Targeting prostate tumor low–molecular weight tyrosine phosphatase for oxidation-sensitizing therapy Journal Article
| Authors: | Stanford, S. M.; Nguyen, T. P.; Chang, J.; Zhao, Z.; Hackman, G. L.; Santelli, E.; Sanders, C. M.; Katiki, M.; Dondossola, E.; Brauer, B. L.; Diaz, M. A.; Zhan, Y.; Ramsey, S. H.; Watson, P. A.; Sankaran, B.; Paindelli, C.; Parietti, V.; Mikos, A. G.; Lodi, A.; Bagrodia, A.; Elliott, A.; McKay, R. R.; Murali, R.; Tiziani, S.; Kettenbach, A. N.; Bottini, N. |
| Article Title: | Targeting prostate tumor low–molecular weight tyrosine phosphatase for oxidation-sensitizing therapy |
| 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 an d metastasis and validate LMPTP inhibition as a therapeutic strategy for treating PCa through sensitization to oxidative stress. © 2024 American Association for the Advancement of Science. All rights reserved. |
| Keywords: | genetics; cancer growth; mouse; animal; metabolism; animals; mice; pathology; tyrosine; prostatic neoplasms; tumors; prostate tumor; urology; bone; peptides; protein tyrosine phosphatase; amino acids; mammals; therapeutic targets; molecular weight; prostate cancers; diseases; phosphatases; protein tyrosine phosphatases; human prostate; prostate cancer cells; tyrosine phosphatase; humans; human; male; low molecular weight; low molecular weight proteins; protein-tyrosine phosphatase |
| Journal Title: | Science Advances |
| Volume: | 10 |
| Issue: | 5 |
| ISSN: | 2375-2548 |
| Publisher: | Amer Assoc Advancement Science |
| Date Published: | 2024-02-02 |
| Language: | English |
| DOI: | 10.1126/sciadv.adg7887 |
| PUBMED: | 38295166 |
| PROVIDER: | scopus |
| PMCID: | PMC10830117 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
