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hypoxia ovarian cancer

Francesca Vena, Ruochen Jia, Arman Esfandiari, Juan J Garcia-Gomez, Manuel Rodriguez-Justo, Jianguo Ma, Sakeena Syed, Lindsey Crowley, Brian Elenbaas, Samantha Goodstal, John A Hartley, Daniel Hochhauser
Targeting the DNA damage response (DDR) in tumors with defective DNA repair is a clinically successful strategy. The RAS/RAF/MEK/ERK signalling pathway is frequently deregulated in human cancers. In this study, we explored the effects of MEK inhibition on the homologous recombination pathway and explored the potential for combination therapy of MEK inhibitors with DDR inhibitors and a hypoxia-activated prodrug. We studied effects of combining pimasertib, a selective allosteric inhibitor of MEK1/2, with olaparib, a small molecule inhibitor of poly (adenosine diphosphate [ADP]-ribose) polymerases (PARP), and with the hypoxia-activated prodrug evofosfamide in ovarian and pancreatic cancer cell lines...
February 20, 2018: Oncotarget
Maria Giebler, Martin S Staege, Sindy Blauschmidt, Lea I Ohm, Matthias Kraus, Peter Würl, Helge Taubert, Thomas Greither
A wide variety of endogenous retroviral sequences has been demonstrated in the human genome so far, divided into several different families according to the sequence homology to viral strains. While increased expression of human endogenous retrovirus (HERV) elements has already been linked to unfavorable prognosis in hepatocellular carcinoma, breast cancer, and ovarian carcinoma yet less is known about the impact of the expression of different HERV elements on sarcomagenesis in general as well as the outcome of soft tissue sarcoma (STS) patients...
2018: Frontiers in Microbiology
Ke Zhang, Xiangjun Kong, Guangde Feng, Wei Xiang, Long Chen, Fang Yang, Chunyu Cao, Yifei Ding, Hang Chen, Mingxing Chu, Pingqing Wang, Baoyun Zhang
BACKGROUND: Ovarian cancer is a leading cause of the death from gynecologic malignancies. Hypoxia is closely related to the malignant growth of cells. However, the molecular mechanism of hypoxia-regulated ovarian cancer cells remains unclear. Thus, this study was conducted to identify the key genes and pathways implicated in the regulation of hypoxia by bioinformatics analysis. METHODS: Using the datasets of GSE53012 downloaded from the Gene Expression Omnibus (GEO), the differentially expressed genes (DEGs) were screened by comparing the RNA expression from cycling hypoxia group, chronic hypoxia group, and control group...
February 26, 2018: Journal of Ovarian Research
Robert B Jones, Kaitlyn A Dorsett, Anita B Hjelmeland, Susan L Bellis
Aberrant cell surface glycosylation is prevalent in tumor cells, and there is ample evidence that glycans have functional roles in carcinogenesis. Nonetheless, many molecular details remain unclear. Tumor cells frequently exhibit increased α2-6 sialylation on N-glycans, a modification that is added by the ST6Gal-I sialyltransferase, and emerging evidence suggests that ST6Gal-I-mediated sialylation promotes the survival of tumor cells exposed to various cell stressors. Here we report that ST6Gal-I protects cancer cells from hypoxic stress...
February 23, 2018: Journal of Biological Chemistry
Ji Hee Ha, Rangasudhagar Radhakrishnan, Muralidharan Jayaraman, Mingda Yan, Jeremy D Ward, Kar-Ming Fung, Katherine M Moxley, Anil K Sood, Ciro Isidoro, Priyabrata Mukherjee, Yong Sang Song, Danny N Dhanasekaran
Although hypoxia has been shown to reprogram cancer cells toward glycolytic shift, the identity of extrinsic stimuli that induce metabolic reprogramming independent of hypoxia, especially in ovarian cancer, is largely unknown. In this study, we use patient-derived ovarian cancer cells and high-grade serous ovarian cancer cell lines to demonstrate that lysophosphatidic acid (LPA), a lipid growth factor and GPCR ligand whose levels are substantially increased in ovarian cancer patients, triggers glycolytic shift in ovarian cancer cells...
January 31, 2018: Cancer Research
Shojiro Kitajima, Kian Leong Lee, Hiroki Hikasa, Wendi Sun, Ruby Yun-Ju Huang, Henry Yang, Shinji Matsunaga, Takehiro Yamaguchi, Marito Araki, Hiroyuki Kato, Lorenz Poellinger
Ammonia is a toxic by-product of metabolism that causes cellular stresses. Although a number of proteins are involved in adaptive stress response, specific factors that counteract ammonia-induced cellular stress and regulate cell metabolism to survive against its toxicity have yet to be identified. We demonstrated that the hypoxia-inducible factor-1α (HIF-1α) is stabilized and activated by ammonia stress. HIF-1α activated by ammonium chloride compromises ammonia-induced apoptosis. Furthermore, we identified glutamine synthetase (GS) as a key driver of cancer cell proliferation under ammonia stress and glutamine-dependent metabolism in ovarian cancer stem-like cells expressing CD90...
December 29, 2017: Oncotarget
Yi Zhang, Lifeng Li, Liping Wang, Jieyao Li, Zhirui Fan, Li Yang, Zhen Zhang, Chaoqi Zhang, Dongli Yue, Guohui Qin, Tengfei Zhang, Feng Li, Xinfeng Chen, Yu Ping, Dan Wang, Qun Gao, Qianyi He, Lan Huang, Hong Li, Jianmin Huang, Xuan Zhao, Wenhua Xue, Zhi Sun, Jingli Lu, Jane Yu, Jie Zhao, Bin Zhang
Metformin is a broadlyprescribed drug for type 2 diabetes that exerts antitumor activity, yet the mechanisms underlying this activity remain unclear. We show here that metformin treatment blocks the suppressive function of myeloid-derived suppressor cells (MDSC) in patients with ovarian cancer (OC) by downregulating the expression and ectoenzymatic activity of CD39 and CD73 on monocytic and polymononuclear MDSC subsets. Metformin triggered activation of AMP-activated protein kinase α (AMPKα) and subsequently suppressed hypoxia-inducible factor-α (HIF-1α), which was critical for induction of CD39/CD73 expression in MDSC...
January 26, 2018: Cancer Research
Arseniy E Yuzhalin, Tomas Urbonas, Michael A Silva, Ruth J Muschel, Alex N Gordon-Weeks
BACKGROUND: Accumulating evidence implicates the tumour stroma as an important determinant of cancer progression but the protein constituents relevant for this effect are unknown. Here we utilised a bioinformatics approach to identify an extracellular matrix (ECM) gene signature overexpressed in multiple cancer types and strongly predictive of adverse outcome. METHODS: Gene expression levels in cancers were determined using Oncomine. Geneset enrichment analysis was performed using the Broad Institute desktop application...
January 23, 2018: British Journal of Cancer
Jennifer X Ji, Yi Kan Wang, Dawn R Cochrane, David G Huntsman
Clear cell ovarian carcinoma (CCOC) and clear cell renal cell carcinoma (ccRCC) both feature clear cytoplasm due to the accumulation of cytoplasmic glycogen. Genomic studies have demonstrated several mutational similarities between these two diseases including frequent alterations in the chromatin remodeling SWI/SNF and cellular proliferation PI3K/mTOR pathways, as well as a shared hypoxia-like mRNA expression signature. Although many targeted treatment options have been approved for advance stage ccRCC, CCOC patients are still treated with conventional platinum and taxane chemotherapy, to which they are resistant...
January 17, 2018: Journal of Pathology
Min Yong, Tinghe Yu, Si Tian, Shuaibin Liu, Jiao Xu, Jianguo Hu, Lina Hu
Dopamine receptor 2 (DR2) may be a biomarker for various types of cancer. Ovarian cancer cells overexpress DR2; therefore, blocking DR2 may be a novel treatment strategy for ovarian cancer. Thioridazine, a DR2 blocker, has antineoplastic activity in a variety of cancer cells. In view of the requirement for novel therapeutic agents in ovarian cancer, the present study aimed to determine the potential effects of thioridazine in vitro and in vivo. It was revealed that the DR2 blocker thioridazine induced cell death in a dose-dependent manner in ovarian cancer cells...
December 2017: Oncology Letters
Qinglong Guo, Lu Lu, Yan Liao, Xiaoping Wang, Yi Zhang, Yicheng Liu, Shaoliang Huang, Haopeng Sun, Zhiyu Li, Li Zhao
SRC family kinase was documented to have vital roles in adjusting cancer cell malignant behaviors. To date, the role of c-Src, a member of SRC family kinase, in resistance to paclitaxel in human ovarian cancer cells under hypoxia has not been investigated. In the present study, we discovered that hypoxic environment suppressed paclitaxel-induced G2/M phase arrest and blockade of c-Src improved ovarian cancer cells' sensitivity to paclitaxel. FV-429, a derivative of natural flavonoid wogonin, could suppress gene expression and activation of c-Src, followed by deteriorated Stat3 nuclear translocation and its binding to HIF-1α, resulting in paclitaxel resistance reversal through G2/M arrest potentiation...
January 11, 2018: Cell Death & Disease
Xue Feng, Ning Liu, Suo Deng, Dandan Zhang, Kexin Wang, Meisong Lu
Resistance to chemotherapy is a primary problem for the effective treatment of ovarian cancer. Recently, increasing evidence has demonstrated that miRNAs modulate many important molecular pathways involved in chemotherapy. Previous studies demonstrated that miR-199a affected ovarian cancer cell resistance to cisplatin (DDP). However, the role of miR-199a and its target genes in determination of ovarian cancer sensitivity to DDP remains unclear. Quantitative reverse transcription polymerase chain reaction was used to detect the expression levels of miR-199a in ovarian cancer tissues and C13* and OV2008 cell lines...
2017: OncoTargets and Therapy
Jengmin Kang, Seung-Hyun Shin, Haejin Yoon, June Huh, Hyun-Woo Shin, Yang-Sook Chun, Jong-Wan Park
The prolyl hydroxlyases PHD1-3 and the asparaginly hydroxlyase FIH are oxygen sensors for HIF-driven transcription of hypoxia-induced genes, but whether these sensors affect oxygen-dependent epigenetic regulation more broadly is not known. Here we show that FIH exerts an additional role as an oxygen sensor in epigenetic control by the histone lysine methyltransferases G9a and GLP. FIH hydroxylated and inhibited G9a and GLP under normoxia. When the FIH reaction was limited under hypoxia, G9a and GLP were activated and repressed metastasis suppressor genes, thereby triggering cancer cell migration and peritoneal dissemination of ovarian cancer xenografts...
December 19, 2017: Cancer Research
Debra L Richardson, Michael W Sill, Robert L Coleman, Anil K Sood, Michael L Pearl, Siobhan M Kehoe, Michael E Carney, Parviz Hanjani, Linda Van Le, Xun C Zhou, Angeles Alvarez Secord, Heidi J Gray, Lisa M Landrum, Heather A Lankes, Wei Hu, Carol Aghajanian
Importance: Ovarian cancer is the leading cause of gynecologic cancer deaths in the United States. Pazopanib is an oral, multitarget kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptors α and β; and proto-oncogene receptor tyrosine kinase (c-KIT). Objective: To estimate the progression-free survival (PFS) hazard ratio (HR) of weekly paclitaxel and pazopanib compared with weekly paclitaxel and placebo in women with recurrent ovarian cancer...
February 1, 2018: JAMA Oncology
Mara Fanelli, Alessia Camperchioli, Lella Petrella, Marco Petrillo, Cinzia Baranello, Pina Baccaro, Carmela Paolillo, Ettore Capoluongo, Giovanni Scambia
BACKGROUND: In this study we investigated the function of the non-catalytic region of tyrosine kinase adaptor protein 2 (NCK2) and its correlation with ITGB1 and ITGB4 integrins in driving ovarian cancer (OvCa) aggressiveness. We also evaluated whether NCK2 may influence prognosis in OvCa patients. METHODS: Nanofluidic technology was used to analyze expression of NCK2 in 332 OvCa patients. To evaluate mRNA expression of NCK2, integrins and VEGFA in OvCa cell lines, qRT-PCR was performed...
December 5, 2017: International Journal of Biological Markers
Courtney A Penn, Kun Yang, Hong Zong, Jae-Young Lim, Alex Cole, Dongli Yang, James Baker, Sascha N Goonewardena, Ronald J Buckanovich
Antiangiogenic therapies, despite initial encouragement, have demonstrated a limited benefit in ovarian cancer. Laboratory studies suggest antiangiogenic therapy-induced hypoxia can induce tumor "stemness" as resistance to antiangiogenic therapy develops and limits the therapeutic benefit. Resistance to antiangiogenic therapy and an induction of tumor stemness may be mediated by proangiogenic tumor-associated macrophages (TAM). As such, TAMs have been proposed as a therapeutic target. We demonstrate here that ovarian TAMs express high levels of the folate receptor-2 (FOLR2) and can be selectively targeted using G5-dendrimer nanoparticles using methotrexate as both a ligand and a toxin...
January 2018: Molecular Cancer Therapeutics
T Mitamura, S Pradeep, M McGuire, S Y Wu, S Ma, H Hatakeyama, Y A Lyons, T Hisamatsu, K Noh, A Villar-Prados, X Chen, C Ivan, C Rodriguez-Aguayo, W Hu, G Lopez-Berestein, R L Coleman, A K Sood
Anti-vascular endothelial growth factor (VEGF) therapy has demonstrated efficacy in treating human metastatic cancers, but therapeutic resistance is a practical limitation and most tumors eventually become unresponsive. To identify microenvironmental factors underlying the resistance of cancer to antiangiogenesis therapy, we conducted genomic analyses of intraperitoneal ovarian tumors in which adaptive resistance to anti-VEGF therapy (B20 antibody) developed. We found that expression of the microseminoprotein, prostate-associated (MSMP) gene was substantially upregulated in resistant compared with control tumors...
October 23, 2017: Oncogene
Hyo Jeong Yong, Jeong Su Park, Ae Lee Jeong, Sora Han, Sunyi Lee, Hye In Ka, Buyanravjkh Sumiyasuren, Hyun Jeong Joo, Su Jeong So, Ji Young Park, Do-Young Yoon, Jong-Seok Lim, Myeong-Seok Lee, Hee Gu Lee, Young Yang
Hypoxia-induced interleukin-32β (IL-32β) shifts the metabolic program to the enhanced glycolytic pathway. In the present study, the underlying mechanism by which hypoxia-induced IL-32β stability is regulated was investigated in ovarian cancer cells. IL-32β expression increased under hypoxic conditions in ovarian cancer cells as it did in breast cancer cells. The amount of IL-32β was regulated by post-translational control rather than by transcriptional activation. Under normoxic conditions, IL-32β was continuously eliminated through ubiquitin-dependent degradation by the von-Hippel Lindau (VHL) E3 ligase complex...
September 19, 2017: Oncotarget
Tingting Zheng, Yueqiong Ni, Jun Li, Billy K C Chow, Gianni Panagiotou
Background: A range of computational methods that rely on the analysis of genome-wide expression datasets have been developed and successfully used for drug repositioning. The success of these methods is based on the hypothesis that introducing a factor (in this case, a drug molecule) that could reverse the disease gene expression signature will lead to a therapeutic effect. However, it has also been shown that globally reversing the disease expression signature is not a prerequisite for drug activity. On the other hand, the basic idea of significant anti-correlation in expression profiles could have great value for establishing diet-disease associations and could provide new insights into the role of dietary interventions in disease...
2017: Frontiers in Physiology
Michael Conroy, Mitesh J Borad, Alan H Bryce
Breast cancer 1 antigen (BRCA 1) and breast cancer 2 antigen (BRCA2) genes play a significant role in deoxyribonucleic acid (DNA) repair by means of interstrand crosslink repair, and deleterious germline mutations of these are responsible for most hereditary breast and ovarian cancers. Therapeutic strategies which specifically target interstrand crosslink repair can therefore be helpful in patients with harmful mutations. We describe two patients with advanced ovarian cancer and deleterious BRCA1 mutations who were treated with TH-302, a hypoxia-activated alkylating agent...
July 26, 2017: Curēus
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