文献类型：期刊文献

英文题名：PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy

作者：Dou, Xuefeng[1];Fu, Qiang[2];Long, Qilai[3];Liu, Shuning[4];Zou, Yejun[4,5];Fu, Da[6];Xu, Qixia[1];Jiang, Zhirui[1];Ren, Xiaohui[1];Zhang, Guilong[2,7];Wei, Xiaoling[8,9];Li, Qingfeng[10];Campisi, Judith[11,12];Zhao, Yuzheng[4,5];Sun, Yu[1,2,13,14]

机构：[1]Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Nutr & Hlth, Key Lab Tissue Microenvironm & Tumour, Shanghai, Peoples R China;[2]Binzhou Med Univ, Inst Aging Med, Dept Pharmacol, Yantai, Peoples R China;[3]Fudan Univ, Zhongshan Hosp, Dept Urol, Shanghai, Peoples R China;[4]East China Univ Sci & Technol, Optogenet & Synthet Biol Interdisciplinary Res Ctr, Shanghai Frontiers Sci Ctr Optogenet Tech Cell Met, Sch Pharm,State Key Lab Bioreactor Engn, Shanghai, Peoples R China;[5]Chinese Acad Med Sci, Res Unit New Tech Live Cell Metab Imaging, Beijing, Peoples R China;[6]Shanghai Jiao Tong Univ, Ruijin Hosp, Pancreat Dis Inst, Sch Med,Dept Gen Surg, Shanghai, Peoples R China;[7]Binzhou Med Univ, Shandong Technol Innovat Ctr Mol Targeting & Intel, Dept Pharmacol, Yantai, Peoples R China;[8]Fudan Univ, Shanghai Stomatol Hosp & Sch Stomatol, Dept Endodont, Shanghai, Peoples R China;[9]Fudan Univ, Shanghai Key Lab Craniomaxillofacial Dev & Dis, Shanghai, Peoples R China;[10]Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Sch Med, Dept Plast & Reconstruct Surg, Shanghai, Peoples R China;[11]Buck Inst Res Aging, Novato, CA USA;[12]Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA USA;[13]Univ Washington, Dept Med, Seattle, WA 98195 USA;[14]Univ Washington, VAPSHCS, Seattle, WA 98195 USA

年份：2023

卷号：5

期号：11

外文期刊名：NATURE METABOLISM

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001089767800001)】；

基金：We are grateful to the members of Sun laboratory for reagents, comments and other contributions to this project. We thank Y. Tao for thoughtful discussion of the metabolic datasets. The work was supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB39010500) to Y.S.; National Key Research and Development Program of China (2020YFC2002800 to Y.S.; 2019YFA0904800 to Y. Zhao), National Natural Science Foundation of China (31871380, 82130045 and 82350710221 to Y.S.; 32150030, 32030065, 32121005 and 92049304 to Y. Zhao; 81370730 and 81571512 to Q.F.; and 22007006 to G.Z.); the Shanghai Municipal Science and Technology Commission Excellent Academic Leader Program (20XD1404300) to Y.S.; the Taishan Scholar Project of Shandong Province to Y.S. (tstp20230634); the Anti-Ageing Collaborative Program of SIBS and BY-HEALTH (C01201911260006, C01202112160005, C01202210146923) to Y.S.; the University and Locality Collaborative Development Program of Yantai (2019XDRHXMRC08, 2020XDRHXMXK02 to Y.S.; 2021XDHZ082 to Q.F.); the Natural Science Foundation of Shandong Province Joint Fund Program (ZR202108130049, ZR2021LSW021) to Y.S.; the US DoD PCRP (Idea Development Award PC111703) to Y.S.; the Research Unit of New Techniques for Live-cell Metabolic Imaging (Chinese Academy of Medical Sciences, 2019-I2M-5-013 to Y. Zhao), the innovative research team of high-level local universities in Shanghai (Y. Zhao); the Yantai Double Hundred Program to Q.F.; the Taishan Scholar Project of Shandong Province (tsqn201909144), and the Special Project of the Central Government for Local Science and Technology Development of Shandong Province (YDZX20203700001291) to G.Z.

语种：英文

摘要：Senescent cells remain metabolically active, but their metabolic landscape and resulting implications remain underexplored. Here, we report upregulation of pyruvate dehydrogenase kinase 4 (PDK4) upon senescence, particularly in some stromal cell lines. Senescent cells display a PDK4-dependent increase in aerobic glycolysis and enhanced lactate production but maintain mitochondrial respiration and redox activity, thus adopting a special form of metabolic reprogramming. Medium from PDK4+ stromal cells promotes the malignancy of recipient cancer cells in vitro, whereas inhibition of PDK4 causes tumor regression in vivo. We find that lactate promotes reactive oxygen species production via NOX1 to drive the senescence-associated secretory phenotype, whereas PDK4 suppression reduces DNA damage severity and restrains the senescence-associated secretory phenotype. In preclinical trials, PDK4 inhibition alleviates physical dysfunction and prevents age-associated frailty. Together, our study confirms the hypercatabolic nature of senescent cells and reveals a metabolic link between cellular senescence, lactate production, and possibly, age-related pathologies, including but not limited to cancer. PDK4-dependent lactate production by senescent stromal cells is shown to promote cancer growth and drug resistance and might have a broader role in the emergence of age-associated diseases.