Abstract 3673: Plk1 phosphorylation of PHGDH to regulate serine metabolism

Abstract Polo-like kinase 1 (Plk1) has been reported to be highly expressed in most tumors, especially in advanced tumors, while how Plk1 elevation benefits tumor growth remains elusive. Metabolic reprogramming is one of the hallmarks of cancer, but how the tumors fully take advantage of deregulated metabolism is an enigma. Here, we found that Plk1 could divert serine metabolism from de novo synthesis to exogenous uptake by regulating PHGDH (phosphoglycerate dehydrogenase), the first rate-limiting enzyme of de novo serine biosynthesis. We show that PHGDH is phosphorylated by Plk1 at a cluster site (S512, S513, S517) and that Plk1-associated phosphorylation of PHGDH results in its protein degradation, thus reduced de novo serine biosynthesis. As a compensatory response, cells with an elevated level of Plk1 significantly increase the uptake of serine to produce more sphingosines, which are pivotal metabolites for the growth of cancer cells. Our finding may provide guidance on how to target de novo biosynthesis of serine, serine uptake or sphingosine metabolism to treat advanced prostate cancer. Citation Format: Xiongjian Rao, Derek B. Allison, Robert M. Flight, Yuanyuan Wu, Timothy Scott, Daheng He, RuiXing Wang, Zhiguo Li, Chaohao Li, Yifan Kong, Fengyi Mao, Chi Wang, Richard M. Higashi, Andrew N. Lane, Hunter NB Moseley, Xiaoqi Liu. Plk1 phosphorylation of PHGDH to regulate serine metabolism. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3673.