Protein kinase C epsilon promotes de novo lipogenesis and tumor growth in prostate cancer cells by regulating the phosphorylation and nuclear translocation of pyruvate kinase isoform M2

Xiaoju Lai; Yanling Liang; Jie Jin; Hanyun Zhang; Zhicong Wu; Guihuan Li; Jinxiang Wang; Zhishuai Zhang; Hua Chen; Fangyin Zeng; Fan Deng

doi:10.1016/j.yexcr.2022.113427

Protein kinase C epsilon promotes de novo lipogenesis and tumor growth in prostate cancer cells by regulating the phosphorylation and nuclear translocation of pyruvate kinase isoform M2

Exp Cell Res. 2023 Jan 1;422(1):113427. doi: 10.1016/j.yexcr.2022.113427. Epub 2022 Nov 15.

Authors

Xiaoju Lai¹, Yanling Liang², Jie Jin², Hanyun Zhang³, Zhicong Wu⁴, Guihuan Li¹, Jinxiang Wang¹, Zhishuai Zhang¹, Hua Chen¹, Fangyin Zeng⁵, Fan Deng⁶

Affiliations

¹ Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
² Department of Clinical Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou, 510900, China; Department of Clinical Laboratory, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, 510282, China.
³ Department of Clinical Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou, 510900, China; Department of Clinical Laboratory, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, 510282, China; Department of Blood Transfusion, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
⁴ Department of Clinical Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou, 510900, China.
⁵ Department of Clinical Laboratory, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, 510282, China.
⁶ Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: fandeng@smu.edu.cn.

PMID: 36400183
DOI: 10.1016/j.yexcr.2022.113427

Abstract

Protein kinase C epsilon (PKCε) belongs to a family of serine/threonine kinases that control cell proliferation, differentiation and survival. Aberrant PKCε activation and overexpression is a frequent feature of numerous cancers. However, its role in regulation of lipid metabolism in cancer cells remains elusive. Here we report a novel function of PKCε in regulating of prostate cancer cell proliferation by modulation of PKM2-mediated de novo lipogenesis. We show that PKCε promotes de novo lipogenesis and tumor cell proliferation via upregulation of lipogenic enzymes and lipid contents in prostate cancer cells. Mechanistically, PKCε interacts with NABD (1-388) domain of C-terminal deletion on pyruvate kinase isoform M2 (PKM2) and enhances the Tyr105 phosphorylation of PKM2, leading to its nuclear localization. Moreover, forced expression of mutant Tyr105 (Y105F) or PKM2 inhibition suppressed de novo lipogenesis and cell proliferation induced by overexpression of PKCε in prostate cancer cells. In a murine tumor model, inhibitor of PKM2 antagonizes lipogenic enzymes expression and prostate cancer growth induced by overexpression of PKCε in vivo. These data indicate that PKCε is a critical regulator of de novo lipogenesis, which may represent a potential therapeutic target for the treatment of prostate cancer.

Keywords: De novo lipogenesis; PKCε; PKM2; Prostate cancer; Tumor growth.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Humans
Lipogenesis / genetics
Male
Mice
Phosphorylation / physiology
Prostatic Neoplasms* / metabolism
Protein Isoforms / metabolism
Protein Kinase C-epsilon* / genetics
Protein Kinase C-epsilon* / metabolism
Pyruvate Kinase / genetics
Pyruvate Kinase / metabolism

Substances

Protein Isoforms
Protein Kinase C-epsilon
Pyruvate Kinase