GSTP1介导的乳酸信号通过PPP氧化分支促进肿瘤发生
Cell Death & Disease
(
IF8.1
)
Pub Date : 2023-07-25, DOI: 10.1038/s41419-023-05998-4
Yandi Sun
1,
2
,
Qian He
3,
4
,
Jingjia Li
3,
4
,
Ze Yang
3,
4
,
Mashaal Ahmad
3,
4
,
Yindan Lin
3,
4
,
Di Wu
5
,
Lei Zheng
6
,
Jiangtao Li
5
,
Ben Wang
1,
2
,
Chitty Chen
7
,
Yue Hu
8
,
Heng Luo
9,
10
,
Yan Luo
3,
4
Affiliation
Cancer Institute, The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China.
Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Department of Biochemistry & Cancer Medicine, International Institutes of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China.
Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, 866 Yu Hang Tang Road, Hangzhou, Zhejiang, China.
Department of General Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Departments of Oncology and Surgery, the Pancreatic Cancer Center of Excellence Program, the Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Research and Development, SysDiagno Biotech, Nanjing, 211800, Jiangsu Province, China.
Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou, China.
The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang, Guizhou, China.
A GSTP1-mediated lactic acid signaling promotes tumorigenesis through the PPP oxidative branch
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.
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