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, Changsha, 410013, Hunan, China.
University of South China, Hengyang, 421001, Hunan, China.
J Exp Clin Cancer Res. 2022 Jan 31;41(1):44. doi: 10.1186/s13046-022-02252-1.
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.
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-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.
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-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.
TRPM7 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.
肿瘤细胞代谢重编程对于促进癌细胞增殖至关重要。然而，TRPM7 如何调节卵巢癌细胞代谢重编程知之甚少。
研究了 TRPM7 沉默对卵巢癌细胞转录组谱、葡萄糖摄取、乳酸生成、细胞外酸化率（ECAR）、耗氧率（OCR）、细胞内 ROS 和 ATP 水平以及 NAD+/NADH 比值的影响。检测了 TRPM7 沉默对卵巢癌细胞中糖酵解相关 HK2、PDK1 和氧化磷酸化（OXPHOS）相关 IDH3B 和 UQCRC1、HIF-1α表达和 AMPK 磷酸化水平的影响。在卵巢癌细胞中研究了 AMPK 活性对 HIF-1α泛素化降解的影响。
与对照组相比，TRPM7 沉默通过将偏好的糖酵解转移到 OXPHOS 来抑制卵巢癌细胞的增殖。平行地，TRPM7 沉默降低了荷瘤小鼠的葡萄糖摄取，TRPM7 水平与卵巢癌组织中的 IDH3B 和 UQCRC1 呈负相关，但与 HK2 和 PDK1 表达呈正相关。在机制上，TRPM7 沉默显著增加了卵巢癌细胞中 AMPK 的磷酸化，降低了 HIF-1α 蛋白水平，尤其是在 HIF-1α 沉默的细胞中。TRPM7 沉默通过增加 AMPK 活性和抑制卵巢癌细胞中的 AMPK 活性来减弱从糖酵解到 OXPHOS 的转变。此外，增强的 AMPK 激活抑制了糖酵解，这在卵巢癌细胞中被 HIF-1α 过表达所阻断。此外，增强的 AMPK 激活促进了 HIF-1α 的泛素化降解。
TRPM7 沉默通过促进 HIF-1α 泛素化降解来增强 AMPK 激活，从而将糖酵解转移到氧化磷酸化，在卵巢癌中。因此，TRPM7 可能是干预卵巢癌的治疗靶点。
