axl is necessary for in vivo angiogenesis in a mouse model. Furthermore, we show that Axl is also required for human breast carcinoma cells to form a tumor in vivo. These findings indicate that Axl regulates processes vital for both neovascularization and tumorigenesis. Disruption of Axl signaling using a small-molecule inhibitor will hence simultaneously affect both the tumor and stromal cell compartments and thus represents a unique approach for cancer therapeutic development.
Therapeutic Cure against Human Tumor Xenografts in Nude Mice by a Microtubule Stabilization Agent, Fludelone, via Parenteral or Oral Route
Authors: Chou Ting-Chao , Dong Huajin , Zhang Xiuguo , Tong William P. , Danishefsky Samuel J. 
Published: October 2005

Abstract
Epothilones, 16-membered macrolides isolated from a myxobacterium in soil, exert their antitumor effect, like Taxol, by induction of microtubule polymerization and microtubule stabilization. They are effective against tumor cells that are resistant to Taxol or vinblastine. We recently designed, via molecular editing and total synthesis, a new class of epothilones represented by 26-trifluoro-(E)-9,10-dehydro-12,13-desoxy-epothilone B (Fludelone), which has emerged as a lead candidate for clinical development. Treatment of nude mice bearing MX-1 human mammary carcinoma xenografts (as large as 3.4% body weight) with Fludelone (6-hour i.v. infusion, 25 mg/kg, q3d × 5, q3d × 4) led to complete disappearance and de facto “cure” (i.e., remission without a relapse for over 15% of the average life span of 2 years). The toxicities induced by bolus i.v. injection could be avoided through prolonged i.v. infusion, which allowed for a 10-fold increase in maximal tolerated dose. Complete remission of MX-1 xenografts was achieved with only one third of this maximal tolerated dose. Parallel studies with Taxol and Fludelone [20 mg/kg, 6-hour i.v. infusion (q2d × 4) ×3] against HCT-116 human colon carcinoma xenografts revealed that both drugs achieved tumor remission; however, all Taxol-treated mice relapsed in ∼1.3 months, whereas the Fludelone-treated mice were cured without any relapse for over 7 months. Furthermore, tumor remission was achieved by Fludelone against SK-OV-3 (ovary), PC-3 (prostate), and the Taxol-resistant CCRF-CEM/Taxol (leukemia) xenograft tumors. Most remarkably, p.o. administration of Fludelone (30 mg/kg, q2d × 7, q2d × 9, q2d × 5) against MX-1 xenografts achieved a nonrelapsing cure for as long as 8.4 months. The above results indicate that Fludelone is a highly promising compound for cancer chemotherapeutics.
Lack of Expression of the EP2 but not EP3 Receptor for Prostaglandin E2 Results in Suppression of Skin Tumor Development
Authors: Sung You Me , He Guobin , Fischer Susan M. 
Published: October 2005

Abstract
The EP2 receptor for prostaglandin E2 (PGE2) is a membrane receptor that mediates at least part of the action of PGE2. It has been shown that EP2 plays a critical role in tumorigenesis in mouse mammary gland and colon. However, the possibility that the EP2 receptor is involved in the development of skin tumors was unknown. The purpose of this study was to investigate the role of the EP2 receptor in mouse skin carcinogenesis. Unlike EP3 knockout mice, the EP2 knockout mice produced significantly fewer tumors and reduced tumor incidence compared with wild type (WT) mice in a 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) two-stage carcinogenesis protocol. EP2 knockout mice had significantly reduced cellular proliferation of mouse skin keratinocytes in vivo and in vitro compared with that in WT mice. In addition, the epidermis of EP2 knockout mice 48 hours after topical TPA treatment was significantly thinner compared with that of WT mice. The inflammatory response to TPA was reduced in EP2 knockout mice, based on a reduced number of macrophages in the dermis and a reduced level of interleukin-1α mRNA expression, compared with WT mice. EP2 knockout mice also had significantly reduced epidermal cyclic AMP levels after PGE2 treatment compared with WT mice. Tumors from WT mice produced more blood vessels and fewer apoptotic cells than those of EP2 knockout mice as determined by immunohistochemical staining. Our data suggest that the EP2 receptor plays a significant role in the protumorigenic action of PGE2 in skin tumor development.
Regulation of Krüppel-like Factor 6 Tumor Suppressor Activity by Acetylation
Authors: Li Dan , Yea Steven , Dolios Georgia , Martignetti John A. , Narla Goutham , Wang Rong , Walsh Martin J. , Friedman Scott L. 
Published: October 2005

Abstract
Krüppel-like factor 6 (KLF6) is a zinc finger transcription factor and tumor suppressor that is inactivated in a number of human cancers by mutation, allelic loss, and/or promoter methylation. A key mechanism of growth inhibition by wild-type KLF6 is through p53-independent up-regulation of p21WAF1/cip1 (CDKN1A), which is abrogated in several tumor-derived mutants. Here we show by chromatin immunoprecipitation that transactivation of p21WAF1/cip1 by KLF6 occurs through its direct recruitment to the p21WAF1/cip1 promoter and requires acetylation by histone acetyltransferase activity of either cyclic AMP–responsive element binding protein–binding protein or p300/CBP-associated factor. Direct lysine acetylation of KLF6 peptides can be shown by mass spectrometry. A single lysine-to-arginine point mutation (K209R) derived from prostate cancer reduces acetylation of KLF6 and abrogates its capacity to up-regulate endogenous p21WAF1/cip1 and reduce cell proliferation. These data indicate that acetylation may regulate KLF6 function, and its loss in some tumor-derived mutants could contribute to its failure to suppress growth in prostate cancer.
Polymorphisms in Cytokine and Cellular Adhesion Molecule Genes and Susceptibility to Hematotoxicity among Workers Exposed to Benzene
Authors: Lan Qing , Zhang Luoping , Shen Min , Smith Martyn T. , Li Guilan , Vermeulen Roel , Rappaport Stephen M. , Forrest Matthew S. , Hayes Richard B. , Linet Martha , Dosemeci Mustafa , Alter Blanche P. , Weinberg Rona S. , Yin Songnian , Yeager Meredith , Welch Robert , Waidyanatha Suramya , Kim Sungkyoon , Chanock Stephen , Rothman Nathaniel 
Published: October 2005

AbstractBenzene is a recognized hematotoxin and leukemogen but its mechanism of action and the role of genetic susceptibility are still unclear. Cytokines, chemokines, and cellular adhesion molecules are soluble proteins that play an important regulatory role in hematopoiesis. We therefore hypothesized that variation in these genes could influence benzene-induced hematotoxicity. We analyzed common, well-studied single-nucleotide polymorphisms (SNPs) in 20 candidate genes drawn from these pathways in a study of 250 workers exposed to benzene and 140 unexposed controls in China. After accounting for multiple comparisons, SNPs in five genes were associated with a statistically significant decrease in total WBC counts among exposed workers [IL-1A (−889C&gt;T), IL-4 (−1098T&gt;G), IL-10 (−819T&gt;C), IL-12A (8685G&gt;A), and VCAM1 (−1591T&gt;C)], and one SNP [CSF3 (Ex4−165C&gt;T)] was associated with an increase in WBC counts. The adhesion molecule VCAM1 variant was particularly noteworthy as it was associated with a decrease in B cells, natural killer cells, CD4+ T cells, and monocytes. Further, VCAM1 (−1591T&gt;C) and CSF3 (Ex4−165C&gt;T) were associated, respectively, with decreased (P = 0.041) and increased (P = 0.076) CFU-GEMM progenitor cell colony formation in 29 benzene-exposed workers. This is the first report to provide evidence that SNPs in genes that regulate hematopoiesis influence benzene-induced hematotoxicity.