Chen Jiaqing, Zou Li, Lu Guang, Grinchuk Oleg, Fang Lei, Ong Derrick Sek Tong, Taneja Reshma, Ong Choon-Nam, Shen Han-Ming
NUS Graduate School Integrative Sciences and Engineering Programme (ISEP), National University of Singapore, Singapore, Singapore.
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Cell Discov. 2022 May 31;8(1):52. doi: 10.1038/s41421-022-00406-1.
Cancer cells adopt metabolic reprogramming to promote cell survival under metabolic stress. A key regulator of cell metabolism is AMP-activated protein kinase (AMPK) which promotes catabolism while suppresses anabolism. However, the underlying mechanism of AMPK in handling metabolic stress in cancer remains to be fully understood. In this study, by performing a proteomics screening of AMPK-interacting proteins in non-small-cell lung cancer (NSCLC) cells, we discovered the platelet isoform of phosphofructokinase 1 (PFKP), a rate-limiting enzyme in glycolysis. Moreover, PFKP was found to be highly expressed in NSCLC patients associated with poor survival. We demonstrated that the interaction of PFKP and AMPK was greatly enhanced upon glucose starvation, a process regulated by PFKP-associated metabolites. Notably, the PFKP-AMPK interaction promoted mitochondrial recruitment of AMPK which subsequently phosphorylated acetyl-CoA carboxylase 2 (ACC2) to enhance long-chain fatty acid oxidation, a process helping maintenance of the energy and redox homeostasis and eventually promoting cancer cell survival under glucose starvation. Collectively, we revealed a critical non-glycolysis-related function of PFKP in regulating long-chain fatty acid oxidation via AMPK to alleviate glucose starvation-induced metabolic stress in NSCLC cells.
癌细胞通过代谢重编程在代谢应激下促进细胞存活。细胞代谢的关键调节因子是AMP激活的蛋白激酶（AMPK），它促进分解代谢而抑制合成代谢。然而，AMPK在处理癌症代谢应激中的潜在机制仍有待充分了解。在本研究中，通过对非小细胞肺癌（NSCLC）细胞中与AMPK相互作用的蛋白质进行蛋白质组学筛选，我们发现了磷酸果糖激酶1（PFKP）的血小板异构体，它是糖酵解中的限速酶。此外，发现PFKP在生存不良的NSCLC患者中高表达。我们证明，在葡萄糖饥饿时，PFKP与AMPK的相互作用大大增强，这一过程受PFKP相关代谢物调节。值得注意的是，PFKP-AMPK相互作用促进了AMPK向线粒体的募集，随后AMPK磷酸化乙酰辅酶A羧化酶2（ACC2）以增强长链脂肪酸氧化，这一过程有助于维持能量和氧化还原稳态，并最终促进癌细胞在葡萄糖饥饿下的存活。总的来说，我们揭示了PFKP在通过AMPK调节长链脂肪酸氧化以减轻NSCLC细胞中葡萄糖饥饿诱导的代谢应激方面的关键非糖酵解相关功能。
