TRPM7 silencing modulates glucose metabolic reprogramming to inhibit the growth of ovarian cancer by enhancing AMPK activation to promote HIF-1α degradation

Journal of Experimental & Clinical Cancer Research

He Li¹  Nayiyuan Wu¹  Jing Wang¹  Xue Chen¹  Zhaoyi Liu¹  Longzheng Xia¹  Qianjin Liao¹  Xiaoye Zhang¹  Lu Liu¹  Ying Wang¹  Miaochen Zhu²  Yongchang Chen² 

[1] Hunan clinicaI research center in gynecologic cancer, Hunan Key Laboratory of Cancer Metabolism, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University and Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410013, Changsha, Hunan, China;Hunan clinicaI research center in gynecologic cancer, Hunan Key Laboratory of Cancer Metabolism, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University and Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410013, Changsha, Hunan, China;University of South China, 421001, Hengyang, Hunan, China;

关键词: TRPM7;    AMPK;    HIF-1α;    Glycolysis;    Oxidative phosphorylation;    Ubiquitination;    Ovarian cancer;   

DOI  :  10.1186/s13046-022-02252-1

来源: Springer

【 摘 要 】

BackgroundTumor 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.MethodsThe 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-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.ResultsCompared 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-1α protein levels in ovarian cancer, particularly in HIF-1α silencing cells. The shifting from glycolysis to OXPHOS by TRPM7 silencing was abrogated by HIF-1α over-expression and impaired by inhibiting AMPK activity in ovarian cancer cells. Moreover, enhanced AMPK activation inhibited glycolysis, which was abrogated by HIF-1α over-expression in ovarian cancer cells. Moreover, the enhanced AMPK activation promoted HIF-1α ubiquitination degradation.ConclusionsTRPM7 silencing enhanced AMPK activation to shift glycolysis to oxidative phosphorylation by promoting HIF-1α ubiquitination degradation in ovarian cancer. Hence, TRPM7 may be a therapeutic target for intervention of ovarian cancer.

【 授权许可】

CC BY