Tautomycin and enzalutamide combination yields synergistic effects on castration-resistant prostate cancer
Abstract The androgen receptor (AR) plays an essential role in prostate cancer progression and is a key target for prostate cancer treatment. However, patients with prostate cancer undergoing androgen deprivation therapy eventually experience biochemical relapse, with hormone-sensitive prostate canc...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-11-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-022-01257-1 |
| _version_ | 1797985507482796032 |
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| author | Mayao Luo Yifan Zhang Zhuofan Xu Chenwei Wu Yuedian Ye Rui Liu Shidong Lv Qiang Wei |
| author_facet | Mayao Luo Yifan Zhang Zhuofan Xu Chenwei Wu Yuedian Ye Rui Liu Shidong Lv Qiang Wei |
| author_sort | Mayao Luo |
| collection | DOAJ |
| description | Abstract The androgen receptor (AR) plays an essential role in prostate cancer progression and is a key target for prostate cancer treatment. However, patients with prostate cancer undergoing androgen deprivation therapy eventually experience biochemical relapse, with hormone-sensitive prostate cancer progressing into castration-resistant prostate cancer (CRPC). The widespread application of secondary antiandrogens, such as enzalutamide, indicates that targeting AR remains the most efficient method for CRPC treatment. Unfortunately, neither can block AR signaling thoroughly, leading to AR reactivation within several months. Here, we report an approach for suppressing reactivated AR signaling in the CRPC stage. A combination of the protein phosphatase 1 subunit α (PP1α)-specific inhibitor tautomycin and enzalutamide synergistically inhibited cell proliferation and AR signaling in LNCaP and C4-2 cells, as well as in AR variant-positive 22RV1 cells. Our results revealed that enzalutamide competed with residual androgens in CRPC, enhancing tautomycin-mediated AR degradation. In addition, the remaining competitive inhibitory role of enzalutamide on AR facilitated tautomycin-induced AR degradation in 22RV1 cells, further decreasing ARv7 levels via a full-length AR/ARv7 interaction. Taken together, our findings suggest that the combination of tautomycin and enzalutamide could achieve a more comprehensive inhibition of AR signaling in CRPC. AR degraders combined with AR antagonists may represent a new therapeutic strategy for CRPC. |
| first_indexed | 2024-04-11T07:18:13Z |
| format | Article |
| id | doaj.art-d451570a45044b8689feae9b7fab266a |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-04-11T07:18:13Z |
| publishDate | 2022-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-d451570a45044b8689feae9b7fab266a2022-12-22T04:37:51ZengNature Publishing GroupCell Death Discovery2058-77162022-11-018111010.1038/s41420-022-01257-1Tautomycin and enzalutamide combination yields synergistic effects on castration-resistant prostate cancerMayao Luo0Yifan Zhang1Zhuofan Xu2Chenwei Wu3Yuedian Ye4Rui Liu5Shidong Lv6Qiang Wei7Department of Urology, Nanfang Hospital, Southern Medical UniversityDepartment of Urology, Nanfang Hospital, Southern Medical UniversityDepartment of Urology, Nanfang Hospital, Southern Medical UniversityDepartment of Urology, Nanfang Hospital, Southern Medical UniversityDepartment of Urology, Nanfang Hospital, Southern Medical UniversitySchool of Basic Medical Sciences, Southern Medical UniversityDepartment of Urology, Nanfang Hospital, Southern Medical UniversityDepartment of Urology, Nanfang Hospital, Southern Medical UniversityAbstract The androgen receptor (AR) plays an essential role in prostate cancer progression and is a key target for prostate cancer treatment. However, patients with prostate cancer undergoing androgen deprivation therapy eventually experience biochemical relapse, with hormone-sensitive prostate cancer progressing into castration-resistant prostate cancer (CRPC). The widespread application of secondary antiandrogens, such as enzalutamide, indicates that targeting AR remains the most efficient method for CRPC treatment. Unfortunately, neither can block AR signaling thoroughly, leading to AR reactivation within several months. Here, we report an approach for suppressing reactivated AR signaling in the CRPC stage. A combination of the protein phosphatase 1 subunit α (PP1α)-specific inhibitor tautomycin and enzalutamide synergistically inhibited cell proliferation and AR signaling in LNCaP and C4-2 cells, as well as in AR variant-positive 22RV1 cells. Our results revealed that enzalutamide competed with residual androgens in CRPC, enhancing tautomycin-mediated AR degradation. In addition, the remaining competitive inhibitory role of enzalutamide on AR facilitated tautomycin-induced AR degradation in 22RV1 cells, further decreasing ARv7 levels via a full-length AR/ARv7 interaction. Taken together, our findings suggest that the combination of tautomycin and enzalutamide could achieve a more comprehensive inhibition of AR signaling in CRPC. AR degraders combined with AR antagonists may represent a new therapeutic strategy for CRPC.https://doi.org/10.1038/s41420-022-01257-1 |
| spellingShingle | Mayao Luo Yifan Zhang Zhuofan Xu Chenwei Wu Yuedian Ye Rui Liu Shidong Lv Qiang Wei Tautomycin and enzalutamide combination yields synergistic effects on castration-resistant prostate cancer Cell Death Discovery |
| title | Tautomycin and enzalutamide combination yields synergistic effects on castration-resistant prostate cancer |
| title_full | Tautomycin and enzalutamide combination yields synergistic effects on castration-resistant prostate cancer |
| title_fullStr | Tautomycin and enzalutamide combination yields synergistic effects on castration-resistant prostate cancer |
| title_full_unstemmed | Tautomycin and enzalutamide combination yields synergistic effects on castration-resistant prostate cancer |
| title_short | Tautomycin and enzalutamide combination yields synergistic effects on castration-resistant prostate cancer |
| title_sort | tautomycin and enzalutamide combination yields synergistic effects on castration resistant prostate cancer |
| url | https://doi.org/10.1038/s41420-022-01257-1 |
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