Mitochondrial complex I promotes kidney cancer metastasis.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Bezwada Divya, Perelli Luigi, Lesner Nicholas P, Cai Ling, Brooks Bailey, Wu Zheng, Vu Hieu S, Sondhi Varun, Cassidy Daniel L, Kasitinon Stacy, Kelekar Sherwin, Cai Feng, Aurora Arin B, Patrick McKenzie, Leach Ashley, Ghandour Rashed, Zhang Yuanyuan, Do Duyen, McDaniel Phyllis, Sudderth Jessica, Dumesnil Dennis, House Sara, Rosales Tracy, Poole Alan M, Lotan Yair, Woldu Solomon, Bagrodia Aditya, Meng Xiaosong, Cadeddu Jeffrey A, Mishra Prashant, Garcia-Bermudez Javier, Pedrosa Ivan, Kapur Payal, Courtney Kevin D, Malloy Craig R, Genovese Giannicola, Margulis Vitaly, DeBerardinis Ralph J
Аннотация
Most kidney cancers are metabolically dysfunctional1-4, but how this dysfunction affects cancer progression in humans is unknown. We infused 13C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-13C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-13C]acetate and [U-13C]glutamine infusions in patients, coupled with measurements of respiration in isolated human kidney and tumour mitochondria, reveal lower electron transport chain activity in ccRCCs that contributes to decreased oxidative and enhanced reductive TCA cycle labelling. However, ccRCC metastases unexpectedly have enhanced TCA cycle labelling compared with that of primary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufficient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These findings in humans and mice indicate that metabolic properties and liabilities evolve during kidney cancer progression, and that mitochondrial function is limiting for metastasis but not growth at the original site.