Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Development, Bethesda, Maryland, USA.
Cancer Cell. 2011 Sep 13;20(3):315-27. doi: 10.1016/j.ccr.2011.07.018.
Inactivation of the TCA cycle enzyme, fumarate hydratase (FH), drives a metabolic shift to aerobic glycolysis in FH-deficient kidney tumors and cell lines from patients with hereditary leiomyomatosis renal cell cancer (HLRCC), resulting in decreased levels of AMP-activated kinase (AMPK) and p53 tumor suppressor, and activation of the anabolic factors, acetyl-CoA carboxylase and ribosomal protein S6. Reduced AMPK levels lead to diminished expression of the DMT1 iron transporter, and the resulting cytosolic iron deficiency activates the iron regulatory proteins, IRP1 and IRP2, and increases expression of the hypoxia inducible factor HIF-1α, but not HIF-2α. Silencing of HIF-1α or activation of AMPK diminishes invasive activities, indicating that alterations of HIF-1α and AMPK contribute to the oncogenic growth of FH-deficient cells.
三羧酸循环酶琥珀酸水合酶（FH）失活会促使 FH 缺陷型肾肿瘤和遗传性平滑肌瘤性肾细胞癌（HLRCC）患者的细胞系发生有氧糖酵解代谢转变，导致 AMP 激活的蛋白激酶（AMPK）和抑癌蛋白 p53 水平降低，合成代谢因子乙酰辅酶 A 羧化酶和核糖体蛋白 S6 被激活。AMPK 水平降低会导致二价金属离子转运蛋白 1（DMT1）的表达减少，由此导致的细胞溶质铁缺乏会激活铁调节蛋白 1（IRP1）和铁调节蛋白 2（IRP2），增加低氧诱导因子 HIF-1α的表达，但不增加 HIF-2α的表达。沉默 HIF-1α 或激活 AMPK 会减弱侵袭活性，表明 HIF-1α 和 AMPK 的改变有助于 FH 缺陷型细胞的致癌生长。
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