Targeting prostate tumor low-molecular weight tyrosine phosphatase for oxidation-sensitizing therapy
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 gene-is overexpressed in prostate tumors. We found up-regulated in human prostate tumors and expression inversely correlated...
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| Veröffentlicht in: | Science advances 2024-02, Vol.10 (5), p.eadg7887 |
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| creator | 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 |
| description | 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
gene-is overexpressed in prostate tumors. We found
up-regulated in human prostate tumors and
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
. 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. |
| doi_str_mv | 10.1126/sciadv.adg7887 |
| format | Article |
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gene-is overexpressed in prostate tumors. We found
up-regulated in human prostate tumors and
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
. 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.</description><identifier>ISSN: 2375-2548</identifier><identifier>EISSN: 2375-2548</identifier><identifier>DOI: 10.1126/sciadv.adg7887</identifier><identifier>PMID: 38295166</identifier><language>eng</language><publisher>United States: AAAS</publisher><subject>60 APPLIED LIFE SCIENCES ; Animals ; Biomedicine and Life Sciences ; Cancer ; Humans ; Male ; Mice ; Molecular Weight ; Prostatic Neoplasms - drug therapy ; Prostatic Neoplasms - genetics ; Protein Tyrosine Phosphatases - metabolism ; SciAdv r-articles ; Science & Technology - Other Topics ; Tyrosine</subject><ispartof>Science advances, 2024-02, Vol.10 (5), p.eadg7887</ispartof><rights>Copyright © 2024 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. 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gene-is overexpressed in prostate tumors. We found
up-regulated in human prostate tumors and
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
. 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. 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Advanced Light Source (ALS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting prostate tumor low-molecular weight tyrosine phosphatase for oxidation-sensitizing therapy</atitle><jtitle>Science advances</jtitle><addtitle>Sci Adv</addtitle><date>2024-02-02</date><risdate>2024</risdate><volume>10</volume><issue>5</issue><spage>eadg7887</spage><pages>eadg7887-</pages><issn>2375-2548</issn><eissn>2375-2548</eissn><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
gene-is overexpressed in prostate tumors. We found
up-regulated in human prostate tumors and
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
. 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.</abstract><cop>United States</cop><pub>AAAS</pub><pmid>38295166</pmid><doi>10.1126/sciadv.adg7887</doi><orcidid>https://orcid.org/0000-0003-3979-4576</orcidid><orcidid>https://orcid.org/0000-0003-0934-5462</orcidid><orcidid>https://orcid.org/0000-0002-0433-7167</orcidid><orcidid>https://orcid.org/0000-0002-8739-2750</orcidid><orcidid>https://orcid.org/0000-0002-7230-0307</orcidid><orcidid>https://orcid.org/0000-0003-4092-9386</orcidid><orcidid>https://orcid.org/0000-0002-2104-5713</orcidid><orcidid>https://orcid.org/0000-0001-8494-8031</orcidid><orcidid>https://orcid.org/0000-0002-7264-2614</orcidid><orcidid>https://orcid.org/0000-0001-8211-9117</orcidid><orcidid>https://orcid.org/0009-0001-2383-0408</orcidid><orcidid>https://orcid.org/0000-0001-9025-7501</orcidid><orcidid>https://orcid.org/0000-0002-6096-8254</orcidid><orcidid>https://orcid.org/0009-0009-0944-3338</orcidid><orcidid>https://orcid.org/0000-0001-7439-5138</orcidid><orcidid>https://orcid.org/0000-0001-6916-5418</orcidid><orcidid>https://orcid.org/0000-0003-1631-5122</orcidid><orcidid>https://orcid.org/0000-0002-8384-2793</orcidid><orcidid>https://orcid.org/0000-0001-8170-6416</orcidid><orcidid>https://orcid.org/0000-0002-3266-8131</orcidid><orcidid>https://orcid.org/0000000339794576</orcidid><orcidid>https://orcid.org/0000000272300307</orcidid><orcidid>https://orcid.org/0000000181706416</orcidid><orcidid>https://orcid.org/0009000123830408</orcidid><orcidid>https://orcid.org/0000000184948031</orcidid><orcidid>https://orcid.org/0000000232668131</orcidid><orcidid>https://orcid.org/0000000260968254</orcidid><orcidid>https://orcid.org/0000000272642614</orcidid><orcidid>https://orcid.org/0000000283842793</orcidid><orcidid>https://orcid.org/0000000309345462</orcidid><orcidid>https://orcid.org/0009000909443338</orcidid><orcidid>https://orcid.org/0000000204337167</orcidid><orcidid>https://orcid.org/0000000316315122</orcidid><orcidid>https://orcid.org/0000000174395138</orcidid><orcidid>https://orcid.org/0000000169165418</orcidid><orcidid>https://orcid.org/0000000221045713</orcidid><orcidid>https://orcid.org/0000000190257501</orcidid><orcidid>https://orcid.org/0000000182119117</orcidid><orcidid>https://orcid.org/0000000287392750</orcidid><orcidid>https://orcid.org/0000000340929386</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2375-2548 |
| ispartof | Science advances, 2024-02, Vol.10 (5), p.eadg7887 |
| issn | 2375-2548 2375-2548 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10830117 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | 60 APPLIED LIFE SCIENCES Animals Biomedicine and Life Sciences Cancer Humans Male Mice Molecular Weight Prostatic Neoplasms - drug therapy Prostatic Neoplasms - genetics Protein Tyrosine Phosphatases - metabolism SciAdv r-articles Science & Technology - Other Topics Tyrosine |
| title | Targeting prostate tumor low-molecular weight tyrosine phosphatase for oxidation-sensitizing therapy |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-14T08%3A07%3A56IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Targeting%20prostate%20tumor%20low-molecular%20weight%20tyrosine%20phosphatase%20for%20oxidation-sensitizing%20therapy&rft.jtitle=Science%20advances&rft.au=Stanford,%20Stephanie%20M&rft.aucorp=Lawrence%20Berkeley%20National%20Laboratory%20(LBNL),%20Berkeley,%20CA%20(United%20States).%20Advanced%20Light%20Source%20(ALS)&rft.date=2024-02-02&rft.volume=10&rft.issue=5&rft.spage=eadg7887&rft.pages=eadg7887-&rft.issn=2375-2548&rft.eissn=2375-2548&rft_id=info:doi/10.1126/sciadv.adg7887&rft_dat=%3Cproquest_pubme%3E2921115196%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2921115196&rft_id=info:pmid/38295166&rfr_iscdi=true |