TRPM7 silencing modulates glucose metabolic reprogramming to inhibit the growth of ovarian cancer by enhancing AMPK activation to promote HIF-1alpha degradation #MMPMID35101076
Chen Y; Liu L; Xia L; Wu N; Wang Y; Li H; Chen X; Zhang X; Liu Z; Zhu M; Liao Q; Wang J
J Exp Clin Cancer Res 2022[Jan]; 41 (1): 44 PMID35101076show ga
BACKGROUND: Tumor cell metabolic reprogramming is crucial for the malignant behavior of cancer cells by promoting their proliferation. However, little is known on how transient receptor potential 7 (TRPM7) modulates metabolic reprogramming in ovarian cancer. 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 IDH3B and UQCRC1, HIF-1alpha expression and AMPK phosphorylation were determined in ovarian cancer. The effect of AMPK activity on HIF-1alpha ubiquitination degradation was investigated in ovarian cancer cells. RESULTS: Compared with the control, TRPM7 silencing suppressed the proliferation of ovarian cancer cells by shifting preferable glycolysis to OXPHOS. In parallel, TRPM7 silencing decreased the glucose uptake of tumor-bearing mice and TRPM7 levels were negatively correlated with IDH3B and UQCRC1, but positively with HK2 and PDK1 expression in ovarian cancer tissues. Mechanistically, TRPM7 silencing significantly increased AMPK phosphorylation and decreased HIF-1alpha protein levels in ovarian cancer, particularly in HIF-1alpha silencing cells. The shifting from glycolysis to OXPHOS by TRPM7 silencing was abrogated by HIF-1alpha over-expression and impaired by inhibiting AMPK activity in ovarian cancer cells. Moreover, enhanced AMPK activation inhibited glycolysis, which was abrogated by HIF-1alpha over-expression in ovarian cancer cells. Moreover, the enhanced AMPK activation promoted HIF-1alpha ubiquitination degradation. CONCLUSIONS: TRPM7 silencing enhanced AMPK activation to shift glycolysis to oxidative phosphorylation by promoting HIF-1alpha ubiquitination degradation in ovarian cancer. Hence, TRPM7 may be a therapeutic target for intervention of ovarian cancer.
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J+Exp+Clin+Cancer+Res 2022 ; 41 (1): 44
