Anticancer Strategy Targeting Mitochondrial Biogenesis in Ovarian Cancer

Abstract

IntroductionOvarian cancer is the most lethal gynecologic malignancy worldwide typically in the post-menopausal women and 5 th leading cause of death in the United States [1][2][3]. About 80% of women are diagnosed at the advanced-stage of disease and have poor prognosis. The 5-year overall survival rate is 45% or below [4][5][6]. Despite the first complete response after the front-line platinum-based chemotherapeutic drugs [7,8], approximately 25% patients suffer from relapse within 6 months who are thought, by definition, to have a chemoresistance [9][10][11][12]. Combination of platinum and other drugs might improve the survival rate [13], but is not out of the danger of additive toxicity [14].Several genetic alterations have been observed in ovarian cancer, involving deactivation mutations in tumor suppressor genes, such as p53, BRCA1 and BRCA2, and activation mutation and/or amplification of proto-oncogenes, like c-MYC, KRAS and AKT [15]. Recent genomic analysis of The Cancer Genome Atlas reported mutations in p53 gene in 96% of 316 cases of high-grade ovarian serous carcinoma (HGOSC) [16]. Other important genetic changes affect phosphatidyinositol-3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) cascade. The mTOR plays a central role in energy metabolism, cell growth/division through macromolecular synthesis and is found to be activated in ovarian cancer [6], which indicates a close relationship between genetic alteration and energy metabolism. It was observed that hexokinase (HK) II, the rate limiting initial enzyme in glycolysis, is overexpressed in ovarian cancer [12]. The genetic alterations and subsequent metabolic remodeling have been found to be associated with the chemoresistance [17], such as association of rictor (mTORC2 component) with resistance to cisplatin [2]. Cisplatin-induced caspase activation causing PTEN cleavage has also been reported as a potential mechanism of chemoresistance in ovarian cancer [18].Mitochondria is a well-adapted endosymbiotic intracellular organelles, became efficient for energy production through-out the course of evolution [19]. They are critical for survival and proliferation of living organisms under aerobic conditions and produce ATP through oxidative phosphorylation (OXPHOS) [20]. Beyond the conventional function they have crucial role in certain neurodegenerative diseases and cancer [21][22][23]. Cellular proliferation largely depends on mitochondrial amount, governed by the process of MtBIO [20]. MtBIO is the production of daughter mitochondria usually from previously existed one through a division process of called fission, subsequent growth, and maintenance by fusion and autophagy of mitochondria (mitophagy) [24]. Currently it has been observed that MtBIO is associated with cancer chemoresistance [25,26] through the modulation of associated proteins such as methylation-controlled J-protein (MCJ, also known as DNAJC15) [25,27], prohibitin 1 (PHB-1) [28][29][30], myeloid cell leukemia sequence 1 (MCL-1) [31,32] etc. in ovarian cancer. Thus it can be s...

Sirtuin 3 silencing impairs mitochondrial biogenesis and metabolism in colon cancer cells

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Conformational profile, vibrational assignments, NLO properties and molecular docking of biologically active herbicide1,1-dimethyl-3-phenylurea

“…The importance of mitochondria as potential targets in cancer cells stems from the fact that they are a pool of proteins that promote the apoptotic death when mobilized into the cytosol [41, 42]. Mitochondrial biogenesis (MtBIO) is to be involved in chemo resistance, the foremost obstacle in the treatment of patients with ovarian cancer [43]. Thus mitochondrial ubiquinol-cytochrome-c reductase is chosen as target for docking study.…”