bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4883: YM155 potentiates chemosensitivity to gemcitabine in human pancreatic cancer cell line, MiaPaCa-2
Authors: Jung Kyungah , Yoon Dokhyun , Shin Jaesik , Kim Taewon 
Published: August 2012

Abstract
Pancreatic cancer is a highly aggressive malignancy with a median overall survival of less than 1 year. Although gemcitabine is a standard chemotherapeutic agent, response rates range only from 20% to 40% and ultimately all patients acquire resistance to the chemotherapy. In this study, we evaluated the potential efficacy of YM155, a selective survivin suppressant, in pancreatic cancer cell line, MiaPaCa-2 showing resistance to gemcitabine. YM155 inhibited the expression of survivin in the pancreatic cancer cell line and gemcitabine upregulated survivin on the contrary. However, YM155 enhanced chemosensitivity to gemcitabine resulting in apoptotic cell death, which accompanied a decrease in survivin expression. Knockdown of endogenous survivin via RNA interference also enhanced sensitivity to gemcitabine. In addition, YM155 potentiated the anti-tumor effect of gemcitabine in the xenograft tumors of MiaPaCa-2. While gemcitabine induced cell cycle arrest at S-phase, co-treatment of YM155 bypassed the cell cycle arrest resulting in apoptotic cell death. Therefore, our results suggest that YM155 potentiates chemosensitivity to gemcitabine in pancreatic cancer cells through suppression of survivin, which is induced by gemcitabine. Combination of gemcitabine and YM155 might be a potential therapeutic strategy for the treatment of pancreatic cancer to be explored in clinical investigation.
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 4883. doi:1538-7445.AM2012-4883
Abstract 4884: The oncogenic phosphatase PPM1D confers cisplatin resistance in ovarian carcinoma cells by attenuating checkpoint kinase 1 and p53 activation
Authors: Ali Ahmed Y. , Abedini Mohammad R. , Tsang Benjamin K. 
Published: August 2012

Abstract
Cisplatin (CDDP: cis-diamminedichloroplatinum) resistance is a major hurdle in the treatment of human ovarian cancer (OVCA). A better understanding of the mechanisms of CDDP resistance can greatly improve therapeutic outcome for patients. p53, a determinant of CDDP sensitivity in ovarian cancer, is activated by Chk1 in response to DNA damage. Although the oncogenic phosphatase Protein Phosphatase Magnesium-dependent 1 (PPM1D) can deactivate both p53 and Chk1 through site-specific dephosphorylation, whether PPM1D plays a role in CDDP resistance is unknown. Here, using pair-matched wt-p53 CDDP-sensitive (OV2008) and -resistant (C13*) cells, and p53-compromised CDDP-resistant cells (A2780cp, OCC-1, OVCAR-3, and SKOV3), we have demonstrated (i) the existence of site-specific differences in phospho-Ser-Checkpoint kinase 1 (Chk1) content between sensitive and resistant cells in response to CDDP; (ii) PPM1D, but not phosphoinositide-3-kinase-related kinase (ATR), is important in the regulation of CDDP-induced Chk1 activation and ovarian cancer cell chemosensitivity; (iii) PPM1D down-regulation sensitizes resistant cells to CDDP primarily by activating Chk1 and p53. Our findings establish for the first time that PPM1D confers CDDP resistance in ovarian cancer cells through attenuating CDDP-induced, Chk1-mediated, p53-dependent apoptosis. These findings extend the current knowledge on the molecular and cellular basis of cisplatin resistance and offer the rationale for PPMID as a potential target for treatment of chemoresistant ovarian 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 4884. doi:1538-7445.AM2012-4884
Abstract 4887: Curcuminoid CLEFMA induces autophagy-associated apoptosis in lung cancer
Authors: Sahoo Kaustuv K. , Yadav Vivek R. , Awasthi Vibhudutta 
Published: August 2012

Abstract
CLEFMA (4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid) is a novel curcuminoid discovered in our laboratory. Earlier we showed that CLEFMA induces oxidative stress-dependent cell death in lung adenocarcinoma H441 cells. Although apoptosis is the desired mechanism for chemotherapy-induced cell death, the associated pathways are often defective in lung cancers resulting in high levels of chemoresistance. Therefore, drugs that induce alternate modes of cell death, such as autophagy, may be beneficial. Drug-induced hyperinduction of autophagy is classified as type 2 programmed cell death. In most circumstances, autophagy parallels apoptosis, and such composite cell death is described as “autophagy-associated apoptosis”. Whether autophagy plays a synergistic or antagonistic role in overall cell death response to anticancer drugs is an important focus in cancer research. In this study, we have investigated the interaction between autophagy and apoptosis in CLEFMA mediated cell death. Methods: The human non-small cell lung carcinoma (H441) cell line was treated with CLEFMA (10 µM) and the molecular mechanisms of cell death were investigated. Growth inhibition was assessed by MTT or hexosaminidase assay. Apoptosis was measured by flow cytometry of annexin V-stained cells, RT-PCR and immunoblotting for apoptosis-related biomarkers. Induction of autophagy was established by electron microscopy and immunobloting for LC3B, ATG, beclin1, AKT and mTOR. Autophagy was inhibited by 3-methyladenine (3-MA 1 mM) as well as chloroquine and E64D+pepstatin combination. The tumor suppressive efficacy of CLEFMA was demonstrated in H441 xenograft mice intraperitoneally receiving 0, 5 and 10 µg/day of CLEFMA for 32 days. The mice were imaged for F-18-fluorodeoxyglucose uptake in tumor tissue. Results: CLEFMA suppressed the viability of H441 cell line in a dose-dependent manner (IC50 = 6.25 µM). It induced cell cycle arrest at G2/M phase with accompanying accumulation of p21 protein. Caspase 3/7 immunoblotting and annexin V flow cytometry confirmed the induction of apoptosis. At the same time, we observed induction of LC3BII and suppression of AKT/mTOR phosphorylation. The suppression of autophagy significantly increased CLEFMA-induced cell death and increased caspase cleavage. In the xenograft model, 5 and 10 µg CLEFMA significantly reduced the tumor volume by 72% and 96.2%, respectively; the tumor uptake of F-18-fluorodeoxyglucose was also reduced. Conclusions: We demonstrate the efficacy of CLEFMA as a potent tumor suppressive agent. The mechanistic results suggest that autophagy is a survival mechanism in CLEFMA-treated lung cancer cells and it antagonizes apoptosis.
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 4887. doi:1538-7445.AM2012-4887
Abstract 4904: Acetaminophen enhances the chemotherapeutic effect of cisplatin and paclitaxel on human ovarian carcinoma cells in vitro
Authors: Wu Jeffrey J. , Neuwelt Alexander J. , Muldoon Leslie L. , Neuwelt Edward A. 
Published: August 2012

Abstract
Chemoresistance is commonly found in treating cancer patients. Acetaminophen enhances the cytotoxicity of cisplatin in human liver cancer cells by depleting glutathione and increasing production of toxic metabolites in vitro. The objective of this study was to investigate potential molecular mechanisms for chemoenhancement in non-hepatic cells. Human ovarian carcinoma SKOV3 cells were treated with cisplatin or paclitaxel with or without acetaminophen in vitro. Cellular mitochondrial membrane potential and reactive oxygen species concentration was measured by using JC-1 and DHR123 stain, respectively. Cellular platinum level was analyzed using ICP-MS. Apoptosis and signaling pathways were examined by immunoblotting and immunohistochemical analyses. A 2 h incubation with acetaminophen (10 mM) decreased cellular glutathione levels and increased mitochondrial membrane potential without affecting reactive oxygen species. Overnight acetaminophen treatment increased reactive oxygen species and enhanced both cisplatin- and paclitaxel-induced apoptosis. In contrast, the combination of acetaminophen with cisplatin but not paclitaxel blocked nuclear translocation of nrf2, a transcription factor that has been implicated in regulation of the antioxidant response. Pretreatment with acetaminophen for 2 h did not affect cellular platinum uptake when compared to cisplatin alone. Regardless of different oxidative stress pathways involved between cisplatin and paclitaxel, the addition of acetaminophen enhanced the cytotoxic effects of both chemotherapeutic drugs in human ovarian carcinoma cells. Our results suggest that acetaminophen could be used as a chemoenhancing adjuvant for conventional chemotherapy drugs in treating ovarian and other malignancies.
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 4904. doi:1538-7445.AM2012-4904
Abstract 4905: The BH3 mimetic navitoclax (ABT-263) selectively induces apoptosis in cholangiocarcinoma-associated fibroblasts thereby reducing tumor growth
Authors: Mertens Joachim C. , Fingas Christian D. , Christensen John D. , Kakisaka Keisuke , Smoot Rory L. , Bronk Steven F. , Mott Justin L. , Gustafson Michael P. , Dietz Allan B. , Roberts Lewis R. , Sirica Alphonse E. , Gores Gregory J. 
Published: August 2012

Abstract
Background and Aims: Cholangiocarcinomas (CCA) are highly desmoplastic tumors containing abundant cancer associated myofibroblasts (CAF). An inverse association between the abundance of CAF and survival has been demonstrated in CCA, suggesting that CAF play a pivotal role in CCA development and progression. The CAF phenotype represents an ‘activated cell state’ and as such may be uniquely susceptible to apoptosis. BH3 mimetics induce apoptosis in cells ‘primed’ for cell death, representing a therapeutic strategy for cancer. Herein we examine whether CAF display a selective sensitivity to the BH3 mimetic ABT-263 and whether ABT-263 induced ablation of CAF reduces tumor growth and progression. Methods: We employed human and rat CAF, myofibroblastic human LX2 cells, human and rat control fibroblasts, the rat cholangiocarcinoma cell line BDEneu and human CCA cell lines for these studies. In-vivo experiments were conducted using a syngeneic, orthotopic rat CCA model. Results: We observed a significant and dose dependent induction of apoptosis by ABT-263 in human and rat primary CAF as well as activated LX2 cells as compared to rat BDEneu and human CCA cell lines. Comparison of Bcl-2 protein expression in quiescent fibroblasts versus CAF demonstrated a consistent upregulation of Bax in the CAF, likely explaining their enhanced sensitivity to pro-death stimuli. Indeed, ABT-263 treatment of CAF was associated with Bax activation as compared to human CCA cell lines. Finally, administration of ABT-263 decreased tumor size and metastasis in a human-like in-vivo rat model of CCA. Analysis of the rat tumors revealed a decrease in Tenascin C positive tumor stroma and an increase of TUNEL-positive apoptotic stromal cells. Conclusions: CCA associated CAF appear to be ‘primed’ for cell death, possibly due to overexpression of the pro-apoptotic Bcl-2 protein Bax. Consequently CAF display increased sensitivity to the BH3 mimetic ABT-263, which selectively depletes them from a rat in-vivo model of CCA, thereby reducing tumor growth and metastasis. Thus targeting CCA tumor stroma by inducing apoptosis in CAF may represent a new therapeutic approach in human CCA.
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 4905. doi:1538-7445.AM2012-4905
Abstract 4972: Phosphorylation of caspase-3 and caspase-7 by p21-activated protein kinase (PAK)2 inhibits chemotherapeutic drug-induced apoptosis of breast cancer cell lines
Authors: Li Xiang , Zhu Feng , Bode Ann M. , Dong Ziming , Dong Zigang 
Published: August 2012

Abstract
P21-activated kinase (PAK)2, a member of PAK family of serine/threonine protein kinases, plays an important role in physiological processes such as motility, survival, mitosis, and apoptosis. However, the role of PAK2 in chemotherapy resistance remains unclear. Here we report that PAK2 is highly expressed in human breast cancer cell lines and human breast invasive carcinoma tissue compared with human non-tumorigenic mammary epithelial cell lines and adjacent normal breast tissue respectively. Interestingly, we found that PAK2 can phosphorylate caspase-3 at Thr77, Thr152 and Thr245. Moreover, PAK2 can bind with caspase-7 and phosphorylate caspase-7 at Ser30, Thr173 and Ser239. Functionally, the phosphorylation of caspase-3 and caspase-7 decreases their activity, thereby inhibiting staurosporine and doxorubicin HCl-induced cellular apoptosis. Our data indicate that highly expressed PAK2 mediates chemotherapy resistance in human breast invasive ductal carcinoma by negatively regulating caspase-3 and caspase-7 activity.
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 4972. doi:1538-7445.AM2012-4972
Abstract 4975: Api6/AIM/SPα/CD5L overexpression in alveolar type II epithelial cells induces spontaneous lung adenocarcinoma
Authors: Du Hong , Li Yuan , Qu Peng , Wu Lingyan , Li Beilin , Yan Cong 
Published: August 2012

Abstract
Chronic inflammation is an important contributor to the development of lung cancers, one of the most common malignancies worldwide, but the underlying molecular mechanisms of inflammation that specifically cue cancer risk remains poorly understood. We have previously found that blocking neutral lipid metabolism in lysosomal acid lipase knock-out mice (lal-/-) leads to severe tissue inflammation and diseases in multiple organs, including the lung. In an effort to identify downstream target genes of LAL to promote lung inflammation, Affymetrix GeneChip microarray analysis were performed and identified apoptosis inhibitor 6 (Api6, AIM, Sp-alpha, CD5L) as one of top increased expression gene (70 folds in the lal-/- lung). This aberrant up-regulation of Api6 occurs primarily in alveolar type II (AT II) epithelial cells of lal-/- mice and this up-regulation of Api6 can be reduced by treatment of ligands for peroxisome proliferator-activated receptor gamma (PPARgamma) in lal-/- mice. To determine the functional role of Api6 in AT II epithelial cells, an epithelial-specific CCSP-rtTA/(TetO)7-CMV-Api6 bitransgenic mouse model has been generated. Here we report that Api6 is a pro-inflammatory and oncogenic molecule. Api6 overexpression inhibited apoptosis and activated oncogenic signaling in AT II lung epithelial cells, inducing emphysema and adenocarcinoma. Additionally, Api6 overexpression in AT II cells increased the concentrations of pro-inflammatory cytokines/chemokines in bronchoalveolar lavage fluid and serum, which promote expansion of myeloid derived suppressor cells (MDSCs) in the lung and blood but not in bone marrow or spleen. Lung MDSCs suppressed T cell proliferation and activity in vitro and reduced levels of T cells in vivo following doxycycline treatment to activate Api6. Together, our findings establish that Api6 promotes lung tumorigenesis by blocking a mechanism of epithelial apoptosis that would normally support immunosurveillance. In humans, expression of the Api6 gene is up-regulated in chronic obstructive pulmonary disease (COPD, the major phenotype is emphysema) and lung 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 4975. doi:1538-7445.AM2012-4975
Abstract 498: Anti-invasive potential of alginate microcapsule encapsulating TIMP 2-engineered cells against malignant glioma cells
Authors: Jung Shin , Jung Young-il , Jang Woo-Youl , Jung Tae-Young , Moon Kyung-Sub , Kim In-Young 
Published: August 2012

Abstract
Objectives. 293T was genetically modified to secrete tissue inhibitor of metalloproteinase-2 (TIMP-2) (abbreviated as 293TIMP2 cells) and 293TIMP2 cells were encapsulated into alginate microcapsules to produce TIMP-2 protien continuously. Since TIMP-2 is known to inhibit matrix metalloproteinase-2 (MMP-2) expression of tumor cells, it could be inhibit invasion of tumor cells through extracellular matrix. The anti-invasive potential of the microcapsules was studied in vitro against U87MG glioma cells. Experimental. The TIMP-2 gene was transfected to 293T cells and the genetically engineered 293TIMP2 cells were encapsulted into alginate microcapsules. The released TIMP-2 protein was examined with Western blot analysis and the anti-invasive potential against U86MG glioma cells was tested with gelatin zymography for matrix metalloproteinase-2 (MMP-2) and a Matrigel assay for invasion. Results. Cell viability within the alginate microcapsules was properly maintained at a cell density of 5×106 cell density. Since polycationic polymers are helpful to maintain mechanical strength of microcapsules with good cell viability, alginate microcapsules were reinforced with chitosan (0.1 % wt/vol). Expression of TIMP-2 protein in cell lysate and the secreted TIMP-2 into conditioned media were confirmed with Western blot analysis. Alginate microcapsules encapsulating 293TIMP2 cells properly released TIMP-2 protein into the medium and the released TIMP-2 protein was effective in inhibiting MMP-2 expression and invasion of U87MG glioma cells. Conclusion. These results indicated that alginate microcapsules encapsulating 293TIMP2 cells are superior candidates for anti-invasive therapy of glioma.
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 498. doi:1538-7445.AM2012-498
Abstract 4986: Nuclear PRAS40 regulates the cellular response to nucleolar stress
Authors: Havel Jonathan Joseph , Li Zenggang , Fu Haian 
Published: August 2012

Abstract
The Proline-rich Akt Substrate of 40kDA (PRAS40) has recently been identified as a binding partner and inhibitor of the mammalian Target of Rapamycin Complex 1 (mTORC1), a growth factor- and nutrient-sensitive kinase whose activity promotes protein synthesis and cell growth. Despite its inhibitory effect on mTORC1, PRAS40 has been shown to promote cell survival in rodent models of spinal cord injury and tumorigenesis. Importantly, PRAS40 levels have also been found to correlate with poor prognosis in lung cancer patients, an effect not readily explained by mTORC1 inhibition. Here we demonstrate that in addition to its known cytoplasmic role in inhibiting mTORC1, PRAS40 also actively shuttles to the nucleus, where it congregates at the periphery of nucleoli and exists in a high-molecular weight complex void of mTORC1 components. Through immunoprecipitation and mass spectrometry analyses we have begun to identify members of this nuclear PRAS40 complex. Furthermore, we demonstrate that PRAS40 overexpression attenuates Actinomycin D-mediated induction of nucleolar stress markers. These findings may help to explain the apparent pro-tumorigenic effects of PRAS40 and identify the PRAS40 nuclear complex as a potential target for anti-cancer drug discovery.
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 4986. doi:1538-7445.AM2012-4986
Abstract 499: NFATc1 is a novel invasion promoter in colorectal cancer
Authors: Tripathi Manish K. , Mima Shinji , Freeman Tanner J. , Weaver Connie , Deane Natasha G. , Zhang Bing , Beauchamp R. Daniel 
Published: August 2012

Abstract
Colorectal carcinoma is the third leading cause of cancer-related death in the United States. In order to understand the mechanism/signaling pathways responsible for invasion, migration and metastasis in colorectal cancer, our lab successfully modeled human cancer invasion/metastasis using mouse colon cancer cells. We have developed an integrative and comparative computational approach to reveal transcriptional regulatory mechanisms underlying colon cancer progression. Applying this approach to fourteen human colorectal cancer (CRC) microarray data sets and to one microarray dataset from an immunocompetent mouse model of metastasis, we identified known and novel transcriptional regulators in CRC. Among these transcriptional regulators, the Nuclear Factor of Activated T cells (NFAT) family of transcription factors play a central role in inducible gene transcription in various signaling pathways including regulation of cell differentiation, development, adaption, immune system response, inflammation, adipocyte metabolism, and lipolysis, and carcinogenesis. We found that an NFAT-driven transcriptional program significantly correlates with disease-free survival in multiple CRC Stage II patients. Using quantitative real time RT-PCR, we validated high NFATc1 expression in a subgroup of stage II colorectal cancer patients and differential expression of predicted NFATc1 targets in the same patients. The tumor-associated NFATc1 co-regulated gene signature was associated with worse clinical survival outcomes in stage II colorectal cancer patients. In comparison with parental MC38 mouse colon cancer cells, NFATc1 expression is increased in MC38met cells selected for invasive and metastatic ability, RNAi-based inhibition of NFATc1 expression in the MC38met cells resulted in decreased invasiveness in a transendothelial invasion model. Our studies suggest a role for NFATc1 as a tumor promoting transcription factor that contributes to invasion in 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 499. doi:1538-7445.AM2012-499