Targeting Prostate Tumor Low-Molecular Weight Tyrosine Phosphatase for Oxidation-Sensitizing Therapy

Authors

Stephanie M Stanford
Tiffany P Nguyen
Joseph Chang
Zixuan Zhao
G Lavender Hackman
Eugenio Santelli
Colton M Sanders
Madhusudhanarao Katiki
Eleonora Dondossola
Brooke L Brauer
Michael A Diaz
Yuan Zhan
Sterling H Ramsey
Philip A Watson
Banumathi Sankaran
Claudia Paindelli
Vanessa Parietti
Antonios G Mikos
Alessia Lodi
Aditya Bagrodia
Andrew Elliott
Rana R McKay
Ramachandran Murali
Stefano Tiziani
Arminja N Kettenbach
Nunzio Bottini

Publication Date

2-2-2024

Journal

Science Advances

Abstract

Protein tyrosine phosphatases (PTPs) play major roles in cancer and are emerging as therapeutic targets. Recent reports suggest low-molecular weight PTP (LMPTP)-encoded by the ACP1 gene-is overexpressed in prostate tumors. We found ACP1 up-regulated in human prostate tumors and ACP1 expression inversely correlated with overall survival. Using CRISPR-Cas9-generated LMPTP knockout C4-2B and MyC-CaP cells, we identified LMPTP as a critical promoter of prostate cancer (PCa) growth and bone metastasis. Through metabolomics, we found that LMPTP promotes PCa cell glutathione synthesis by dephosphorylating glutathione synthetase on inhibitory Tyr270. PCa cells lacking LMPTP showed reduced glutathione, enhanced activation of eukaryotic initiation factor 2-mediated stress response, and enhanced reactive oxygen species after exposure to taxane drugs. LMPTP inhibition slowed primary and bone metastatic prostate tumor growth in mice. These findings reveal a role for LMPTP as a critical promoter of PCa growth and metastasis and validate LMPTP inhibition as a therapeutic strategy for treating PCa through sensitization to oxidative stress.

Keywords

Male, Humans, Mice, Animals, Molecular Weight, Prostatic Neoplasms, Tyrosine, Protein Tyrosine Phosphatases

Comments

Supplementary Materials

PMID: 38295166