Allosteric inhibition of HSP70 in collaboration with STUB1 augments enzalutamide efficacy in antiandrogen resistant prostate tumor and patient-derived models
Ubiquitin proteasome activity is suppressed in enzalutamide resistant prostate cancer cells, and the heat shock protein 70/STIP1 homology and U-box-containing protein 1 (HSP70/STUB1) machinery are involved in androgen receptor (AR) and AR variant protein stabilization. Targeting HSP70 could be a via...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-03-01
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| Series: | Pharmacological Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661823000488 |
| _version_ | 1797448098292695040 |
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| author | Pengfei Xu Joy C. Yang Shu Ning Bo Chen Christopher Nip Qiang Wei Liangren Liu Oleta T. Johnson Allen C. Gao Jason E. Gestwicki Christopher P. Evans Chengfei Liu |
| author_facet | Pengfei Xu Joy C. Yang Shu Ning Bo Chen Christopher Nip Qiang Wei Liangren Liu Oleta T. Johnson Allen C. Gao Jason E. Gestwicki Christopher P. Evans Chengfei Liu |
| author_sort | Pengfei Xu |
| collection | DOAJ |
| description | Ubiquitin proteasome activity is suppressed in enzalutamide resistant prostate cancer cells, and the heat shock protein 70/STIP1 homology and U-box-containing protein 1 (HSP70/STUB1) machinery are involved in androgen receptor (AR) and AR variant protein stabilization. Targeting HSP70 could be a viable strategy to overcome resistance to androgen receptor signaling inhibitor (ARSI) in advanced prostate cancer. Here, we showed that a novel HSP70 allosteric inhibitor, JG98, significantly suppressed drug-resistant C4–2B MDVR and CWR22Rv1 cell growth, and enhanced enzalutamide treatment. JG98 also suppressed cell growth in conditional reprogramed cell cultures (CRCs) and organoids derived from advanced prostate cancer patient samples. Mechanistically, JG98 degraded AR/AR-V7 expression in resistant cells and promoted STUB1 nuclear translocation to bind AR-V7. Knockdown of the E3 ligase STUB1 significantly diminished the anticancer effects and partially restored AR-V7 inhibitory effects of JG98. JG231, a more potent analog developed from JG98, effectively suppressed the growth of the drug-resistant prostate cancer cells, CRCs, and organoids. Notably, the combination of JG231 and enzalutamide synergistically inhibited AR/AR-V7 expression and suppressed CWR22Rv1 xenograft tumor growth. Inhibition of HSP70 using novel small-molecule inhibitors coordinates with STUB1 to regulate AR/AR-V7 protein stabilization and ARSI resistance. |
| first_indexed | 2024-03-09T14:05:28Z |
| format | Article |
| id | doaj.art-0aa5beefd47948149ef46484906a60a3 |
| institution | Directory Open Access Journal |
| issn | 1096-1186 |
| language | English |
| last_indexed | 2024-03-09T14:05:28Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj.art-0aa5beefd47948149ef46484906a60a32023-11-30T05:05:46ZengElsevierPharmacological Research1096-11862023-03-01189106692Allosteric inhibition of HSP70 in collaboration with STUB1 augments enzalutamide efficacy in antiandrogen resistant prostate tumor and patient-derived modelsPengfei Xu0Joy C. Yang1Shu Ning2Bo Chen3Christopher Nip4Qiang Wei5Liangren Liu6Oleta T. Johnson7Allen C. Gao8Jason E. Gestwicki9Christopher P. Evans10Chengfei Liu11Department of Urologic Surgery, University of California, Davis, CA, USADepartment of Urologic Surgery, University of California, Davis, CA, USADepartment of Urologic Surgery, University of California, Davis, CA, USADepartment of Urologic Surgery, University of California, Davis, CA, USA; Department of Urology, West China Hospital, Sichuan University, Sichuan, ChinaDepartment of Urologic Surgery, University of California, Davis, CA, USADepartment of Urology, West China Hospital, Sichuan University, Sichuan, ChinaDepartment of Urology, West China Hospital, Sichuan University, Sichuan, ChinaDepartment of Pharmaceutical Chemistry, University of California, San Francisco, CA, USADepartment of Urologic Surgery, University of California, Davis, CA, USA; University of California, Davis Comprehensive Cancer Center, CA, USADepartment of Pharmaceutical Chemistry, University of California, San Francisco, CA, USADepartment of Urologic Surgery, University of California, Davis, CA, USA; University of California, Davis Comprehensive Cancer Center, CA, USADepartment of Urologic Surgery, University of California, Davis, CA, USA; University of California, Davis Comprehensive Cancer Center, CA, USA; Correspondence to: 4645 2nd Ave, Research III Bldg, Suite 2300C, Sacramento, CA 95817, USA.Ubiquitin proteasome activity is suppressed in enzalutamide resistant prostate cancer cells, and the heat shock protein 70/STIP1 homology and U-box-containing protein 1 (HSP70/STUB1) machinery are involved in androgen receptor (AR) and AR variant protein stabilization. Targeting HSP70 could be a viable strategy to overcome resistance to androgen receptor signaling inhibitor (ARSI) in advanced prostate cancer. Here, we showed that a novel HSP70 allosteric inhibitor, JG98, significantly suppressed drug-resistant C4–2B MDVR and CWR22Rv1 cell growth, and enhanced enzalutamide treatment. JG98 also suppressed cell growth in conditional reprogramed cell cultures (CRCs) and organoids derived from advanced prostate cancer patient samples. Mechanistically, JG98 degraded AR/AR-V7 expression in resistant cells and promoted STUB1 nuclear translocation to bind AR-V7. Knockdown of the E3 ligase STUB1 significantly diminished the anticancer effects and partially restored AR-V7 inhibitory effects of JG98. JG231, a more potent analog developed from JG98, effectively suppressed the growth of the drug-resistant prostate cancer cells, CRCs, and organoids. Notably, the combination of JG231 and enzalutamide synergistically inhibited AR/AR-V7 expression and suppressed CWR22Rv1 xenograft tumor growth. Inhibition of HSP70 using novel small-molecule inhibitors coordinates with STUB1 to regulate AR/AR-V7 protein stabilization and ARSI resistance.http://www.sciencedirect.com/science/article/pii/S1043661823000488Prostate cancerEnzalutamide resistanceHSP70STUB1Androgen receptor variantPatient-derived model |
| spellingShingle | Pengfei Xu Joy C. Yang Shu Ning Bo Chen Christopher Nip Qiang Wei Liangren Liu Oleta T. Johnson Allen C. Gao Jason E. Gestwicki Christopher P. Evans Chengfei Liu Allosteric inhibition of HSP70 in collaboration with STUB1 augments enzalutamide efficacy in antiandrogen resistant prostate tumor and patient-derived models Pharmacological Research Prostate cancer Enzalutamide resistance HSP70 STUB1 Androgen receptor variant Patient-derived model |
| title | Allosteric inhibition of HSP70 in collaboration with STUB1 augments enzalutamide efficacy in antiandrogen resistant prostate tumor and patient-derived models |
| title_full | Allosteric inhibition of HSP70 in collaboration with STUB1 augments enzalutamide efficacy in antiandrogen resistant prostate tumor and patient-derived models |
| title_fullStr | Allosteric inhibition of HSP70 in collaboration with STUB1 augments enzalutamide efficacy in antiandrogen resistant prostate tumor and patient-derived models |
| title_full_unstemmed | Allosteric inhibition of HSP70 in collaboration with STUB1 augments enzalutamide efficacy in antiandrogen resistant prostate tumor and patient-derived models |
| title_short | Allosteric inhibition of HSP70 in collaboration with STUB1 augments enzalutamide efficacy in antiandrogen resistant prostate tumor and patient-derived models |
| title_sort | allosteric inhibition of hsp70 in collaboration with stub1 augments enzalutamide efficacy in antiandrogen resistant prostate tumor and patient derived models |
| topic | Prostate cancer Enzalutamide resistance HSP70 STUB1 Androgen receptor variant Patient-derived model |
| url | http://www.sciencedirect.com/science/article/pii/S1043661823000488 |
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