Liu Yuan-Rong, Song Dan-Dan, Liang Dong-Min, Li You-Jie, Yan Yun-Fei, Sun Hong-Fang, Zhang Mei-Ling, Hu Jin-Xia, Zhao Yu-Long, Liang Yan, Li Yan-Mei, Yang Zhen, Wang Ran-Ran, Zheng Hou-Feng, Wang Pingyu, Xie Shu-Yang
Department of Biochemistry and Molecular Biology, Binzhou Medical University, 264003, YanTai, Shandong, PR China.
Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, 266071, QingDao, Shandong, PR China.
Cell Death Discov. 2022 Jul 5;8(1):306. doi: 10.1038/s41420-022-01095-1.
PKM2 is an important regulator of the aerobic glycolysis that plays a vital role in cancer cell metabolic reprogramming. In general, Trib2 is considered as a "pseudokinase", contributing to different kinds of cancer. However, the detailed roles of TRIB2 in regulating cancer metabolism by PKM2 remain unclear. This study demonstrated that TRIB2, not a "pseudokinase", has the kinase activity to directly phosphorylate PKM2 at serine 37 in cancer cells. The elevated pSer37-PKM2 would subsequently promote the PKM2 dimers to enter into nucleus and increase the expression of LDHA, GLUT1, and PTBP1. The aerobic glycolysis is then elevated to promote cancer cell proliferation and migration in TRIB2- or PKM2-overexpressed cultures. The glucose uptake and lactate production increased, but the ATP content decreased in TRIB2- or PKM2-treated cultures. Experiments of TRIB2 mice further supported that TRIB2 could regulate aerobic glycolysis by PKM2. Thus, these results reveal the new kinase activity of TRIB2 and its mechanism in cancer metabolism may be related to regulating PKM2 to promote lung cancer cell proliferation in vitro and in vivo, suggesting promising therapeutic targets for cancer therapy by controlling cancer metabolism.
丙酮酸激酶M2（PKM2）是有氧糖酵解的重要调节因子，在癌细胞代谢重编程中发挥着至关重要的作用。一般来说，TRIB2被认为是一种“假激酶”，与多种癌症有关。然而，TRIB2通过PKM2调节癌症代谢的具体作用仍不清楚。本研究表明，TRIB2并非“假激酶”，而是具有激酶活性，能够在癌细胞中直接将PKM2的丝氨酸37位点磷酸化。磷酸化的丝氨酸37-PKM2水平升高会促使PKM2二聚体进入细胞核，并增加乳酸脱氢酶A（LDHA）、葡萄糖转运蛋白1（GLUT1）和多聚嘧啶结合蛋白1（PTBP1）的表达。随后，有氧糖酵解增强，从而促进TRIB2或PKM2过表达培养物中的癌细胞增殖和迁移。在TRIB2或PKM2处理的培养物中，葡萄糖摄取和乳酸生成增加，但ATP含量降低。对TRIB2基因敲除小鼠的实验进一步证实，TRIB2可通过PKM2调节有氧糖酵解。因此，这些结果揭示了TRIB2的新激酶活性，其在癌症代谢中的机制可能与通过调节PKM2促进肺癌细胞在体内外的增殖有关，这为通过控制癌症代谢进行癌症治疗提供了有前景的治疗靶点。
