TRPM7 Regulates Glucose Metabolism Reprogramming Through AMPK/HIF-1α Pathway To Promote Ovarian Cancer Cell Proliferation

Objective: Based on the previous research,this project explores the effect of TRPM7 on the metabolic reprogramming of ovarian cancer cells and its potential molecular mechanism.Methods: The effects of TRPM7 silencing on transcriptome profile,glucose uptake,lactic acid production,extracellular acidification rate(ECAR),oxygen consumption rate(OCR),intracellular ROS and ATP levels,and NAD+/NADH ratios in ovarian cancer cells were examined.The impacts of TRPM7 silencing on the levels of glycolysis-related HK2,PDK1 and oxidative phosphorylation(OXPHOS)-related IDH3 B and UQCRC2,HIF-1α expression and AMPK phosphorylation were determined in ovarian cancer.The effect of AMPK activity on HIF-1α ubiquitination degradation was investigated in ovarian cancer cells.Results: 1.Silencing TRPM7 can inhibit the proliferation of ovarian cancer cells and promote their apoptosis.2.Silencing TRPM7 can inhibit the glucose uptake rate,extracellular lactate production and ECAR of ovarian cancer cells,and can promote OCR,ROS levels,ATP levels and NAD + / NADH ratio oxidative phosphorylation in cancer cells.3.Silencing TRPM7 can inhibit glucose uptake of ovarian cancer cells in nude mice.4.Silencing TRPM7 can promote the expression of oxidative phosphorylation markers IDH3 B and UQCRC2 in ovarian cancer,and inhibit the expression of glycolysis markers HK2 and PDK1.5.TRPM7 silencing can promote the phosphorylation of AMPK in ovarian cancer cells and inhibit the nuclear displacement of PKM2 and the expression of HIF-1α.6.Activating AMPK can inhibit glycolysis of ovarian cancer cells,and overexpression of HIF-1α can reverse the inhibitory effect of AMPK.7.Silencing TRPM7 can activate AMPK-mediated oxidative phosphorylation and inhibit HIF-1α-mediated glycolysis.8.Silencing TRPM7 can inhibit HIF-1α by activating AMPK to alter glycolysis and oxidative phosphorylation of ovarian cancer.9.Silencing TRPM7 can promote the degradation of HIF-1α ubiquitination by activating AMPK phosphorylation.Conclusions: TRPM7 silencing enhanced AMPK activation to shift glycolysis to oxidative phosphorylation by promoting HIF-1αubiquitination degradation in ovarian cancer.Hence,TRPM7 may be a therapeutic target for intervention of ovarian cancer.