bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 240: Transcriptional knockdown of urokinase-type plasminogen activator receptor (uPAR) induces apoptosis in glioblastoma xenograft cells via activation of p53
Authors: Chetty Chandramu , Ponnala Shivani , Veeravalli Krishna Kumar , Gujrati Meena , Dinh Dzung H. , Rao Jasti S. 
Published: August 2012

Abstract
Elevated levels of urokinase plasminogen activator receptor (uPAR), a glycoprotein tethered to the cell membrane with a glycosylphosphotidylinositol (GPI) anchor, is associated with tumor malignancy in a variety of cancers including glioblastoma (GBM). In this study, we show that inhibition of uPAR via RNA interference (puPAR-Si) induced p53-mediated massive cell death in human GBM xenograft cell lines, 4910 and 5310. Induction of Fas expression and cleavage of caspases-8, -9 and -3 and PARP (poly (ADP-ribose) polymerase) revealed induction of the extrinsic apoptotic pathway. Inhibition of Fas death receptor blocked puPAR-Si-induced apoptosis. Further, uPAR inhibition induced the expression of tumor suppressor p53 and its downstream target gene p21. Transcriptional knockdown of p53 rescued cells from apoptosis, thereby indicating that p53 was critical for induction of apoptosis. Moreover, puPAR-Si treatment inhibited pre-established tumor growth in an intracranial model. Indeed, histological analysis of tumor sections collected from mice that were treated with uPAR siRNA revealed increased immunoreactivity of phosphorylated p53, Fas, active caspase 3 and induction of programmed cell death. These data suggest a novel function of uPAR acting as a survival factor for GBM by downregulating p53; inhibition of uPAR induces a pro-apoptotic signaling pathway via p53. These findings may offer new treatment strategies for GBM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 240. doi:1538-7445.AM2012-240
Abstract 2403: DNAJB6 suppresses the Wnt/β-catenin pathway
Authors: Mitra Aparna , Menezes Mitchell E. , Honkanen Richard E. , Shevde Lalita A. , Samant Rajeev S. 
Published: August 2012

Abstract
DNAJB6 is an HSP40 family protein which plays an important role in regulating tumorigenicity and metastasis of breast cancer and melanoma. Expression of DNAJB6 is found to be reduced in advanced stages of the disease. Restoration of its expression significantly decreases tumor growth and metastasis in xenograft studies. DNAJB6 expressing cells also show altered morphology, gain in epithelial markers and loss of mesenchymal markers and increased expression of DKK1, a secreted Wnt/β-catenin signaling. Our current studies elaborate the intricate mechanistic details about contributions of DNAJB6 to the negative regulation of the Wnt/β-catenin pathway. We describe the important role of the “J” domain of DNAJB6 in inhibiting Wnt/β-catenin. Deletion of “J” domain renders DNAJB6 incapable of impeding tumor growth and metastasis. Co-immunoprecipitation, mammalian-two-hybrid and FPLC studies show that DNAJB6 can form a multimeric complex with HSPA8 (HSC70), GSK3β and PP2A. DNAJB6 binds HSC70 and dephosphorylates GSK3β by recruiting PP2A. Activated GSK3β in-turn degrades β-catenin protein. Deletion of the J domain does not allow the formation of this multiprotein complex, which inactivates GSK3β and restores β-catenin levels. We further noted that the morphology of the cells grown in three dimensional matrix show distinct difference in WT-DNAJB6 and J-domain deleted expressors. In vivo and in vitro studies done with J domain deleted expressors showed increased malignancy. We also demonstrate the importance of J domain of DNAJB6 in suppressing osteopontin as one of the critical factors contributing to its reduced malignant activity in suppressing invasion and growth of xenografts. In summary, our studies unravel a novel mechanistic role of DNAJB6 in regulating GSK3β, a critical kinase which restricts tumor progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2403. doi:1538-7445.AM2012-2403
Abstract 2464: Novel MMP-3 generated PTHrP peptides promote osteoblast proliferation: Implications for prostate to bone metastases
Authors: Frieling Jeremy S. , Pamen Lizzie Atomi , Lynch Conor C. 
Published: August 2012

Abstract
Up to 90% of patients that succumb to prostate cancer will have evidence of bone metastasis. Prostate to bone metastases generate mixed lesions hallmarked by areas of extensive bone resorption and formation mediated by osteoclasts and osteoblasts respectively. Tumor derived PTHrP has been defined as a major molecule facilitating tumor-osteoblast interaction. Mature PTHrP is comprised of 36 amino-acids and new data from our lab has identified that MMP-3, one of several MMPs we have found highly expressed in the prostate cancer-bone microenvironment, can process PTHrP to yield novel distinct peptides. We posit that MMP-3 generated PTHrP peptides can have distinct biological effects on osteoblasts. Our results to date demonstrate that MMP-3 processes mature PTHrP to yield PTHrP1-16, PTHrP17-26, and PTHrP27-36 amino acid peptides in vitro as determined by N-terminal amino acid sequencing and MALDI-TOF analysis. Next, we determined the biological activity of the MMP-3 generated PTHrP peptides by treating osteoblast cell lines and examining differentiation and proliferation. We found using alizarin red staining that the MMP-3 generated PTHrP peptides did not impact osteoblast differentiation. However, analysis of cell proliferation, using an MTT assay, identified that the PTHrP1-16 peptide stimulated osteoblast proliferation over a 24-hour period. Follow-up studies revealed that the MMP-3 generated PTHrP1-16 fragment significantly enhanced phosphorylation of MAPK 42/44 and CREB, presumably via the PTHrP receptor, PTH1R. In conclusion, our data identify for the first time that PTHrP is an MMP substrate and that MMP-3 generated PTHrP peptide PTHrP1-16, can promote osteoblast proliferation. These findings suggest that MMP-3 expression in the prostate tumor microenvironment can potentially impact osteoblast expansion and may play a role in the generation of osteoblastic lesions that are commonly associated with prostate to bone metastases.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2464. doi:1538-7445.AM2012-2464
Abstract 247: Aldose reductase inhibition sensitizes colon cancer cells to TRAIL-induced apoptosis
Authors: Ramana Kota V. , Shoeb Mohammad , Srivastava Satish K. 
Published: August 2012

Abstract
Sensitization of cancer cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), particularly TRAIL-resistant cancer cells, could improve the effectiveness of TRAIL as a potential chemotherapy drug. Therefore, development of safe novel pharmacological agents that could sensitize the tumor cells to TRAIL should be an effective strategy to kill the chemotherapy resistance cancer cells. We have recently shown that inhibition of polyol pathway enzyme, aldose reductase (AR) that mediates NF-kB-dependent expression of inflammatory markers, prevents human colon cancer cell growth and metastasis in culture as well in nude mouse models. We now have investigated the role of AR in sensitizing cancer cells to TRAIL and potentiating TRAIL-induced apoptosis of human colon cancer cells. Our results demonstrate that inhibition of AR potentiates TRAIL-induced apoptosis in colon cancer cells (HT-29, HCT-116) by upregulation of both death receptor (DR)-5 and DR4. Specific siRNAs -mediated knockdown of DR5 and DR4 significantly (&gt;85%) reduced the sensitizing effect of AR inhibition by pharmacological agent, fidarestat, on TRAIL-induced apoptosis. AR inhibition also down-regulated TRAIL-induced cell survival proteins such as Bcl-xL, Bcl-2, survivin, XIAP, and cFLIP, and up-regulated the expression of pro-apoptotic proteins such as Bax. Further, AR inhibition also altered the mitochondrial membrane potential leading to cytochrome c release, caspases-3 activation and PARP cleavage. Furthermore, our results indicate that AR inhibition regulates AKT/PI3K-dependent activation of forkhead transcription factor FOXO3a. Knockdown of FOXO3a significantly (&gt;80%) abolished AR inhibition-induced upregulation of DR5 and DR4 and apoptosis in colon cancer cells. Overall, our results show that AR inhibition potentiates TRAIL-induced apoptosis through down-regulation of cell survival proteins and upregulation of death receptors and thus AR inhibitors along with TRAIL could be effective therapy for the treatment of colon cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 247. doi:1538-7445.AM2012-247
Abstract 2483: Inhibition of the polycomb group gene EZH2 suppresses growth and radiosensitizes ATRT cells by promoting senescence and inhibiting the CycinD-E2F1 axis
Authors: Alimova Irina N. , Venkataraman Sujatha , Harris Peter , Marquez Victor E. , Birks Diane , Foreman Nicholas K. , Vibhakar Rajeev 
Published: August 2012

Abstract
Overexpression of the polycomb group gene Enhancer of Zeste 2 (EZH2) occurs in many tumors including prostate cancer, breast cancer and brain tumors such as Glioblastoma multiform and Medulloblastoma. Recent evidence suggests it may also have a role in rhabdoid tumors. Atypical teratoid rhabdoid tumor (ATRT) is a rare high-grade brain tumor with very poor survival that occurs most commonly in children. AT/RT tumors are characterized by deletion of the chromatin associated protein SMARCB1. Given the role of EZH2 in regulating epigenetic changes we chose to investigate the role of EZH2 in AT/RT. Here we show that targeted disruption of EZH2 by RNAi or pharmacologic means strongly impairs ATRT cell growth, induces apoptosis and potently sensitizes these cells to radiation. Using functional analysis of transcription factor activity we found the Cyclin D-E2F1 axis to be repressed upon EZH2 depletion in ATRT cells. Taken together our observations provide evidence that EZH2 regulates cell cycle progression by targeting the G1-S transition machinery and may be an important new therapeutic target particularly in combination with radiation in ATRT.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2483. doi:1538-7445.AM2012-2483
Abstract 2498: Differential rapamycin sensitivity distinguishes two distinct populations of tumor cells in murine glioma
Authors: Kaul Aparna , Solga Anne , Lee Da Yong , Gianino Scott M. , Gutmann David H. 
Published: August 2012

Abstract
Solid tumors are complex ecosystems, composed of a heterogeneous ensemble of cells that comprise the tumor mass (neoplastic compartment) and the surrounding stroma (non-neoplastic compartment). Currently, research efforts are aimed at defining the individual contributions of each cell type to tumor development and maintenance. Previous studies using a genetically-engineered mouse model of Neurofibromatosis type 1 (NF1)-associated optic glioma have underscored the critical role of one stromal cell type (microglia) in the growth of these tumors. In the current study, we analyze neoplastic cell heterogeneity and demonstrate that two distinct proliferating populations of neoplastic cells exist in the tumor. These distinct cell types, neuroglial progenitors and differentiated astrocytes, are distinguished by their sensitivity to rapamycin. The molecular basis for this differential sensitivity to rapamycin reflects dramatic differences in mammalian target of rapamycin (mTOR) complex protein expression and basal mTOR activation. We leverage this cell type-specific sensitivity to target neuroglial progenitor cells in the tumor and inhibit optic glioma formation in vivo. Collectively, these findings emphasize the importance of cellular diversity in glioma formation and growth, and highlight the importance of developing novel treatment strategies that co-target multiple cell populations for maximal therapeutic benefit.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2498. doi:1538-7445.AM2012-2498
Abstract 2505: Targeting the p53 response in pediatric B-cell acute lymphoblastic leukemia
Authors: Wolak Kathryn E. , Skol Andrew , Bainer Russell , Onel Kenan 
Published: August 2012

Abstract
B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy in children. Despite a cure rate of approximately 85%, the prevalence of this disease causes B-ALL to be the leading cause of cancer-related death in children. Additionally, the toxic drugs necessary for cures can cause severe side effects in developing children. Thus, there is a tremendous need for innovative therapies to combat B-ALL. The p53 tumor suppressor is a key regulator of apoptosis and is almost always wild-type in pediatric B-ALL, in stark contrast to virtually all other cancers. Alterations in the p53 pathway are associated with drug resistance, underscoring its central role in determining response to chemotherapy. We identified a set of p53-regulated transcriptional targets that comprise an apoptotic gene signature significantly associated with response to therapy and independently prognostic for outcome in pediatric ALL. We hypothesize that cells can be primed for an enhanced apoptotic response to chemotherapy by modulating expression levels of the p53-regulated apoptotic signature genes with small molecules before administering chemotherapy. We conducted a high-throughput screen to identify novel compounds that prime ALL cells for apoptosis to convert a chemotherapy-resistant cell into one that is sensitive. This screen was performed using 83,745 compounds in both the wild-type p53 cell line TK6 and the mutant-p53 line, WTK1. Cells were treated with either compound alone or compound plus daunorubicin, a drug used to treat ALL. Compounds were normalized and scored by using both the B-score and the robust Z-score. “Hits” were defined as compounds that do not significantly alter viability of the cells alone, but significantly increase daunorubicin-induced cell death. As our primary screen takes a functional approach with an endpoint of viability rather than expression of our gene signature, it's possible that compounds we have identified function through alternative mechanisms. As our secondary screen, we interrogate these hits for induction of the signature. Because patient outcome was associated with the gene signature, we hypothesize that the most successful compounds will act by altering the signature from the “bad risk” expression to the “good risk” expression, thereby having the potential to convert a chemoresistant cell into one that is sensitive.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2505. doi:1538-7445.AM2012-2505
Abstract 2516: Immunohistochemical characterization of a novel, highly sensitive monoclonal antibody to folate receptor α
Authors: O'Shannessy Daniel J. , Somers Elizabeth B. , Fu Yao-Shi , Smale Robert , Thiel Robert P. , Nicolaides Nicholas C. 
Published: August 2012

Abstract
Background: Folate receptor ≤ (FRα) has restricted expression in normal tissues but high-level expression in a subset of epithelial-derived tumors, including non-mucinous ovarian carcinomas and non-small cell lung (NSCL) adenocarcinomas. FRα has shown significant potential for targeted cancer therapy and several promising agents are in late-stage clinical development. As such, robust reagents are needed that can be used across diverse diagnostic platforms to identify patients who have FRα-expressing tumors. The immunohistochemical (IHC) characterization of a novel, high-affinity monoclonal antibody (MAb) against FRα is described. Methods: MAbs were generated to modified full-length FRα protein using standard methods. One MAb, 26B3.F2, displayed high affinity and the ability to bind FRα on both fresh/frozen and formalin-fixed, paraffin-embedded tissue sections. An optimized IHC protocol was developed and FRα expression was assessed on commercial tissue microarrays (US Biomax). Data were analyzed using an M-score, a newly introduced, weighted-intensity score that incorporates both the proportion of FRα-positive cells and the staining intensity. A board-certified pathologist scored the level of FRα expression. Results: Normal tissue staining for MAb 26B3.F2 demonstrated a limited distribution on focal epithelial surfaces of pancreas, lung, salivary gland, kidney, hypophysis, thyroid, and breast samples. Staining was mainly located in the lumen. The tissue distribution is consistent with the published literature. Strong staining was observed in 100% of serous ovarian samples and a significant proportion of ovarian endometrioid adenocarcinoma samples. FRα expression, as determined by MAb 26B3.F2 in NSCL cancer samples, demonstrated high discrimination between adenocarcinoma (positive) and squamous cell carcinomas (negative) (P &lt; 0.001). Conclusion: MAb 26B3.F2 is a highly sensitive, robust agent suitable for identifying FRα expression by IHC and other diagnostic platforms. In addition to the expected distribution in normal tissue, MAb 26B3.F2 revealed high-level expression of FRα in ovarian cancer and NSCL adenocarcinoma samples, and the ability to discriminate differential expression between two NSCL cancer subtypes, squamous cell carcinoma and adenocarcinoma. Preliminary evidence therefore suggests that MAb 26B3.F2 IHC will be a useful tool to support further development of FRα-targeted therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2516. doi:1538-7445.AM2012-2516
Abstract 2517: Potent antitumor activity of AbGn-ADC, a humanized monoclonal antibody conjugated with dolastatin analogue, to gastric and pancreatic cancers expressing AbGn carbohydrate epitope
Authors: Huang Chiu-Chen , Hsieh Yu-Chi , Tsai Yu-Ying , Lee Shu-Hua , Chiang Evelyn , Liu Meng-Ru , Lin Shih-Yao 
Published: August 2012

Abstract
AbGn is a glycotope-specific humanized monoclonal antibody recognizing Lewisa- like carbohydrate expressed in gastric and pancreatic cancer cells. While AbGn binding to normal tissues is restricted to only luminal surface of the epithelium in gastro-intestinal track and secretory glands, about 50% of gastric and pancreatic cancer samples tested express AbGn epitope and can be recognized by AbGn antibody. FACS analysis and confocal microscopic studies demonstrated extensive internalization of AbGn after binding to the cell surface. The internalized AbGn co-localized with lysosomal marker LAMP1, suggesting that AbGn-mediated internalization followed the lysosomal pathway. A novel antibody-drug conjugate (AbGn-ADC) was generated by linking AbGn to a dolastatin analogue, a potent inhibitor of microtubulin polymerization, through a dipeptide-based cleavable linker. This AbGn-ADC was evaluated for antitumor activity in vitro and in mouse xenograft models. AbGn-ADC eliminated cancer cell lines with nanomolar potency in vitro. No cell death could be detected in SW480 cells, a gastric cell line with no AbGn epitope expression, suggesting high selectivity of AbGn-ADC. When used to treat mice with established human gastric (SNU-16) or pancreatic (Panc.02.03B) cancer xenografts, AbGn-ADC significantly reduced the size of the established tumors (p&lt;0.01). No body weight loss or signs of toxicity was observed in AbGn-ADC treated mice. These findings support the potential of further development of AbGn-ADC for treating gastric and pancreatic cancers. Data from pre-clinical AbGn-ADC tolerability study in relevant non-human primate will be presented.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2517. doi:1538-7445.AM2012-2517
Abstract 2611: Role of circadian genes in breast cancer: Analysis of the CECILE study, a population-based case-control study conducted in France
Authors: Truong Therese , Menegaux Florence , Richardson Sylvia , Guénel Pascal 
Published: August 2012

Abstract
Breast cancer risk has been associated with shift work and light exposure at night. It has been suggested that disruption of circadian rhythms induced by these exposure may play a role in tumorigenesis. Circadian rhythms regulate diverse physiologic processes, including regulation of sex hormone levels, and genes controlling the circadian rhythm were found to regulate cell proliferation, cell cycle regulation and apoptosis. However, only few studies have investigated the role of these genes in breast cancer. The purpose of this study was to analyze the association between polymorphisms in circadian genes and breast cancer risk. The CECILE study is a population-based case-control study on environmental and genetic factors. A total of 1135 incident cases and 1167 controls provided DNA samples. We genotyped 570 tagging and functional SNPs from the 22 genes in the circadian rhythm pathway defined by KEGG. Preliminary results based on a SNP by SNP analysis using unconditional logistic regression highlighted 36 SNPs with p-value&lt;0.05 in RORA, CUL1, NPAS2, CRY1, CRY2 and CLOCK genes. Of these, 3 SNPs in RORA were significantly associated with breast cancer after Bonferroni correction for multiple testing (p&lt;0.0001). In ongoing analyses, we use the Multilevel Inference for SNP Association (MISA) method, which is a more powerful method that allows estimating associations at the SNP, gene and pathway level. These analyses will be presented. Our results suggest a role of the circadian gene in breast cancer risk. Further analysis on possible interaction between shift work and genetic variants highlighted in this study in relation to breast cancer risk will be conducted in the CECILE study.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2611. doi:1538-7445.AM2012-2611