bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4088: Targeting glutamine metabolism in breast cancer
Authors: Korangath Preethi C. , Zhang Huafeng , Zhang Zhe , Huso David , Stearns Vered , Dang Chi , Semenza Gregg , Sukumar Saraswati 
Published: July 2012

Abstract
Background: Unlike normal cells, most cancer cells primarily metabolize glucose by glycolysis rather than oxidative phosphorylation (Warburg effect). The cancer cells are reprogrammed to acquire these fundamental metabolic alterations during malignant transformation via different mechanisms. These mechanisms include mitochondrial defects and malfunction, adaptation to a hypoxic tumor microenvironment, oncogenic signaling, and abnormal expression of metabolic enzymes. Cancer cells also rely on glutamine for anabolism and ATP synthesis. Recent studies have shown that inhibiting glycolytic pathways leads to a significant inhibition of growth of tumor xenografts. Our group has previously shown the MYC oncogene activates glutamine metabolism which serves as a major energy source in transformed cells.
Objective: Examine the antitumor effect of a glutamine metabolic inhibitor, aminooxyacetate (AOA; aminotransferases/malate-aspartate shuttle inhibitor), alone and in combination with chemotherapy (doxorubicin and carboplatin) in a breast cancer xenograft model.
Methods: Immunodeficient mice bearing MDA-MB-231 breast cancer cells were treated with AOA alone, doxorubicin or carboplatin alone, or AOA in combination with the chemotherapeutic agent for four weeks. The tumors were evaluated for histopathological and molecular alterations.
Statistical analysis: Tumor growth was analyzed using a mixed-effects model for repeated measures data to account for dependence among observations within the same animal.
Results: We observed a significant inhibition of tumor volume in mice treated with AOA in combination with doxorubicin or carboplatin compared to groups receiving single drugs (p&lt;0.01). Western blot analysis of tumors treated with drug combinations showed decreased cyclin D1 level and increased p21 levels. Changes in key components of the glycolytic pathway are being examined.
Conclusion: Our results suggest that targeting the metabolic pathway results in significant tumor inhibition in preclinical models of breast cancer and potentially could serve as attractive therapeutic targets for breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4088. doi:10.1158/1538-7445.AM2011-4088
Abstract 4092: Alteration of caspase-mediated events following DNA damage due to the absence of poly(ADP-ribose) glycohydrolase
Authors: Zhou Yiran , Feng Xiaoxing , Koh David W. 
Published: July 2012

Abstract
The synthesis of poly(ADP-ribose) (PAR) is an immediate cellular response to DNA damaging stresses. We reported previously that the absence of PAR glycohydrolase (PARG) led to increased cell death following DNA-damaging treatments. OBJECTIVE: To investigate the possible mechanism underlying the ability of PARG inhibition to produce cell hypersensitivity of DNA-damaging stresses. METHODS: Utilizing PARG null trophoblast stem (TS) cells, DNA damage following treatment with N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) or UV radiation were examined by immunocytochemistry. Cell viability was measured by DAPI staining and caspase 3/7 activity was measured by activity assay and the immunoblotting detection of procaspase-3 and PARP-1 cleavage. RESULTS: Increased amounts of DNA alkylation and UV-induced DNA damage were observed in PARG null TS cells. In addition, elevated amounts of cell death were detected following those treatments. However, both procaspase-3 and PARP-1 cleavage were detected at decreased levels and in a delayed fashion after UV treatment in PARG null TS cells. Caspase-3/7 activity assay confirmed the decreased activation of caspase-3/7 in PARG null-TS cells. Furthermore, PARG null-TS cells exhibited less caspase-3/7 activity after UV radiation than wild type TS cells. CONCLUSION: The results show that the functionality of caspase-3 following DNA damage is decreased and delayed due to the absence of PARG. This suggests that PAR or PARG itself may play a role in modulating caspase-mediated apoptosis after UV-induced DNA damage and cell death.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4092. doi:10.1158/1538-7445.AM2011-4092
Abstract 4093: Prostate apoptosis response-4 (Par-4): A novel substrate of caspase-3 during apoptosis
Authors: Chaudhry Parvesh , Singh Mohan , Asselin Eric 
Published: July 2012

Abstract
Prostate apoptosis response-4 (Par-4) is a ubiquitously expressed pro-apoptotic tumor suppressor protein. Par-4 is known to selectively induce apoptosis in cancer cells either by activating apoptosis or by inhibiting cell survival. Here, we show, for the first time, that Par-4 is a novel substrate of caspase-3 during apoptosis. We found that Par-4 is cleaved during cisplatin-induced apoptosis in human normal and cancer cell lines. Caspase-3-deficient MCF-7 cells did not show Par-4 cleavage in response to cisplatin treatment. This Par-4 cleavage was concomitant with Parp cleavage and generated a C-terminal fragment of approx. 25kDa. The cleavage of Par-4 was completely inhibited by Z-VAD-fmk (an inhibitor of caspase like protease) suggesting that caspase-3 like activity is involved in the cleavage of Par-4. Consistently, recombinant caspase-3 efficiently cleaved Par-4 in vitro for all cell lines tested, suggesting the involvement of this protease in Par-4 processing in vivo. Overexpression of caspase-3 in PC-3 cells increased caspase-3 activity, which further resulted in the cleavage of Par-4 in these cells. However, overexpression of a catalytic mutant caspase-3 (C163A) failed to induce Par-4 cleavage. Further, restoration of caspase-3 in MCF-7 cells showed a decrease in Par-4 levels with the appearance of the cleaved fragment. The cleavage of Par-4 in caspase-3 expressing MCF-7 cells was efficiently blocked by a caspase-3 inhibitor. These results establish for the first time that Par-4 is a novel substrate of caspase-3 both in vitro and in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4093. doi:10.1158/1538-7445.AM2011-4093
Abstract 4094: A human antibody to death receptor 5 has potent antitumor activity against rhabdomyosarcoma with the expression of caspase-8 predictive of response
Authors: Kang Zhigang , Chen Junjie , Yu Yunkai , Zhang Baolin , Cao Liang 
Published: July 2012

Abstract
Purpose: Rhabdomyosarcoma (RMS) is a common pediatric soft-tissue tumor. In this study, we evaluated the efficacy and selectivity of drozitumab, a death receptor DR5-targeted therapeutic antibody, in RMS preclinical models.
Experimental design: A panel of 12 RMS cell lines was used for in vitro studies. The molecular marker predictive of response was interrogated. Selected RMS cell lines were injected into the gastrocnemius muscle of mice for in vivo assessment of both potency and selectivity of drozitumab.
Results: We report that DR5, but not DR4, persisted at high levels and on the surface of all RMS cell lines. DR5 antibody drozitumab was effective in vitro against the majority of RMS cell lines. There was a strong correlation between caspase-8 expression and the sensitivity to drozitumab, which induced the rapid assembly of the death-induced signaling complex (DISC) and the cleavage of caspase-8 only in sensitive cells. More importantly, caspase-8 catalytic activity was both necessary and sufficient in mediating the sensitivity to drozitumab. Furthermore, drozitumab had potent anti-tumor activity against established RMS xenografts with specificity as predicted from in vitro analysis, and with tumor free status in half of the treated mice.
Conclusion: Our study provides the first preclinical evaluation on the potency and selectivity of a death receptor antibody in sarcoma. Drozitumab is effective against the majority of RMS in vitro with caspase-8 expression predictive of sensitivity and, in vivo, drozitumab may provide long-term control and cure of RMS.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4094. doi:10.1158/1538-7445.AM2011-4094
Abstract 4095: Decreased caspase 8 protein expression and incomplete caspase 3 activation in TRAIL-resistant normal human fibroblasts and epithelial cells
Authors: Crowder Roslyn N. , Dicker David T. , El-Deiry Wafik S. 
Published: July 2012

Abstract
TNF-related apoptosis-inducing ligand (TRAIL)-mediated cell death is currently being utilized in newly developed cancer therapies. The molecular basis of normal cell resistance to TRAIL-mediated apoptosis, and thus therapeutic index, remains largely unexplored. We investigated TRAIL sensitivity in normal fibroblasts (HFF, WI-38, MRC-5) and epithelial cells (FHs 74 Int). We found that MRC-5 cells were moderately sensitive to TRAIL after 18 hours of treatment while WI-38, HFF, and FHs 74 Int cells were not. Normal fibroblasts and epithelial cells expressed both pro-apoptotic TRAIL receptors DR4 and DR5, although normal cell DR4 and DR5 expression was slightly lower when compared to human lung and colon cancer cells. While normal and cancer cells showed comparable DcR2 expression, normal fibroblasts and epithelial cells expressed little DcR1. c-Myc, a major determinant of TRAIL sensitivity in cancer cells, was found to be decreased in all normal cells compared to cancer cells. Expression of initiator caspase 8, required for complete TRAIL signaling, was assessed. Markedly reduced caspase 8 protein expression was detected in WI-38, HFF and FHs 74 Int cells compared to tumor cells that generally show robust caspase 8 expression. MRC-5 caspase 8 protein expression was found to be noticeably increased compared to TRAIL-resistant normal fibroblasts and epithelial cells and may be a contributing factor in MRC-5 TRAIL sensitivity. Expression and activation of effector caspase 3 was also examined. After 4 hours of TRAIL exposure, expression of full length caspase 3 declined in normal fibroblasts, epithelial cells and tumor cells. Yet, appearance of the mature active caspase 3 subunit p17 was only seen in MRC-5 fibroblasts and cancer cells. Interestingly, cleavage of caspase 3 substrate, PARP, was only seen in cancer cells after 4 hours of TRAIL exposure suggesting that MRC-5 fibroblasts have a delayed cytotoxic response to TRAIL. TRAIL-insensitive normal cells were treated with TRAIL and a proteasome inhibitor to increase susceptibility to TRAIL-mediated cell death. TRAIL-induced cell death was observed in WI-38, HFF and FHs 74 Int cells after combined treatment of TRAIL and MG132. Our current studies are focused on further analysis of caspase 3 activation and stabilization after TRAIL treatment in TRAIL-resistant normal cells. Additionally, we are investigating whether treatment of normal fibroblasts and epithelial cells with histone deacetylase inhibitors, and/or DNA methylation inhibitors might result in increased caspase 8 protein expression and susceptibility to TRAIL-mediated apoptosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4095. doi:10.1158/1538-7445.AM2011-4095
Abstract 4098: Triple negative breast cancer: Cisplatin plus TRAIL treatment enhance tumor and cancer stem cell death in vitro and in vivo models
Authors: Yin Shuping , Xu Liping , Reddy Kaladhar B. 
Published: July 2012

Abstract
Women with triple negative breast cancer (TNBC) do not benefit from hormonal or herceptin-based therapies due to loss of target receptors such as ER, PR and HER-2 amplification. Current therapeutic approaches such as chemo- and/ or radiation therapy are in effective because cancer stem cells (CSC) were shown to be resistant to conventional chemo- and/or radiation therapy after treatment; they can regenerate all the cell types in the tumor through their stem cell-like behavior. The goal of this proposal is develop treatment strategy to effectively target tumor as well as CSC without significantly affecting the normal cells thereby improving therapeutic outcome or completely eliminate the tumor. Our data shows: (1) Treatment of TNBC cells, CRL-2335 and MDA-MB-468, with cisplatin plus Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) significantly enhanced cell death (by∼ 60-70%) as compared with untreated cells. (2) Similar treatment had a minimal effect (∼10-15% cell death) on CRL-8799 normal breast cells. (3) Human triple-negative breast cancers have high levels of cancer stem cells in breast carcinoma (∼ 41%) compared to surrounding benign/normal (∼5-10%) areas by CD44 positivity (cancer stem cell staining). (4) CRL-2335 TNBC cells treated with cisplatin plus TRAIL exhibited significant reduction (from ∼45% to ∼9% after treatment) in CSC. Treatment with cisplatin/TRAIL also inhibited the expression of EGFR, p63, survivin, Bcl-2 and Bcl-xL in TNBC cells. Specific inhibition of EGFR and/or p63 protein in TNBC cells by siRNA does not increase TRAIL-induced apoptosis. However, inhibition of survivin by siRNA enhances TRAIL-induced apoptosis. These observations suggested the possibility that Survivin played an important role in cisplatin plus TRAIL-induced apoptosis in TNBC cells. In vivo experiments, treatment of mice with cisplatin plus TRAIL resulted in a significant inhibition of CRL2335 xenograft tumors compared to untreated control tumors. Taken together the data suggests that cisplatin plus TRAIL treatment have the potential of providing a new strategy for improving the therapeutic outcome in TNBC patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4098. doi:10.1158/1538-7445.AM2011-4098
Abstract 410: Platelet derived growth factor AA mediated the tropism of human mesenchymal stem cells for renal cell carcinoma
Authors: Hsiao Wan-Chi , Liao Chia-Hui , Wu Hsi-Chin , Hsieh Chia-Ling 
Published: July 2012

Abstract
Recent evidence has suggested that bone marrow-derived mesenchymal stem cells (MSCs) may be effective cellular vehicles for delivering anti-cancer agents, as they have shown to home to tumor sites. However, the signals required for homing and recruitment of MSCs to tumor sites are not well understood. In this communication, we characterized the biomediators and the possible downstream signaling pathways that responsible for the migration of MSCs toward RCC. Our in vitro migration assay demonstrated that RCC attracted MSCs much more efficient than normal human renal epithelial cells (HRE) did. Systemic administration of MSCs into RCC-bearing mice also caused rapid recruitment of MSCs at the site of tumor xenografts as well as distant metastases. To identify RCC-derived soluble factor(s) involved in MSC migration, we used antibody-based cytokine arrays to screened conditioned media (CM) from RCC cells and normal HRE cells. Among 180 cytokines we tested, solely one cytokine, PDGF-AA, was significantly up-regulated in RCC cells with a 10 fold-increased expression to HRE. On the other hand, MSC expressed high level of PDGF receptor-α in both RNA and protein level, as determined by qRT-PCR and Western blotting analysis, respectively. Functional blockage of PDGF-AA in RCC cells using either neutralizing antibody or targeting siRNA abrogated RCC-CM induced MSC migration. Pretreatment of MSCs with inhibitory antibodies against PDGF receptor-α or PDGF receptor kinase inhibitor also reduced MSC migration toward either rPDGF-AA or RCC-CM, indicating that increased MSC migration by RCC is dependent on PDGF-AA signaling through the PDGF receptor-α. We also found that RCC-CM but not HRE-CM elicited a time-dependent phosphorylation of Akt and downstream GSK3, and sustained accumulation of β-catenin protein in MSCs. These effects were abolished when MSC were pretreated with kinase inhibitor for PDGF receptor-α. Collectively, our data demonstrate that RCC tumor cells specifically recruit MSCs, which is mediated by PDGF-AA through activation of PDGF receptor signaling and AKT/GSK-3 pathways. These findings may expose new targets for diagnostic and therapeutic strategies and reduce the morbidity and mortality from metastatic disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 410. doi:10.1158/1538-7445.AM2011-410
Abstract 4103: Sulforaphane downregulates the expression of pAkt and enhances TRAIL-mediated apoptosis in human bladder cancer cells
Authors: Choi Yung Hyun , Kim Cheng-Yun , Park Cheol , Hong Su Hyun , Kim Gi-Young , Kim Wun-Jae , Kim Dong Hwan , Yoo Young Hyun , Kim Nam Deuk 
Published: July 2012

Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF gene superfamily that induces apoptosis upon engagement of cognate death receptors. While TRAIL is relatively non-toxic to normal cells, it can selectively induce apoptosis in many types of transformed cells. Nevertheless, some bladder cancer cells are particularly resistant to the effects of TRAIL. Here, we report that in combination with the sulforaphane, exposure to TRAIL induced apoptosis in TRAIL-resistant bladder cancer cells. The increased apoptosis by combined treatment with sulforaphane and TRAIL was associated with the marked increased activation of caspases and cleavage of Bid proteins. However, siRNA-mediated silencing of Bid reduced the sensitizing effect of sulforaphane in TRAIL-induced apoptosis and loss of mitochondrial membrane potential (MMP), as did caspase inhibitors, but increased cell survival. The data also indicated that following exposure to sulforaphane, DR5 proteins were up-regulated and knockdown of DR5 expression by siRNA attenuated sulforaphane plus TRAIL-induced apoptosis. In addition, following exposure to sulforaphane, the levels of pAkt proteins were significantly down-regulated without the alteration of whole Bid expression, and inhibition of pAkt by LY294002 increased sulforaphane plus TRAIL-induced apoptosis. In summary, our results indicate that treatment with a combination of TRAIL and sulforaphane may be a safe strategy for treatment of TRAIL-resistant bladder cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4103. doi:10.1158/1538-7445.AM2011-4103
Abstract 4105: Hedgehog inhibition promotes type I TRAIL cytotoxicity in human cholangiocarcinoma cells
Authors: Kurita Satoshi , Mott Justin L. , Fernandez-Zapico Martin E. , Bronk Steve F. , Guicciardi Maria E. , Roberts Lewis R. , Hibi Toshifumi , Gores Gregory J. 
Published: July 2012

Abstract
[Background and Aim] TRAIL is a promising therapeutic agent for human malignancies that can activate apoptosis via mitochondria-independent (Type I) or mitochodria-dependent (Type II) death receptor signaling. However, many malignant cells are resistant to TRAIL cytotoxicity and fail to trigger Type I or Type II killing. Using cholangiocarcinoma cells, we identified a role for Hedgehog signaling via GLI transcription factors in the regulation of TRAIL cytotoxicity, and provide new mechanistic insights whereby Hedghog inhibition increases apoptosis. [Materials and Methods] The human cholangiocarcinoma cell lines KMCH, HuCCT-1, and Mz-ChA-1 were employed. Hedgehog signaling was inhibited with cyclopamine or an shRNA construct targeting smootherned (SMO). Type II TRAIL signaling was inhibited with shRNA constructs for Bid or Bim and siRNA for Bax and Bak. Antiapoptotic mediators including Inhibitor of Apoptosis Proteins (IAPs) and Bcl-2 family proteins were examined by immunoblot analysis and/or real time RT-PCR. Apoptosis was quantified morphologically by DAPI and fluorescence microscopy, and biochemically by caspase-3/7 activity. GLI transcription factor binding to the XIAP promoter was examined by EMSA and chromatin immuneprecipitation (ChIP) assay. [Results] Pharmacologic or genetic inhibition of Hedgehog signaling down-regulates both XIAP and cIAP-1 mRNA and protein expression. Knockdown of XIAP, but not cIAP-1, by small-interfering RNA markedly sensitized cells to TRAIL-induced apoptosis, suggesting XIAP is the functional target. Putative GLI-binding sites were identified in the XIAP promoter, and EMSA and ChIP assays demonstrated direct binding by GLI proteins. Sensitization to TRAIL-induced apoptosis was not altered by knockdown of the BH3-only proteins Bim and Bid, or by knockdown of Bax plus Bak, implicating a mitochondria-independent Type I pathway of apoptosis. [Conclusion] These data provide evidence for up-regulation of XIAP by an oncogenic Hedgehog pathway and demonstrate that Hedgehog inhibition sensitizes cells to TRAIL via decreasing XIAP levels. Hedgehog inhibition thereby promotes Type I death receptor signaling and sensitizes cells to apoptosis, which suggests Hedgehog and XIAP inhibition may be a therapeutic approach for TRAIL-resistant neoplasms.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4105. doi:10.1158/1538-7445.AM2011-4105