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

Author:

Stanford Stephanie M.1ORCID,Nguyen Tiffany P.1ORCID,Chang Joseph1ORCID,Zhao Zixuan1,Hackman G. Lavender2ORCID,Santelli Eugenio13ORCID,Sanders Colton M.1ORCID,Katiki Madhusudhanarao4ORCID,Dondossola Eleonora5ORCID,Brauer Brooke L.67,Diaz Michael A.1ORCID,Zhan Yuan8ORCID,Ramsey Sterling H.1,Watson Philip A.9ORCID,Sankaran Banumathi10ORCID,Paindelli Claudia5,Parietti Vanessa5ORCID,Mikos Antonios G.11ORCID,Lodi Alessia2ORCID,Bagrodia Aditya12,Elliott Andrew13ORCID,McKay Rana R.1,Murali Ramachandran4ORCID,Tiziani Stefano28ORCID,Kettenbach Arminja N.67ORCID,Bottini Nunzio13ORCID

Affiliation:

1. Department of Medicine, University of California, San Diego, La Jolla, CA, USA.

2. Department of Nutritional Sciences, College of Natural Sciences and Department of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, TX, USA.

3. Kao Autoimmunity Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

4. Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

5. Department of Genitourinary Medical Oncology and David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

6. Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.

7. Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.

8. Department of Pediatrics and Department of Oncology, Dell Medical School, Livestrong Cancer Institutes, College of Natural Sciences, The University of Texas at Austin, Austin, TX USA.

9. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

10. Department of Molecular Biophysics and Integrated Bioimaging, Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.

11. Department of Bioengineering, Rice University, Houston, TX, USA.

12. Department of Urology, University of California, San Diego, La Jolla, CA, USA.

13. Department of Clinical and Translational Research, Caris Life Sciences, Phoenix, AZ, USA.

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 Tyr 270 . 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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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