Targeting Glutaminolysis Reverse Cis-platinum Resistance And M-TOR Inhibitor Resistance In Epithelial Ovarian Cancer And The Mechanism

BackgroudEpithelial ovarian cancer is the commonest cause of gynaecological cancer-associated death. Due to the absence of reliable screening tests for asymptomatic early-stage diagnosis, the fact that nearly 75% of the patients were present with advanced (stage III or IV) disease at the time of diagnosis. The standard of care remains surgery and platinum-based cytotoxic chemotherapy. Although more than 80% of these women benefit from first-line therapy, tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis. The 5-year survival rate remains approximately 40% only. At present, no major breakthrough in solving the tumors develop chemoresistance, especially the treatment of recurrent ovarian cancer. It becomes a major dilemma faced by the clinical obstetrics and gynecology doctors. Therefore, there is an urgent need to explore mechanisms of chemoresistance of ovarian cancer and develop an alternative way to rapidly reverse chemoresistance in clinical treatment of EOC. Conventional Warburg effect and emerging concepts is that cancer cells depend on anaerobic glycolysis for transformation and proliferation, regardless of the available oxygen level. Emerging evidence shows that metabolic reprogramming is considered a hallmark of cancer. In addition to the dependency on glycolysis, cancer cells have other atypical metabolic characteristics such as increased fatty acid synthesis,reverse Warburg effect and truncation of the Krebs cycle and increased rates of glutamine metabolism,support cell growth and proliferation. Cancer cells reprogram their metabolism by disruptive metabolic adjustment in order to satisfy their bioenergetic and biosynthetic requirements. Activation of oncogenes and loss of tumour suppressors selectively activated or"closed "specific metabolic pathways, change the flow of nutrients in the different biochemical pathways and flow, resulting in enhanced nutrient uptake to supply energetic and biosynthetic pathways to satisfy the unlimited proliferation of malignant biological behavior of tumor cells. Dysregulated glutaminolysis occurs at very high rates in cancer cell. The increased glutaminolysis is caused by multiple mechanisms, including activation of oncogenes and loss of tumour suppressors, which induced the elevated-expression of metabolic key enzymes, activated the glutamine metabolic pathways. Thus, understand the mechanisms of metabolic enzymes in relative to glutaminolysis participate in ovarian cancer progression and drug resistant, so as to develop novel therapeutic molecular targets of metabolism to manage ovarian cancer. GLS is the key metabolic enzymes of glutaminolysis, which is highly expression in eukeia?bladder and breast tumors. It has become an attractive target for the therapeutic intervention of malignant. However, the role of GLS in ovarian cancer has not to be reported.In this study, we identify associations with glutamine metabolism and drug resistance in EOC. We hypothesize glutamine may lead to drug resistance in EOC. To further explore the therapeutic effect and the potential mechanism of GLS inhibition reversed drug resistance of cisplatin and m-TOR inhibitor for ovarian cancer treatment, the effect of GLS gene silencing on biological behavior of ovarian cancer cells were assessed. It was expected to provide a new target for targeting dysregulated metabolic enzymes to reverse the drug resistance in ovarian cancer treatment.