Targeting prostate tumor low–molecular weight tyrosine phosphatase for oxidation-sensitizing therapy

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

doi:10.1126/sciadv.adg7887

Title: Targeting prostate tumor low–molecular weight tyrosine phosphatase for oxidation-sensitizing therapy

Journal Article · 30 January 2024 · Science Advances

DOI: https://doi.org/10.1126/sciadv.adg7887 · OSTI ID:2471047

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^[1]; Zhao, Zixuan ^[1];

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^[5]; Brauer, Brooke L. ^[6];

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^[2]; Ramsey, Sterling H. ^[1];

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^[8]; Paindelli, Claudia ^[5];

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^[2]; Bagrodia, Aditya ^[1] more »

Univ. of California, San Diego, CA (United States)
Univ. of Texas, Austin, TX (United States)
Univ. of California, San Diego, CA (United States); Cedars‐Sinai Medical Center, Los Angeles, CA (United States)
Cedars‐Sinai Medical Center, Los Angeles, CA (United States)
Univ. of Texas, Houston, TX (United States)
Dartmouth College, Hanover, NH (United States). Geisel School of Medicine; Dartmouth College, Lebanon, NH (United States). Geisel School of Medicine
Memorial Sloan Kettering Cancer Center, New York, NY (United States). Sloan Kettering Institute
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Rice Univ., Houston, TX (United States)
Caris Life Sciences, Phoenix, AZ (United States)

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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); USDOD; National Institutes of Health (NIH); American Cancer Society (ACS)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2471047

Journal Information:: Science Advances, Journal Name: Science Advances Journal Issue: 5 Vol. 10; ISSN 2375-2548

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

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