Targeting PSAT1 to mitigate metastasis in tumors with p53-72Pro variant.

Autor: Jiang J; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China.; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, P.R. China., Chen HN; Colorectal Cancer Center, Department of General Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China., Jin P; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China.; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, P.R. China., Zhou L; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China., Peng L; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China., Huang Z; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China., Qin S; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China., Li B; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China., Ming H; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, P.R. China., Luo M; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China.; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, P.R. China., Xie N; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, P.R. China., Gao W; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, P.R. China., Nice EC; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia., Yu Q; Cancer Precision Medicine, Genome Institute of Singapore, Agency for Science, Technology, and Research, Biopolis, Singapore, 138672, Singapore., Huang C; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China. hcanhua@hotmail.com.; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, P.R. China. hcanhua@hotmail.com.
Jazyk: angličtina
Zdroj: Signal transduction and targeted therapy [Signal Transduct Target Ther] 2023 Feb 15; Vol. 8 (1), pp. 65. Date of Electronic Publication: 2023 Feb 15.
DOI: 10.1038/s41392-022-01266-7
Abstrakt: The single-nucleotide polymorphism (SNP) of p53, in particular the codon 72 variants, has recently been implicated as a critical regulator in tumor progression. However, the underlying mechanism remains elusive. Here we found that cancer cells carrying codon 72-Pro variant of p53 showed impaired metastatic potential upon serine supplementation. Proteome-wide mapping of p53-interacting proteins uncovered a specific interaction of the codon 72 proline variant (but not p53 72R ) with phosphoserine aminotransferase 1 (PSAT1). Interestingly, p53 72P -PSAT1 interaction resulted in dissociation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) that otherwise bound to p53 72P , leading to subsequent nuclear translocation of PGC-1α and activation of oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle. Depletion of PSAT1 restored p53 72P -PGC-1α interaction and impeded the OXPHOS and TCA function, resulting in mitochondrial dysfunction and metastasis suppression. Notably, pharmacological targeting the PSAT1-p53 72P interaction by aminooxyacetic acid (AOA) crippled the growth of liver cancer cells carrying the p53 72P variant in both in vitro and patient-derived xenograft models. Moreover, AOA plus regorafenib, an FDA-proved drug for hepatocellular carcinoma and colorectal cancer, achieved a better anti-tumor effect on tumors carrying the p53 72P variant. Therefore, our findings identified a gain of function of the p53 72P variant on mitochondrial function and provided a promising precision strategy to treat tumors vulnerable to p53 72P -PSAT1 perturbation.
(© 2022. The Author(s).)
Databáze: MEDLINE
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