bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1208: Glutamine modulates cellular NAD+/NADH homeostasis thereby regulating cancer metastasis, drug sensitivity in cancer cells
Authors: Yang Lifeng , Achreja Abhinav , Moss Tyler , Baddour Joelle , Stilles Katherine , Chiba Lisa , Kim Sun Hye , Morse Josh , Marini Juan , Sood Anil K. , Ram Prahlad T. , Nagrath Deepak 
Published: August 2015

Abstract
Glutamine can play a critical role in cellular growth in multiple cancers. Glutamine-addicted cancer cells are dependent on glutamine for viability, and their metabolism is reprogrammed for glutamine utilization through the tricarboxylic acid (TCA) cycle. Recently, we uncovered a missing link between cancer invasiveness and glutamine dependence. Using isotope tracer and bioenergetic analysis, we found that low-invasive ovarian cancer (OVCA) cells are glutamine independent, whereas high-invasive OVCA cells are markedly glutamine dependent. Consistent with our findings, OVCA patients’ microarray data suggest that glutaminolysis correlates with poor survival. Notably, the ratio of gene expression associated with glutamine anabolism versus catabolism has emerged as a novel biomarker for patient prognosis. Significantly, we found that glutamine regulates the cellular NAD+/NADH homeostasis, which mediates cancer metastasis and progression. On the other hand, the overexpression of NAD+ biosynthesis pathway enhances glutamine's entry into TCA cycle for cancer metastasis, as well as chemo-drug resistance. Our findings suggest that a combined approach of targeting high-invasive OVCA cells by blocking glutamine's entry into the TCA cycle, along with targeting NAD+ biosynthesis pathway may lead to potential therapeutic approaches for treating OVCAs. Our insights will present a unique opportunity for overcoming the drug resistance limitation in clinical trials in ovarian cancers.
Citation Format: Lifeng Yang, Abhinav Achreja, Tyler Moss, Joelle Baddour, Katherine Stilles, Lisa Chiba, Sun Hye Kim, Josh Morse, Juan Marini, Anil K. Sood, Prahlad T. Ram, Deepak Nagrath. Glutamine modulates cellular NAD+/NADH homeostasis thereby regulating cancer metastasis, drug sensitivity in cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1208. doi:10.1158/1538-7445.AM2015-1208
Abstract 1238: Effects of MLH1 on prostate cancer cell function
Authors: Fukuhara Shinichiro , Chang Inik , Mitsui Yozo , Yamamura Soichiro , Chiyomaru Takeshi , Majid Shahana , Saini Sharanjot , Hirata Hiroshi , Deng Guoren , Gill Ankurpreet , Wong Darryn K. , Shiina Hiroaki , Nonomura Norio , Dahiya Rajvir , Tanaka Yuichiro 
Published: August 2015

Abstract
Mismatch repair (MMR) enzymes have been shown to be deficient in prostate cancer. MMR can influence the regulation of tumor development in various cancers but their role on prostate cancer has not been investigated. The aim of the present study was to determine the functional effects of the mutL-homolog 1 (MLH1) gene on growth of prostate cancer cells. The DU145 prostate cancer cell line has been previously established as MLH1-deficient and thus, this cell line was utilized to determine effects of MLH1 by gene expression. Lack of MLH1 expression was confirmed by Western blotting in DU145 cells whereas levels were high in normal prostatic PWR-1E and RWPE-1 cells. Stably expressing MLH1 in DU145 resulted in decreased cell proliferation, migration and invasion properties. Lack of cell growth using athymic nude mice model also indicated a tumor suppressive effect by MLH1. Interestingly, MLH1 caused an increase in apoptosis along with phosphorylated c-Abl, and treatment with MLH1 siRNAs countered this effect. Furthermore, inhibition of c-Abl with imatinib (STI571) also abrogated the effect on apoptosis caused by MLH1. These results demonstrate MLH1 protects against prostate cancer development by inducing c-Abl-mediated apoptosis.
Citation Format: Shinichiro Fukuhara, Inik Chang, Yozo Mitsui, Soichiro Yamamura, Takeshi Chiyomaru, Shahana Majid, Sharanjot Saini, Hiroshi Hirata, Guoren Deng, Ankurpreet Gill, Darryn K. Wong, Hiroaki Shiina, Norio Nonomura, Rajvir Dahiya, Yuichiro Tanaka. Effects of MLH1 on prostate cancer cell function. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1238. doi:10.1158/1538-7445.AM2015-1238
Abstract 1244: Hyperthermia and chemotherapy mediated effects on tumor cell proliferation and heat shock protein expression in human colon cancer
Authors: Grimmig Tanja , Thumm Rebeca , Moench Romana , Moll Eva M. , Germer Christoph T. , Waaga-Gasser Ana Maria , Gasser Martin 
Published: August 2015

Abstract
In patients with peritoneal carcinomatosis (PC) of gastrointestinal cancer hyperthermic intraperitoneal chemotherapy (HIPEC) represents a promising treatment option integrated into multimodal concepts. Heat shock proteins (HSP) play a major role in cellular stress response conferring increased resistance in tumor cells. Therefore we analyzed HSP expression profiles in tumor cells exposed to hyperthermic and chemotherapeutic stress. To mimic HIPEC-like conditions HT29 colon cancer cells were exposed to varying hyperthermic conditions for 60 min with additional 5-fluorouracil (5-FU) treatment. HSP expression was analyzed 30 min, 24 h, 48 h and 72 h after treatment using Western Blot and RT-qPCR. Untreated cells cultivated at 37°C served as controls. Additionally, effects on tumor cell proliferation were determined 24 h, 48 h and 72 h after treatment by MTS-assay. Hyperthermia caused temperature dependent upregulation of HSP27, HSP70, HSP72, and HSP90 gene and protein expression that was further increased by additional cytotoxic 5-FU treatment. 5-FU initiated progressive rise in HSP gene expression up to 72 h after 1 h exposure at normothermia as well as under hyperthermia. After isolated hyperthermia tumor cell proliferation was recovered at 72 h. Antiproliferative effects of 5-FU could not be enhanced by further increased hyperthermia. Antiproliferative effects of hyperthermia induced during HIPEC therapy seem to be negatively influenced by highly conserved HSP mechanisms. Our findings suggest that HSP27, HSP70/72, and HSP90 are significantly involved in hyperthermia and chemotoxicity mediated cell stress repair mechanisms. While initial increase in HSP expression can counteract cytotoxic effects during HIPEC therapy long-term elevated expression levels may cause lasting resistance to cellular stress.
Note: This abstract was not presented at the meeting.
Citation Format: Tanja Grimmig, Rebeca Thumm, Romana Moench, Eva M. Moll, Christoph T. Germer, Ana Maria Waaga-Gasser, Martin Gasser. Hyperthermia and chemotherapy mediated effects on tumor cell proliferation and heat shock protein expression in human colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1244. doi:10.1158/1538-7445.AM2015-1244
Abstract 1249: MLN4924, a protein neddylation inhibitor, induces apoptosis via endoplasmic reticulum (ER)-stress in human cervical cancer
Authors: Kuo Kuan-Lin , Pu Yeong-Shiau , Ho I-LIN , Hsu Chen-Hsun , Hsieh Ju-Ton , Lin Wei-Chou , Chou Chien-Tso , Huang Kuo-How 
Published: August 2015

Abstract
Cervical cancer is the second most common cancer among the women worldwide. The treatment of the cervical cancer includes the surgery, chemotherapy, external and intracavitary radiotherapy adjusted to the different cancer stage. Despite these treatments, a certain proportion of women still die of the cancer due to recurrent or chemoresistent disease. The toxicity and side effect of these therapies are substantial. Therefore, it is important to develop new drugs or combination treatments to improve patient survival and minimize side effect of the therapy. MLN4924 is an inhibitor of NEDD8 activating enzyme (NAE), has been reported to elicit anti-tumor response in various malignancies. In this study, we aim to investigate the anti-tumor effect of MLN4924 on human cervical cancer and underlying mechanism in vitro and in vivo. We used two different grade human bladder cervical cell lines: ME-180 and HeLa. After exposing to MLN4924, the cell viability and apoptosis were measured by MTT and flow cytometry with annexin V-FITC labeling. The efficacy of cell proliferation was determined by BrdU incorporation assay. The cell cycle regulators, cell death-related molecules, and ER stress-related proteins were examined by Western blotting. We also use Nu/Nu xenograft mice model to clarify the effect of MLN4924 on tumor growth in vivo. We demonstrated that MLN4924 effectively induces dose-dependent cytotoxicity, apoptosis and anti-tumor phenomenon in cervical cancer cells. MLN4924 also activate cleaved-Bid, phospho-histone H2A.X, caspases and PARP, decresed phospho-Bcl2, and cause cell cycle arrest. Furthermore, MLN4924 possessed the ability to activate ER stress-related moleculors caspase-4, and CCAAT/enhancer binding protein homologous protein (CHOP), which were involved in UC cell apoptosis, and other stress responses (JNK and c-Jun activations). Moreover, we confirmed MLN4924 inhibited tumor growth and induced ER-stress in a cervical cancer xenograft mice model. Taken together, we demonstrated that MLN4924 induces cytotoxicity and cell cycle retardation, as well as activation of ER stress responses in human cervical cancer. The anti-tumor effect of MLN4924 provides a novel implication in clinical treatment of cervical cancer.
Citation Format: Kuan-Lin Kuo, Yeong-Shiau Pu, I-LIN Ho, Chen-Hsun Hsu, Ju-Ton Hsieh, Wei-Chou Lin, Chien-Tso Chou, Kuo-How Huang. MLN4924, a protein neddylation inhibitor, induces apoptosis via endoplasmic reticulum (ER)-stress in human cervical cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1249. doi:10.1158/1538-7445.AM2015-1249
Abstract 1250: Role of mitochondria elongation in p53-induced cellular senescence
Authors: Kim Young Yeon , Jee Hye Jin , Jeong Na Young , Yun Jeanho 
Published: August 2015

Abstract
Various stresses such as oncogene activation, oxidative stress, and activation of tumor suppressors induce cellular senescence in both normal and cancer cells. This phenomenon, termed premature senescence or accelerated senescence, acts as an important barrier against tumorigenesis and is also considered to be a potential mechanism for controlling human cancers. Although mitochondria has been implicated in cancer, but the exact role of mitochondria in premature senescence has not been fully determined. Here, we studied how morphological and functional change in mitochondria involves in the onset of p53-induced premature senescence. Upon p53 expression in p53-defective cancer cells, extensive elongation of mitochondria network and functional defects in mitochondria were detected. Antioxidant NAC treatment indicates that mitochondria elongation induces increase the level of ROS, which is an important mediator for cellular senescence. Our results suggest that morphology change and subsequent dysfunction of mitochondria play a critical role in p53-induced premature senescence.
Citation Format: Young Yeon Kim, Hye Jin Jee, Na Young Jeong, Jeanho Yun. Role of mitochondria elongation in p53-induced cellular senescence. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1250. doi:10.1158/1538-7445.AM2015-1250
Abstract 1258: The unfolded protein response may contribute to racial disparity in endocrine responsiveness in breast cancer
Authors: Eltayeb Ahreej E. , Demas Diane M. , Clarke Robert , Shajahan-Haq Ayesha N. 
Published: August 2015

Abstract
About 70% of all breast cancers are estrogen receptor alpha positive (ER+) and depend on estrogen to grow and proliferate. Anti-hormone therapy such as antiestrogens (e.g., Tamoxifen; TAM) are often used to treat ER+ breast tumors but the cancer cells can develop resistance to these drugs (endocrine resistance). Unfortunately, ∼50% percent of all antiestrogen treated tumors eventually develop endocrine resistance, and therefore, there is an urgent need to find ways to treat this incurable disease. Nonetheless, little is known about the causes of endocrine resistance, and even less is known about the racial disparities that exist for antiestrogen responsiveness among ER+ breast cancer cases. Clinical investigations into ER+ breast cancer cases with similarly treated tumors showed that progression-free survival (PFS) and overall survival (OS) in African-American (AA) women were worse than in European-American (EA) women. The underlying causes of these racial differences within ER+ breast cancers is unknown. One cellular adaptive mechanism that allow endocrine resistant cells to survive antiestrogen treatment is a called the unfolded protein response (UPR) that is initiated within the endoplasmic reticulum caused by a stress stimulus. Cellular stress induced by antiestrogens can trigger the UPR leading to induce a pro-survival response by inhibiting cell death (by apoptosis) and promoting cell survival (by autophagy). Gene expression analysis for ER+ tumors of AA patients show up-regulation of UPR genes such as glucose-regulated protein 78, GRP78 (also known as HSP5A or BiP), activation transcription factor-6 (ATF6) and spliced X-box-protein-1 (XBP1s). Moreover, ER+ breast cancer cell lines derived from tumors of AA patients show increased levels of GRP78, ATF6 and XBP1 compared with cells derived from EA patients. The ER+ breast cancer cell lines derived from tumors of AA patients also show reduced sensitivity to Tamoxifen compared with cells derived from EA patients. Through our study, we will determine how up-regulation of the UPR contribute to the differences noted in anti-hormone therapy in treatment of ER+ breast cancer in AA versus EA women. Therefore, targeting critical pro-survival signaling molecules of the UPR can inhibit endocrine resistance and reduce growth of ER+ breast cancer cells more efficiently and avoid unsuccessful treatment in AA breast cancer patients.
Citation Format: Ahreej E. Eltayeb, Diane M. Demas, Robert Clarke, Ayesha N. Shajahan-Haq. The unfolded protein response may contribute to racial disparity in endocrine responsiveness in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1258. doi:10.1158/1538-7445.AM2015-1258
Abstract 1266: Autophagy-mediated degradation of nuclear envelope proteins during oncogene-induced senescence
Authors: Lenain Christelle , Gusyatiner Olga , Douma Sirith , Peeper Daniel S. 
Published: August 2015

Abstract
Cellular senescence is a stable form of cell cycle arrest triggered by a variety of damages and stresses including oncogene expression (oncogene-induced senescence or OIS). We and others previously demonstrated that OIS occurs in human benign lesions, acting as a potent tumor suppressor mechanism preventing cancer progression. Numerous phenotypic changes occur during OIS both in the cytoplasm and in the nucleus. These include the activation of autophagy, a catabolic process operating in the cytoplasm, and downregulation of lamin B1, a component of the nuclear lamina. However, it is unknown whether these changes relate to each other. We discovered that cells entering BRAFV600E- or H-RASV12-induced senescence downregulate not only lamin B1 but also lamin A, as well as several other nuclear envelope (NE) proteins. This depletion was associated with an altered NE morphology. We further found that the global loss of NE proteins is a consequence of their degradation by the autophagy machinery. This occurs concomitantly with autophagy induction and increased lysosomal content and activity. Our study reveals for the first time to our knowledge, a connection between autophagy and the disruption of nuclear envelope integrity during OIS.
Note: This abstract was not presented at the meeting.
Citation Format: Christelle Lenain, Olga Gusyatiner, Sirith Douma, Daniel S. Peeper. Autophagy-mediated degradation of nuclear envelope proteins during oncogene-induced senescence. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1266. doi:10.1158/1538-7445.AM2015-1266
Abstract 1267: The senescence-associated secretory phenotype requires the histone variant macroH2A1 and is antagonized by ATM in a novel ER stress response
Authors: Chen Hongshan , Ruiz Penelope D. , McKimpson Wendy , Novikov Leonid , Kitsis Richard N. , Gamble Matthew J. 
Published: August 2015

Abstract
Oncogene induced senescence (OIS) is an important tumor suppressive mechanism typified by permanent proliferative arrest, a persistent DNA damage response and the senescent-associated secretory phenotype (SASP). MacroH2A1, a histone variant that plays tumor suppressive roles in a several cancer types is upregulated during OIS. Our ChIP-seq data demonstrate that SASP genes are found in macroH2A1-containing chromatin. Additionally, we found that macroH2A1 is a critical positive regulator of both the transcriptional upregulation of SASP genes and the persistent ATM activation seen during senescence. SASP factors participate in a positive feedback loop to maintain senescence through autocrine signaling and can also induce paracrine senescence in bystander cells. Strikingly, we find that cells depleted of macroH2A1 are immune to paracrine senescence triggered by SASP factors, indicating that macroH2A1 is a critical regulator of SASP positive feedback. Additionally, ectopic expression of macroH2A1.1, the macroH2A1 splice variant that is typically lost in cancer cells, is sufficient to trigger senescence in normal cells complete with a robust SASP response and persistent activation of ATM.
Due to the increased expression of secreted factors, endoplasmic reticulum (ER) stress is a feature of OIS. ER stress has been shown to lead to the generation of reactive oxygen species which can cause DNA damage and ATM activation. We determined that ER stress, as assayed by the activation of the unfolded protein response, is reduced during OIS in cells depleted of macroH2A1. Furthermore, activated ATM participates in a novel negative feedback loop reducing SASP expression in response to ER stress by triggering the removal of macroH2A1 from SASP genes. Overall, our results demonstrate that SASP gene expression is regulated by the combined actions of a positive feedback loop that requires macroH2A1 and a negative feedback loop where ER stress leads to ATM activation critical for the removal of macroH2A1 from SASP genes and consequently their repression.
Citation Format: Hongshan Chen, Penelope D. Ruiz, Wendy McKimpson, Leonid Novikov, Richard N. Kitsis, Matthew J. Gamble. The senescence-associated secretory phenotype requires the histone variant macroH2A1 and is antagonized by ATM in a novel ER stress response. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1267. doi:10.1158/1538-7445.AM2015-1267
Abstract 1285: Production of interleukin-17 is increased in patients with gastrointestinal cancer and correlates with immune suppression involving MDSC, nutritional impairment, and poor prognosis
Authors: Shibata Masahiko , Gonda Kenji , Nakajima Takahiro , Ohki Shinji , Nakamura Izumi , Shimura Tatsuo , Kono Koji , Takenoshita Seiichi 
Published: August 2015

Abstract
Although a causal relationship between inflammation and innate immunity of cancer is more widely accepted today, many of the precise cellular mechanisms mediating this relationship remain unclear. Th17 cells, which produce the proinflammatory cytokine IL-17, have been recognized as one of the key factors in regulation of inflammatory bowel disease and rheumatoid arthritis. IL-17 also has recently been reported to play an important role in induction of MDSC (myeloid-derived suppressor cells). This study demonstrated that, in patients with gastric and colorectal cancers, IL-17 production was correlated with MDSC level and with markers for nutritional impairment, immune suppression and chronic inflammation. IL-17 was significantly higher in patients with gastrointestinal cancer than in normal volunteers. In addition, IL-17 levels were significantly correlated with neutrophil counts and the neutrophil/lymphocyte ratio, and significantly inversely correlated with cell mediated immune response indicators (lymphocyte PHA-blastogenesis and IL-12 induction) and patients’ nutritional status (prealbumin levels). These patients were separated into two groups with the production of IL-17 and the overall survival of the patients with higher production of IL-17 was significantly worse than those with lower production of it. These results suggest that, in human gastrointestinal cancers, chronic inflammation involving IL-17 may be an important mechanism for disease progression through enhancement of induction of MDSC resulting immune suppression, or cachexia. The production of IL-17 was also demonstrated as one of the effective prognostic indicators in these patients. Controlling activation of Th17 cells may prove to be a valuable strategy for treatment of patients with gastrointestinal cancer. Further studies are warranted to explore this possibility.
Citation Format: Masahiko Shibata, Kenji Gonda, Takahiro Nakajima, Shinji Ohki, Izumi Nakamura, Tatsuo Shimura, Koji Kono, Seiichi Takenoshita. Production of interleukin-17 is increased in patients with gastrointestinal cancer and correlates with immune suppression involving MDSC, nutritional impairment, and poor prognosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1285. doi:10.1158/1538-7445.AM2015-1285