Dataset Information

A GSTP1-mediated lactic acid signaling promotes tumorigenesis through the PPP oxidative branch.

ABSTRACT: Lactic acidosis is a feature of solid tumors and plays fundamental role(s) rendering cancer cells to adapt to diverse metabolic stresses, but the mechanism underlying its roles in redox homeostasis remains elusive. Here we show that G6PD is phosphorylated at tyrosine 249/322 by the SRC through the formation of a GSTP1-G6PD-SRC complex. Lactic acid attenuates this formation and the phosphorylation of G6PD by non-covalently binding with GSTP1. Furthermore, lactic acid increases the activity of G6PD and facilitates the PPP (NADPH production) through its sensor GSTP1, thereby exhibiting resistance to reactive oxygen species when glucose is scarce. Abrogating a GSTP1-mediated lactic acid signaling showed attenuated tumor growth and reduced resistance to ROS in breast cancer cells. Importantly, positive correlations between immuno-enriched SRC protein and G6PD Y249/322 phosphorylation specifically manifest in ER/PR positive or HER negative types of breast cancer. Taken together, these results suggest that GSTP1 plays a key role in tumor development by functioning as a novel lactate sensor.

SUBMITTER: Sun Y

PROVIDER: S-EPMC10368634 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A GSTP1-mediated lactic acid signaling promotes tumorigenesis through the PPP oxidative branch.

Sun Yandi Y He Qian Q Li Jingjia J Yang Ze Z Ahmad Mashaal M Lin Yindan Y Wu Di D Zheng Lei L Li Jiangtao J Wang Ben B Chen Chitty C Hu Yue Y Luo Heng H Luo Yan Y

Cell death & disease 20230725 7

Lactic acidosis is a feature of solid tumors and plays fundamental role(s) rendering cancer cells to adapt to diverse metabolic stresses, but the mechanism underlying its roles in redox homeostasis remains elusive. Here we show that G6PD is phosphorylated at tyrosine 249/322 by the SRC through the formation of a GSTP1-G6PD-SRC complex. Lactic acid attenuates this formation and the phosphorylation of G6PD by non-covalently binding with GSTP1. Furthermore, lactic acid increases the activity of G6P ...[more]

PMID: 37491277

Similar Datasets

Project description:BackgroundRho guanine nucleotide exchange factor 10-like protein (ARHGEF10L) is a member of the guanine nucleotide exchange factor family, which regulates Rho GTPase activities, thus contributing to tumorigenesis. Our previous study demonstrated a strong association between the ARHGEF10L gene and the risk of cervical carcinoma. This study investigated the pathogenic role and mechanism of ARHGEF10L in cervical tumors.MethodsThe HeLa cell line, which was derived from cervical carcinoma, was transfected with ARHGEF10L-overexpressing plasmids or anti-ARHGEF10L siRNA. Cell counting kit-8 assays, wound-healing assays, and cell apoptosis assays were performed to investigate the effects of ARHGEF10L on cell activities. A Rho pull-down assay and RNA-sequencing analysis were performed to investigate the pathogenic pathway of ARHGEF10L involvement in cervical tumors.ResultsARHGEF10L overexpression promoted cell proliferation and migration, reduced cell apoptosis, and induced epithelial-to-mesenchymal transition (EMT) via downregulation of E-cadherin and upregulation of N-cadherin and Slug in transfected HeLa cells. The overexpression of ARHGEF10L also upregulated GTP-RhoA, ROCK1, and phospho-ezrin/radixin/moesin (ERM) expression in HeLa cells. RNA-sequencing analysis detected altered transcription of 31 genes in HeLa cells with ARHGEF10L overexpression. Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) pathway analyses identified significant differences in cyclin-dependent protein serine/threonine kinase activity, cell responses to vitamin A, and Toll-like receptor signaling pathways. Both real-time PCR and Western blotting verified the increased expression of heat shock 70 kDa protein 6 (HSPA6) in ARHGEF10L-overexpressing HeLa cells. Since we reported that ARHGEF10L played a role through RhoA-ROCK1-ERM signaling, an important pathway in tumorigenesis, and stimulated EMT and HSPA6 expression in liver tumors and gastric tumor cells, we suggest that ARHGEF10L is a novel oncogene in many tumors.

Dataset Information

A GSTP1-mediated lactic acid signaling promotes tumorigenesis through the PPP oxidative branch.

Publications

A GSTP1-mediated lactic acid signaling promotes tumorigenesis through the PPP oxidative branch.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets