bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transforming Acidic Coiled Coil 1 Promotes Transformation and Mammary Tumorigenesis
Authors: Cully Megan , Shiu Jessica , Piekorz Roland P. , Muller William J. , Done Susan J. , Mak Tak W. 
Published: November 2005

Abstract
Transforming acidic coiled coil 1 (TACC1) is a putative oncogene located within a breast cancer amplicon found on human chromosome 8p11. Although TACC1 has been reported to transform fibroblasts, it is also down-regulated in a subset of mammary tumors treated with anthracyclin. Here, we show that ectopic TACC1 overexpression can cooperate with Ras to induce focus formation in murine fibroblast cultures and prevent death caused by overexpression of Pten or a dominant-negative form of protein kinase B (PKB)/Akt. In transgenic mice carrying TACC1 under the control of the mouse mammary tumor virus promoter, TACC1 expression reduced apoptosis during mammary gland involution, increased the penetrance of mammary tumors in a pten+/− background, and decreased the average age of mammary tumor onset in a mouse model based on a phosphatidylinositol 3′-kinase (PI3K)–decoupled mutant of polyoma middle T. Elevated levels of both phospho-PKB and phospho-extracellular signal-regulated kinase were found in mammary tissue containing the TACC1 transgene. Thus, TACC1 positively regulates the Ras and PI3K pathways, promotes Ras-mediated transformation, and prevents apoptosis induced by PI3K pathway inhibition. TACC1 also cooperates with tumorigenic mutations in the PI3K pathway and thereby plays an oncogenic role in tumor formation in the murine mammary gland.
Abrogation of Heat Shock Protein 70 Induction as a Strategy to Increase Antileukemia Activity of Heat Shock Protein 90 Inhibitor 17-Allylamino-Demethoxy Geldanamycin
Authors: Guo Fei , Rocha Kathy , Bali Purva , Pranpat Michael , Fiskus Warren , Boyapalle Sandhya , Kumaraswamy Sandhya , Balasis Maria , Greedy Benjamin , Armitage E. Simon M. , Lawrence Nicholas , Bhalla Kapil 
Published: November 2005

Abstract
17-Allylamino-demethoxy geldanamycin (17-AAG) inhibits the chaperone association of heat shock protein 90 (hsp90) with the heat shock factor-1 (HSF-1), which induces the mRNA and protein levels of hsp70. Increased hsp70 levels inhibit death receptor and mitochondria-initiated signaling for apoptosis. Here, we show that ectopic overexpression of hsp70 in human acute myelogenous leukemia HL-60 cells (HL-60/hsp70) and high endogenous hsp70 levels in Bcr-Abl-expressing cultured CML-BC K562 cells confers resistance to 17-AAG-induced apoptosis. In HL-60/hsp70 cells, hsp70 was bound to Bax, inhibited 17-AAG-mediated Bax conformation change and mitochondrial localization, thereby inhibiting the mitochondria-initiated events of apoptosis. Treatment with 17-AAG attenuated the levels of phospho-AKT, AKT, and c-Raf but increased hsp70 levels to a similar extent in the control HL-60/Neo and HL-60/hsp70 cells. Pretreatment with 17-AAG, which induced hsp70, inhibited 1-β-d-arabinofuranosylcytosine or etoposide-induced apoptosis in HL-60 cells. Stable transfection of a small interfering RNA (siRNA) to hsp70 completely abrogated the endogenous levels of hsp70 and blocked 17-AAG-mediated hsp70 induction, resulting in sensitizing K562/siRNA-hsp70 cells to 17-AAG-induced apoptosis. This was associated with decreased binding of Bax to hsp70 and increased 17-AAG-induced Bax conformation change. 17-AAG-mediated decline in the levels of AKT, c-Raf, and Bcr-Abl was similar in K562 and K562/siRNA-hsp70 cells. Cotreatment with KNK437, a benzylidine lactam inhibitor of hsp70 induction and thermotolerance, attenuated 17-AAG-mediated hsp70 induction and increased 17-AAG-induced apoptosis and loss of clonogenic survival of HL-60 cells. Collectively, these data indicate that induction of hsp70 attenuates the apoptotic effects of 17-AAG, and abrogation of hsp70 induction significantly enhances the antileukemia activity of 17-AAG.
Src Tyrosine Kinase and Multidrug Resistance Protein-1 Inhibitions Act Independently but Cooperatively to Restore Paclitaxel Sensitivity to Paclitaxel-Resistant Ovarian Cancer Cells
Authors: George Jessica A. , Chen Ting , Taylor Christopher C. 
Published: November 2005

Abstract
Src tyrosine kinase has been found to be overexpressed in both mouse and human ovarian cancer cells as well as in human primary ovarian cancers. Furthermore, Src inhibition sensitizes ovarian cancer cells to chemotherapeutic agents such as paclitaxel and cisplatin. Interestingly, Src inhibition has also been shown to resensitize paclitaxel-resistant cells to the cytotoxic effects of paclitaxel. The current study was undertaken in an effort to determine the mechanism by which Src resensitizes drug-resistant ovarian cancer cells. The paclitaxel-resistant human (CaOV3TaxR) and mouse (ID8TaxR) ovarian cancer cell lines express large amounts of the multidrug resistance-1 (MDR-1) protein compared with the paclitaxel-sensitive parent cell lines. Src inhibition had no effect on MDR-1 protein expression. Furthermore, Src inhibition did not affect MDR-1 function as determined by rhodamine 123 and paclitaxel uptake or retention. Coinhibition of both Src and MDR-1 synergistically enhanced paclitaxel-induced cytotoxicity in paclitaxel-resistant ovarian cancer cell lines. Inhibition of Src enhanced microtubule stabilization in paclitaxel-resistant ovarian cancer cells treated with paclitaxel without affecting expression of β-tubulin isotypes and resulted in multipolar spindle formation and apoptosis. These results show that Src inhibition restores paclitaxel sensitivity to paclitaxel-resistant ovarian cancer cells by an MDR-independent mechanism, possibly by decreasing the critical intracellular concentration at which paclitaxel induces tubulin stabilization and bundling. Src tyrosine kinase may provide a viable target for therapeutic intervention in drug-resistant ovarian cancer.
Orthotopic Growth of Human Glioma Cells Quantitatively and Qualitatively Influences Radiation-Induced Changes in Gene Expression
Authors: Camphausen Kevin , Purow Benjamin , Sproull Mary , Scott Tamalee , Ozawa Tomoko , Deen Dennis F. , Tofilon Philip J. 
Published: November 2005

Abstract
The effect of radiation on gene expression has been most frequently studied using tissue culture models. To determine the influence of experimental growth condition on radiation-induced changes in gene expression, microarray analysis was done on two human glioma cell lines (U87 and U251) grown in tissue culture and as s.c. or i.c. xenografts. Compared with tissue culture, the number of genes, whose expression was affected by radiation in both cell lines, was increased in the s.c. xenografts and further increased in the orthotopic tumors. Furthermore, in each growth condition, radiation modulated the expression of a different set of genes. In addition, whereas there were few commonly affected genes after irradiation of U87 and U251 in tissue culture, there were 729 common changes after orthotopic irradiation. These results indicate that the influence of the orthotopic environment on radiation-induced modulation of gene expression in glioma cells was both quantitative and qualitative. Moreover, they suggest that investigations of the functional consequence of radiation-induced gene expression will require accounting for experimental growth conditions.
Cancer-Specific Functions of SIRT1 Enable Human Epithelial Cancer Cell Growth and Survival
Authors: Ford Jack , Jiang Ming , Milner Jo 
Published: November 2005

Abstract
SIRT1 is a conserved NAD-dependent deacetylase that regulates life span in accord with nutritional provision. In mammalian cells, SIRT1 also down-regulates stress-induced p53 and FoxO pathways for apoptosis, thus favoring survival under stress. The functioning of SIRT1 under normal, nonstressed conditions of cell growth is unknown. Here we have asked if SIRT1 has the capacity to influence cell viability in the absence of applied stress. For this purpose we used synthetic small interfering RNA to silence SIRT1 gene expression by RNA interference (RNAi). We show that the process of RNAi, by itself, does not affect cell growth and is not sufficient to activate a cellular stress response (indicated by lack of activation of endogenous p53). We also show that, in the absence of applied stress, SIRT1 silencing induces growth arrest and/or apoptosis in human epithelial cancer cells. In contrast, normal human epithelial cells and normal human diploid fibroblasts seem to be refractory to SIRT1 silencing. Combined gene knockout with RNAi cosilencing experiments indicate that SIRT1 and Bcl-2 may suppress separable apoptotic pathways in the same cell lineage and that the SIRT1-regulated pathway is independent of p53, Bax, and caspase-2. Alternatively, SIRT1 may suppress apoptosis downstream from these apoptotic factors. In either case, we show that FoxO4 (but not FoxO3) is required as proapoptotic mediator. We further identify caspase-3 and caspase-7 as downstream executioners of SIRT1/FoxO4–regulated apoptosis. Our work identifies SIRT1 as a novel target for selective killing of cancer versus noncancer epithelial cells.
Inhibition of Intestinal Tumorigenesis in Apcmin/+ Mice by (−)-Epigallocatechin-3-Gallate, the Major Catechin in Green Tea
Authors: Ju Jihyeung , Hong Jungil , Zhou Jian-nian , Pan Zui , Bose Mousumi , Liao Jie , Yang Guang-yu , Liu Ying Ying , Hou Zhe , Lin Yong , Ma Jianjie , Shih Weichung Joe , Carothers Adelaide M. , Yang Chung S. 
Published: November 2005

Abstract
The present study was designed to investigate the effects of two main constituents of green tea, (−)-epigallocatechin-3-gallate (EGCG) and caffeine, on intestinal tumorigenesis in Apcmin/+ mice, a recognized mouse model for human intestinal cancer, and to elucidate possible mechanisms involved in the inhibitory action of the active constituent. We found that p.o. administration of EGCG at doses of 0.08% or 0.16% in drinking fluid significantly decreased small intestinal tumor formation by 37% or 47%, respectively, whereas caffeine at a dose of 0.044% in drinking fluid had no inhibitory activity against intestinal tumorigenesis. In another experiment, small intestinal tumorigenesis was inhibited in a dose-dependent manner by p.o. administration of EGCG in a dose range of 0.02% to 0.32%. P.o. administration of EGCG resulted in increased levels of E-cadherin and decreased levels of nuclear β-catenin, c-Myc, phospho-Akt, and phospho-extracellular signal–regulated kinase 1/2 (ERK1/2) in small intestinal tumors. Treatment of HT29 human colon cancer cells with EGCG (12.5 or 20 μmol/L at different times) also increased protein levels of E-cadherin by 27% to 58%, induced the translocation of β-catenin from nucleus to cytoplasm and plasma membrane, and decreased c-Myc and cyclin D1 (20 μmol/L EGCG for 24 hours). These results indicate that EGCG effectively inhibited intestinal tumorigenesis in Apcmin/+ mice, possibly through the attenuation of the carcinogenic events, which include aberrant nuclear β-catenin and activated Akt and ERK signaling.
Control of Multidrug Resistance Gene mdr1 and Cancer Resistance to Chemotherapy by the Longevity Gene sirt1
Authors: Chu Fei , Chou Pauline M. , Zheng Xin , Mirkin Bernard L. , Rebbaa Abdelhadi 
Published: November 2005

Abstract
Irreversible growth arrest (also called senescence) has emerged recently as a tumor suppressor mechanism and a key determinant of cancer chemotherapy outcome. Previous work from our laboratory suggested that the cellular ability to undergo or to escape senescence dictates its fate to become drug-sensitive or drug-resistant, respectively. In the present study, we made the hypothesis that longevity genes, by virtue of their ability to inhibit senescence, may contribute to the onset of drug resistance. We report that expression of the longevity gene sirt1 increased both at the RNA and protein levels in all the five drug-resistant cell lines tested when compared with their drug-sensitive counterparts. In addition, biopsies from cancer patients treated with chemotherapeutic agents also expressed high levels of this molecule. These changes were specific for sirt1 because the expression of other members of its family was not affected. More importantly, small interfering RNA–mediated down-regulation of sirt1 significantly reversed the resistance phenotype and reduced expression of the multidrug resistance molecule P-glycoprotein. This was further confirmed by ectopic overexpression of sirt1, which induced expression of P-glycoprotein and rendered cells resistant to doxorubicin. Collectively, these findings uncovered a novel function for the longevity gene sirt1 as a potential target for diagnosis and/or treatment of cancer resistance to chemotherapy. They also describe a proof of principle that signaling pathways implicated in longevity may share similarities with those leading to development of drug resistance in cancer.
Extremely Low Dose Ionizing Radiation Up-regulates CXC Chemokines in Normal Human Fibroblasts
Authors: Fujimori Akira , Okayasu Ryuichi , Ishihara Hiroshi , Yoshida Satoshi , Eguchi-Kasai Kiyomi , Nojima Kumie , Ebisawa Satoru , Takahashi Sentaro 
Published: November 2005

AbstractAlthough the public today could be exposed to X-rays as high as 1 cGy due to diagnostic procedures, the biological effects of this low-dose range have not been well established. We searched through &gt;23,000 transcripts in normal human fibroblasts, HFLIII, using a novel comprehensive expression analysis method. More than 200 genes were up-regulated transiently by 1 cGy of X-rays during the 1-hour period after irradiation. We determined the nucleotide sequence of 10 up-regulated transcripts with the greatest rate of increase in the irradiated HFLIII cells. Three of the 10 transcripts encoded CXC chemokines (CXCL1, CXCL2, and CXCL6). The rest included the transcripts of other secretory products (secretogranin II, thrombospondin type I domain containing 2, amphiregulin, and interleukin-6) and unknown genes. To test the involvement of CXC chemokines in cells irradiated with low doses, we irradiated HFLIII cells with 1 to 20 cGy X-rays and transferred the media from HFLIII culture to two melanoma cell lines characteristic of excessive numbers of the CXC chemokine-specific receptors. The growth of these melanoma lines were significantly stimulated by the medium from HFLIII irradiated at 1 to 5 cGy. Our results indicate that human cells respond to doses of radiation as low as 1 cGy, and mechanisms alternative to those involved in moderate/high-dose studies have to be considered in understanding the biological effects of diagnostic level radiation. In addition, our comprehensive approach using a novel expression profiling method is a powerful strategy to explore biological functions associated with very low levels of toxic agents.
Destabilization of Krüppel-Like Factor 4 Protein in Response to Serum Stimulation Involves the Ubiquitin-Proteasome Pathway
Authors: Chen Zhi Yi , Wang Xuesheng , Zhou Yunhong , Offner Gwynneth , Tseng Chi-Chuan 
Published: November 2005

Abstract
Although the zinc finger transcription factor Krüppel-like factor 4 (KLF4) has been shown to be a negative regulator of cell proliferation, the mechanisms underlying the posttranslational modification of KLF4, especially at the level of protein degradation, are poorly understood. Here, we show that KLF4 protein levels in quiescent cells were high, but decreased rapidly as cells entered the proliferating stage following serum stimulation. This decrease was partially reversed by pretreatment with MG132, a proteasome inhibitor. Moreover, KLF4 was an unstable protein that underwent rapid turnover, and exhibited a relatively short half-life (t1/2 ∼120 minutes). To investigate the involvement of the ubiquitin-proteasome pathway in the regulation of the stability of KLF4, HCT116 cells were treated with proteasome inhibitors. Our results showed that, following lactacystin treatment, levels of endogenous KLF4 increased in a time- and dose-dependent manners. Using a cell-free system, in vitro–translated 35S-labeled KLF4 protein was degraded by protein extracts prepared from exponentially growing HCT116 cells in the presence of ATP. These effects were prevented by pretreatment with MG132 or replacement of ATP with ATP-γ-S, a nonhydrolyzable analogue of ATP, suggesting that ATP is required for KLF4 degradation by the 26S proteasome. In addition, KLF4 was subject to ubiquitination when cells were treated with the proteasome inhibitor or transfected with exogenous ubiquitin. Collectively, these results indicate that destabilization of KLF4 following serum stimulation is mediated, at least in part, through a ubiquitin-proteasome pathway.
A Novel RING-Type Ubiquitin Ligase Breast Cancer-Associated Gene 2 Correlates with Outcome in Invasive Breast Cancer
Authors: Burger Angelika M. , Gao Yuguang , Amemiya Yutaka , Kahn Harriette J. , Kitching Richard , Yang Yili , Sun Ping , Narod Steven A. , Hanna Wedad M. , Seth Arun K. 
Published: November 2005

Abstract
The RING finger family of proteins possess ubiquitin ligase activity and play pivotal roles in protein degradation and receptor-mediated endocytosis. In this study, we examined whether the breast cancer-associated gene 2 (BCA2), a novel RING domain protein, has E3 ubiquitin ligase activity and investigated its expression status in breast tumors. The full-length BCA2 gene was cloned from the human breast cancer cell line MDA-MB-468. It encodes an open reading frame of 304 amino acids and contains a RING-H2 domain. BCA2 maps to chromosome 1q21.1, a region known to harbor cytogenetic aberrations in breast cancers. We found that the BCA2 protein has an intrinsic autoubiquitination activity, the hallmark of E3 ligases, whereas mutant RING protein is not autoubiquitinated. This indicates that the BCA2 ubiquitin ligase activity is dependent on the RING-H2 domain. Using tissue microarrays and immunohistochemistry, we found strong to intermediate BCA2 staining in 56% of 945 invasive breast cancers cases, which was significantly correlated with positive estrogen receptor status [odds ratio (OR), 1.51; P = 0.004], negative lymph node status (OR, 0.73; P = 0.02), and an increase in disease-free survival for regional recurrence (OR, 0.45; P = 0.03). Overexpression of BCA2 increased proliferation and small interfering RNA inhibited growth of T47D human breast cancer cells and NIH3T3 mouse cells. The autoubiquitination activity of BCA2 indicates that it is a novel RING-type E3 ligase. Its association with clinical measures and its effects on cell growth indicate that BCA2 may be important for the ubiquitin modification of proteins crucial to breast carcinogenesis and growth.
Interleukin-7-Dependent Expansion and Persistence of Melanoma-Specific T Cells in Lymphodepleted Mice Lead to Tumor Regression and Editing
Authors: Wang Li-Xin , Li Rui , Yang Guojun , Lim May , O'Hara Aisling , Chu Yiwei , Fox Bernard A. , Restifo Nicholas P. , Urba Walter J. , Hu Hong-Ming 
Published: November 2005

AbstractActive-specific immunotherapy with dendritic cells loaded with peptide derived from the melanoma antigen, gp100, failed to mediate regression of established B16F10 melanoma in normal mice. Dendritic cell vaccination induced activation and subsequent deletion of adoptively transferred naive CD8+ T-cell receptor transgenic (pmel-1) T cells specific for gp100 in normal mice. In lymphodepleted mice, dendritic cell vaccination produced greater T-cell expansion, long-term persistence of memory T cells, and tumor regression. Most tumors that persisted in the presence of functional memory T cells had either lost or exhibited reduced expression of MHC class I or gp100 proteins. In contrast to other naive T cells, pmel-1 T cells adoptively transferred to lymphodepleted mice exhibited faster proliferation and a more differentiated phenotype after exposure to peptide-pulsed dendritic cells. Proliferation and persistence of pmel-1 T cells was highly dependent on interleukin-7 (IL-7) in irradiated mice, and IL-15 when IL-7 was neutralized, two critical homeostatic cytokines produced in response to the irradiation-induced lymphodepletion.
Reliable High-Throughput Genotyping and Loss-of-Heterozygosity Detection in Formalin-Fixed, Paraffin-Embedded Tumors Using Single Nucleotide Polymorphism Arrays
Authors: Lips Esther H. , Dierssen Jan Willem F. , van Eijk Ronald , Oosting Jan , Eilers Paul H.C. , Tollenaar Rob A.E.M. , de Graaf Eelco J. , van't Slot Ruben , Wijmenga Cisca , Morreau Hans , van Wezel Tom 
Published: November 2005

Abstract
Most human cancers show genetic instabilities leading to allelic imbalances, including loss of heterozygosity (LOH). Single nucleotide polymorphism (SNP) arrays can be used to detect LOH. Currently, these arrays require intact genomic DNA as obtained from frozen tissue; however, for most cancer cases, only low-quality DNA from formalin-fixed, paraffin-embedded (FFPE) tissue is available. In this study, we tested Illumina BeadArrays to genotype FFPE tissue and detect LOH/allelic imbalances in matched colorectal tumor and normal tissue. Genotypes were compared between leukocyte and FFPE normal tissue as well as between frozen and FFPE tumor tissue. Identical genotypes and LOH profiles were obtained from normal and tumor isolates. LOH was mainly observed on chromosomes 4, 5q, 12q, 14q, 15q, 17p, 18, and 20p, which are commonly detected regions in colorectal cancer. LOH profiles of the BeadArrays were compared with profiles obtained by Affymetrix GeneChip 10K arrays, showing identical LOH patterns. These data show that genome-wide genotyping of FFPE tissue with the BeadArray gives reliable results and is a powerful technique for LOH analysis.
Cyclin-Dependent Kinase 4 Expression Is Essential for Neu-Induced Breast Tumorigenesis
Authors: Reddy Haritha K.D.L. , Mettus Richard V. , Rane Sushil G. , Graña Xavier , Litvin Judith , Reddy E. Premkumar 
Published: November 2005

Abstract
Previous work has shown that cyclin D1 expression is required for neu- and ras-induced, but not wnt- or c-myc–induced, breast tumorigenesis in mice. Although cyclin D1 binds and activates cyclin-dependent kinase 4 (Cdk4), thereby mediating activation of a program of E2F-dependent gene expression, it has been suggested that the oncogenic activities of cyclin D1 are independent of Cdk4. To determine whether Cdk4 expression is required for breast tumorigenesis in mice, we have generated compound mice ectopically expressing the neu or wnt oncogenes in the mammary glands of wild-type and Cdk4−/− mice. Our results show that Cdk4 expression is required for efficient neu-induced tumorigenesis but is dispensable for wnt-induced breast tumorigenesis. In contrast to results previously observed in the mammary glands of cyclin D1−/− virgin females, our results show defects in mammary gland development in Cdk4−/− virgin females, suggesting differences in compensatory mechanisms in the absence of either subunit of the cyclin D1/Cdk4 complex. These results suggest that drugs targeted to inhibit Cdk4 activities could be developed to specifically treat certain breast tumors as Cdk4 is not essential for viability.