bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1849: A novel gene-pathway regulating of microRNA mediates resistance to trastuzumab forgastric cancer.
Authors: Eto Kojiro , Watanabe Masayuki , Iwatsuki Masaaki , Baba Hideo 
Published: August 2014

Abstract
Background: Recently, the efficacy of trastuzumab is indicated in patients with unresectable or recurrent HER2 positive gastric cancer from the results of ToGA trial, and trastuzumab administration was to be done in patients with gastric cancer. However, resistance to trastuzumab has become a problem in breast cancer. MicroRNAs (miRs) are involved in regulating multiple cellular pathways, including cell proliferation, differentiation, and chemotherapy resistance, and thus may function as oncogenes or tumor suppressing genes. The aim of current study is to clarify the miR-gene pathway regulating resistance to trastuzumab. Method: Using 6 gastric cancer cell lines, we examined the following items in vitro. 1. We examined the status of HER2 protein expression by western blotting. 2. We focused on miR-21 and its target gene PTEN and evaluated the expression of miR-21 and PTEN in HER2 positive gastric cancer cell lines by real time PCR and western blotting. 3. We examined the expression of PTEN and downstream gene to clary the target gene of miR-21 by over or down regulation of miR-21. 4. We investigated whether miR-21-PTEN pathway can affect the resistance of trastuzumab. Result: 1.We confirmed the status of HER2 in gastric cell lines. 2. The endogenous expression of PTEN and miR-21 showed inverse correlation in each cell lines. 3. The suppression of miR-21 increased PTEN expression with downregulation of P-Akt, persisting HER2 expression. 4. Overexpression of miR-21 can induce the resistance of trastuzumab, and suppression of miR-21 can restore the sensitivity of trastuzumab. Conclusion: Our current study revealed that miR-21-PTEN pathway can regulate the sensitivity of trastuzumab in HER2-positive gastric cancer cell lines. These findings suggest that this pathway can be crucial clue to the mechanism of resistance to trastuzumab in gastric cancer. To elucidate the mechanism of resistance to trastuzumab can lead to the development of individualized treatment.
Citation Format: Kojiro Eto, Masayuki Watanabe, Masaaki Iwatsuki, Hideo Baba. A novel gene-pathway regulating of microRNA mediates resistance to trastuzumab forgastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1849. doi:10.1158/1538-7445.AM2013-1849
Abstract 1850: BRCA1-regulating microRNAs, miR-146a and miR-638, are overexpressed in triple negative breast cancer tumors.
Authors: Zavala Valentina , Fernandez Wanda , Cruz Adolfo , Segovia Laura , Camus Mauricio , Carvallo Pilar 
Published: August 2014

Abstract
microRNAs are non-coding RNA sequences of about 22 nucleotides long that participate in post transcriptional regulation of mRNAs. Its deregulation has been associated to breast cancer development and treatment resistance. Triple negative breast tumors are characterized by its difficult treatment due to lack of estrogen and progesterone receptors and ERBB2. In addition, a high proportion do not express BRCA1; a breast cancer high susceptibility gene. BRCA1 expression can be regulated by different mechanisms as we have confirmed in our laboratory, such as methylation of its gene promoter, mutations and deletions due genomic rearrangements. Although there are tumors that do not present any of these abnormalities, they express low nuclear BRCA1 levels or they do not express the protein at all. This is why analyzing levels of microRNAs that are shown to regulate BRCA1 mRNA expression is an interesting additional mechanism to be evaluated. There is experimental evidence that miR-146a and mir-638 regulate BRCA1 expression. We therefore analyzed miR-146a and miR-638 in triple negative breast cancer tumors (n=41). Briefly, total RNA was extracted from formalin-fixed tumors. Then, both microRNAs were evaluated using qPCR TaqMan assay and compared with BRCA1 expression previously determined by immunohistochemistry. Our results showed overexpression of miR-146a in 68% of the analyzed tumors and miR-638 in 82%. Among those tumors presenting abnormal BRCA1 expression (n=24), 50% showed an increase of miR-146a and 75% presented miR-638 overexpression. Both microRNAs showed a discrete overexpression in tumors with normal levels of BRCA1 (n=16). Finally, this data suggest that microRNAs might regulate BRCA1 expression in triple negative tumors.
Citation Format: Valentina Zavala, Wanda Fernandez, Adolfo Cruz, Laura Segovia, Mauricio Camus, Pilar Carvallo. BRCA1-regulating microRNAs, miR-146a and miR-638, are overexpressed in triple negative breast cancer tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1850. doi:10.1158/1538-7445.AM2013-1850
Abstract 1851: Resveratrol impairs GLUT-1 mediated glucose uptake in ovarian cancer cells .
Authors: Gwak HyeRan , No Jae Hong , Song Yong Sang 
Published: August 2014

Abstract
Resveratrol(RSV), a phytoalexin found in red wine, has drawn interest due to its anticancer effect through the modulation of cancer cell metabolism in in vitro and in vivo studies. Increased uptake of [18F] fluorodeoxyglucose (FDG) using positron emission tomography (PET) has been found to be effective diagnostic tool for ovarian cancer. Thus, the manipulation of the metabolic derangement could be an effective therapeutic target for ovarian cancer. In this study, we found that RSV inhibited glucose uptake via inhibition of Glut1 translocation to plasma membrane and induced apoptosis irrespective of p53-status, using four ovarian cancer cell lines, PA-1 (p53-wild), OVCAR3, MDAH 2774 (p53-mutant) and SKOV3 (p53-null). RSV (50 μM) treatment in ovarian cancer cells decreased glucose uptake in parallel with cell viability. The facilitative glucose uptake by glucose transporter1 (GLUT1) seems to be a primary step in ovarian cancer. Also in previous data, mRNA of GLUT1 was more highly expressed in tumor tissue than in normal tissue in patients with ovarian cancer. However, RSV did not affect the protein levels of GLUT1. To identify translocation of Glut1, we performed immunofluorescence and immunoblotting of total and membrane-bound proteins. GLUT1 translocation to plasma-membrane was found to be decreased. Furthermore, localization of GLUT1 in ovarian cancer was found to be associated with the inhibition of Akt activity by RSV. In conclusion, RSV induced apoptosis by impairing glucose uptake through modulating Akt-GLUT1 signaling axis in ovarian cancer cells.
Citation Format: HyeRan Gwak, Jae Hong No, Yong Sang Song. Resveratrol impairs GLUT-1 mediated glucose uptake in ovarian cancer cells . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1851. doi:10.1158/1538-7445.AM2013-1851
Abstract 1852: Pyruvate dehydrogenase kinase expression and metabolic changes following dichloroacetate exposure in anoxia in human colorectal cancer cells.
Authors: Ho Nelson , Coomber Brenda L. 
Published: August 2014

Abstract
Introduction: While glycolysis is a suboptimal metabolic strategy used by cells under hypoxic conditions, many cancer cells preferentially utilize glycolysis for energy production in the presence of abundant oxygen, a phenomenon known as the “Warburg Effect”. Dichloroacetate (DCA) is a small molecule metabolic modulator that shifts cellular metabolism to glucose oxidation by inhibition of pyruvate dehydrogenase kinase (PDK), an enzymatic inhibitor of pyruvate dehydrogenase (PDH). Furthermore, DCA has been shown to induce apoptosis in cancer but not normal cells. Our previous work showed that some human colorectal cancer (CRC) cells are protected from anoxia-induced apoptosis upon exposure to DCA, through as yet unclear mechanisms.
Hypothesis: It is hypothesized that differential expression of PDK isoforms will correlate with the ability of different cancer cells to withstand the apoptotic effects of DCA in anoxia.
Methods: SW480, LS174T (CRC) and IEC-18 (normal intestinal epithelial) cell lines were exposed to 10 mM DCA in either normoxic (20% O2) or anoxic (&lt; 0.1% O2) conditions for 24 hours. Following treatment, expression of different PDK isoforms was determined through qRT-PCR and western blotting. Phosphorylation of PDH at Ser293 and Ser300 was assessed through western blotting. Glucose consumption and lactate production was determined using a colorimetric-based assay. Changes in mitochondrial function were quantified through Mitotracker staining and subsequent flow cytometry. Cell viability was assessed using the neutral red assay.
Results: In all three cell lines: A) PDK isoforms 1 and 3 are highly expressed relative to isoforms 2 and 4, B) DCA and/or anoxic treatment induced a greater effect on PDH phosphorylation at Ser300 than Ser293, and C) DCA had minimal effect on glucose consumption in either normoxia or anoxia.
Conclusions: Altered PDK expression and PDH activation may not fully explain the differences in resistance to DCA-induced apoptosis observed in human CRC cells. Investigating the mechanisms by which certain cancer cells are protected from DCA-induced apoptosis will lead to a better understanding of cancer metabolism and thus provide better therapeutic opportunities.
Citation Format: Nelson Ho, Brenda L. Coomber. Pyruvate dehydrogenase kinase expression and metabolic changes following dichloroacetate exposure in anoxia in human colorectal cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1852. doi:10.1158/1538-7445.AM2013-1852
Abstract 1856: Preclinical study for statins as anticancer drug.
Authors: Jiang Pengfei , Mukthavavam Rajesh , Chao Ying , Nomura Natsuko , Fogal Valentina , Pastorino Sandra , Summit Ila , Kesari Santosh 
Published: August 2014

Abstract
Statins are a class of drug that inhibits 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase that is the rate-limiting enzyme of cholesterols synthesis. Now, statins are among the most prescribed drug used for treatment of hypercholesterolemia by lower down the serum cholesterol concentration and it is also a major means to preventing and reducing the risk for cardiovascular diseases. In addition to prevent and treat cardiovascular diseases, the emerging evidences indicated the statins usage has a number of beneficial effect such as anti-inflammation and lowering down the risk of cancer. To investigate the anti-cancer effect statins drugs that have been approved to clinical usage we evaluated the inhibition of breast cancer and GBM cell line growth. Statins are also potent inhibitors to stem cell-like primary GBM cells freshly isolated from patients. Unexpected, statins treatment induces strong cell autophagy death signals as weak if not at all cellular apoptosis. Tumor cells can be rescued after statin treatment by adding intermediated product of cholesterol synthesis (mevalonate and GGPP), it indicates that the target of the statins is specifically related the cholesterols synthesis pathway. Knock-down the expression of geranylgeranyl pyrophosphate synthetase-1 (GGPS-1), another key enzyme in cholesterol synthesis pathway, also stimulated strong cell autophagy and cell death in vitro, also dramatically reduced U87 tumor growth in vivo. In vivo data also showed that directly injection of statin is better than oral administrate to delay GBM tumor growth. This study showed statins are potent anti-cancer drug in vitro and in animal model. These safe and well-tolerate drugs are good candidates for clinical test as cancer chemotherapy reagents.
Citation Format: Pengfei Jiang, Rajesh Mukthavavam, Ying Chao, Natsuko Nomura, Valentina Fogal, Sandra Pastorino, Ila Summit, Santosh Kesari. Preclinical study for statins as anticancer drug. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1856. doi:10.1158/1538-7445.AM2013-1856
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 1874: Phosphatidylcholine synthesis as a potential therapeutic target in multiple myeloma.
Authors: Bardeleben Carolyne , Lichtenstein Alan 
Published: August 2014

Abstract
A metabolics screen with 8226 cells treated with AICAr showed that de novo pyrimidine synthesis was inhibited. AICAr -induced apoptosis in 5 different myeloma cell lines. This screen showed a significant decrease in CDP-choline, an intermediate of the Kennedy pathway involved in de novo synthesis of phosphatidylcholine (PC). Phosphatidylcholine is the most predominant phospholipid in mammalian ER membranes. The rate limiting step in this pathway is the conversion of phosphocholine and CTP to CDP-choline via the enzyme CTP:phosphocholine cytidylyltransferase (CCT). Although it is likely that the decrease in CDP-choline is a consequence of pyrimidine starvation, the fact that this pathway showed a significant decrease within 8 hours of AICAr treatment suggested to us that this pathway may have a high flux in 8226 cells and that phosphatidylcholine synthesis may be a relevant target in myeloma cells.
Multiple myeloma (MM) cells may be particularly dependent on this biosynthetic reaction because of their high consistent level of ER stress and requirement to continuously replenish ER membranes. Indeed, CCT-null mice have a defect in differentiation of B lymphocytes to plasma cells and deficiencies in Ig synthesis. To test whether this pathway remains critical in survival of malignant MM cells, we exposed MM cell lines to an inhibitor shown to inhibit CCT activity, HexPC. HexPC induced apoptosis in all MM cell lines in a concentration- and time-dependent manner. The addition of lysophosphatidylcholine (LPC), presumably converted to PC independently of the Kennedy pathway, completely rescued MM cell apoptosis. Knocking down of CCT with shRNA in myeloma cell lines also resulted in apoptosis. Apoptosis of MM cells induced by HexPC was associated with induction of ER stress as shown by enhanced phosphorylation of IRE1 and eIF-2alpha. This ER stress was also prevented when LPC was added to HexPC although LPC could not prevent similar ER stress induced by bortezomib. These results underscore the importance of this phosphatidylcholine synthesis pathway in MM cells and provide new targets for future therapy.
Citation Format: Carolyne Bardeleben, Alan Lichtenstein. Phosphatidylcholine synthesis as a potential therapeutic target in multiple myeloma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1874. doi:10.1158/1538-7445.AM2013-1874
Abstract 1882: Role of cystathionine beta-synthase in ovarian cancer growth, metastasis and drug sensitivity.
Authors: Saha Sounik , Bhattacharyya Sanjib , Giri Karuna , Lanza Ian R. , Nair K. Sreekumar , Jennings Nicholas B. , Kumar Rakesh , Sood Anil K. , Bhattacharya Resham , Mukherjee Priyabrata 
Published: August 2014

Abstract
Hydrogen sulfide (H2S), the third gasotransmitter, has recently attracted a lot of attention for its cytoprotective action and role in angiogenesis. Dysregulation of the major enzymes which produces H2S namely, cystathionine beta synthase (CBS), cystathionine gamma lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST) have also been implicated in a large number of pathological conditions that range from neurological disorders to cardiovascular diseases. Surprisingly, studies on the role of these enzymes in cancer is scarce, especially, that of CBS. Relapse with a drug resistant and aggressive phenotype is a common occurrence in ovarian cancer with an overall 5-year survival of approximately 30%. Here we report that, CBS, a key enzyme required for sulphur amino acid metabolism, plays a critical role in promoting ovarian cancer growth, metastasis and drug resistance. Overexpression of CBS was observed in a majority of ovarian cancer cell lines utilized in our study compared to normal ovarian surface epithelial cells. Silencing CBS in A2780 cells using siRNA or a CBS-specific inhibitor, aminooxyacetic acid reduced proliferation of ovarian cancer cells by dramatically reducing total glutathione levels, H2S levels and thereby enhancing oxidative stress. Downregulation of CBS reduced activation of NF-kB and upregulated p53 protein levels thereby inactivating the antioxidant network of the cells. A deeper insight into the intracellular localization of CBS by confocal fluorescence microscopy demonstrated a mitochondria specific distribution and silencing CBS caused mitochondrial superoxide accumulation that resulted in decreased mitochondrial respiration, reduced ATP production and increased ADP-to-ATP ratio. Furthermore, silencing CBS, augmented the activity of cisplatin in vitro in A2780 cells and in vivo in an orthotopic model of advanced ovarian cancer. Nanoliposomal delivery of CBS siRNA significantly reduced the number of tumor nodules in a chemoresistant orthotopic mouse model of ovarian cancer. To our knowledge, this is the first study demonstrating the importance of CBS in ovarian cancer progression and drug resistance and therefore is a viable target for future anti-cancer therapies.
Citation Format: Sounik Saha, Sanjib Bhattacharyya, Karuna Giri, Ian R. Lanza, K. Sreekumar Nair, Nicholas B. Jennings, Rakesh Kumar, Anil K. Sood, Resham Bhattacharya, Priyabrata Mukherjee. Role of cystathionine beta-synthase in ovarian cancer growth, metastasis and drug sensitivity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1882. doi:10.1158/1538-7445.AM2013-1882
Abstract 1890: Superoxide modulates tumor cell survival in response to hypoxia and metabolic stress: role of p53 status.
Authors: Chavez-Perez Valery , Strasberg-Rieber Mary , Rieber Manuel 
Published: August 2014

Abstract
Background: Cancer cells from solid tumors become metabolically stressed, when nutrients are insufficient within poorly vascularized regions. Metabolic stress resulting from severe deprivation of glucose and serum-derived growth factors can promote cell death, partly through excessive reactive oxygen species (ROS) production. As possible sources of oxidative stress, NADPH oxidases (NOX) are centrally involved in the control of the malignant state: activated NOX enzymes use NADPH as an electron donor to reduce molecular oxygen generating superoxide anion radical (O2•−), which can act extracellularly as an autocrine/paracrine regulator or intracellularly as a signaling messenger in a variety of mammalian cells. Excessive superoxide can be dismutated to H2O2. by superoxide dismutases (SOD). Objectives: To investigate whether chemical inhibition of NOX or removal of extracellular superoxide by exogenous SOD influences tumor cell survival depending on p53 status or metabolic stress. Experimental: Genetically-matched human melanoma cells with unequal p53 mutational status were exposed to glucose or serum starvation under normoxia, physical hypoxia and/or chemical hypoxia .Differential cell survival was assesed by live-dead fluorometric assays or crystal violet staining. Mechanisms influencing response to glucose limitation were studied by specific immune blotting. Results: Lower cell proliferation under normoxia in 1 % serum was attenuated by chemically or enzymatically decreasing superoxide or by exposing them to hypoxia. Diphenylene iodonium preferentially restored the metabolic activity of mutant p53 cells in 1 % serum, whereas SOD acted preferentially on wt p53 cells under comparable conditions.
Apoptosis-associated PARP cleavage under normoxia in 2.5 mM glucose and 5 % dialyzed serum was counteracted by SOD only in wt p53 cells. Cell death induced by CoCl2 preconditioning in the absence of physical hypoxia was preferential for mut p53 C8161 melanoma and reversed by SOD. Conclusions: Our results support a cytotoxic role for Nox-mediated free radical production in cancer cell death under metabolic stress, and suggests that p53 mutation increases superoxide-mediated toxicity during limitation of intracellular glucose and/ serum-derived growth factors.
Citation Format: Valery Chavez-Perez, Mary Strasberg-Rieber, Manuel Rieber. Superoxide modulates tumor cell survival in response to hypoxia and metabolic stress: role of p53 status. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1890. doi:10.1158/1538-7445.AM2013-1890