GABBR2 as a Downstream Effector of the Androgen Receptor Induces Cisplatin Resistance in Bladder Cancer
The precise molecular mechanisms responsible for resistance to cisplatin-based chemotherapy in patients with bladder cancer remain elusive, while we have indicated that androgen receptor (AR) activity in urothelial cancer is associated with its sensitivity. Our DNA microarray analysis in control vs....
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-09-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/18/13733 |
| _version_ | 1797579774203265024 |
|---|---|
| author | Mohammad Amin Elahi Najafi Masato Yasui Yuki Teramoto Tomoyuki Tatenuma Guiyang Jiang Hiroshi Miyamoto |
| author_facet | Mohammad Amin Elahi Najafi Masato Yasui Yuki Teramoto Tomoyuki Tatenuma Guiyang Jiang Hiroshi Miyamoto |
| author_sort | Mohammad Amin Elahi Najafi |
| collection | DOAJ |
| description | The precise molecular mechanisms responsible for resistance to cisplatin-based chemotherapy in patients with bladder cancer remain elusive, while we have indicated that androgen receptor (AR) activity in urothelial cancer is associated with its sensitivity. Our DNA microarray analysis in control vs. AR-knockdown bladder cancer sublines suggested that the expression of a GABA B receptor GABBR2 and AR was correlated. The present study aimed to determine the functional role of GABBR2 in modulating cisplatin sensitivity in bladder cancer. AR knockdown and dihydrotestosterone treatment considerably reduced and induced, respectively, GABBR2 expression, and the effect of dihydrotestosterone was at least partially restored by an antiandrogen hydroxyflutamide. A chromatin immunoprecipitation assay further revealed the binding of AR to the promoter region of <i>GABBR2</i> in bladder cancer cells. Meanwhile, <i>GABBR2</i> expression was significantly elevated in a cisplatin-resistant bladder cancer subline, compared with control cells. In AR-positive bladder cancer cells, knockdown of GABBR2 or treatment with a selective GABA B receptor antagonist, CGP46381, considerably enhanced the cytotoxic activity of cisplatin. However, no additional effect of CGP46381 on cisplatin-induced growth suppression was seen in GABBR2-knockdown cells. Moreover, in the absence of cisplatin, CGP46381 treatment and GABBR2 knockdown showed no significant changes in cell proliferation or migration. These findings suggest that GABBR2 represents a key downstream effector of AR signaling in inducing resistance to cisplatin treatment. Accordingly, inhibition of GABBR2 has the potential of being a means of chemosensitization, especially in patients with AR/GABBR2-positive bladder cancer. |
| first_indexed | 2024-03-10T22:41:43Z |
| format | Article |
| id | doaj.art-ed6d8999b9a8479e8ee1931c3da84404 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T22:41:43Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ed6d8999b9a8479e8ee1931c3da844042023-11-19T11:02:17ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-09-0124181373310.3390/ijms241813733GABBR2 as a Downstream Effector of the Androgen Receptor Induces Cisplatin Resistance in Bladder CancerMohammad Amin Elahi Najafi0Masato Yasui1Yuki Teramoto2Tomoyuki Tatenuma3Guiyang Jiang4Hiroshi Miyamoto5Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USADepartment of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USADepartment of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USADepartment of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USADepartment of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USADepartment of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USAThe precise molecular mechanisms responsible for resistance to cisplatin-based chemotherapy in patients with bladder cancer remain elusive, while we have indicated that androgen receptor (AR) activity in urothelial cancer is associated with its sensitivity. Our DNA microarray analysis in control vs. AR-knockdown bladder cancer sublines suggested that the expression of a GABA B receptor GABBR2 and AR was correlated. The present study aimed to determine the functional role of GABBR2 in modulating cisplatin sensitivity in bladder cancer. AR knockdown and dihydrotestosterone treatment considerably reduced and induced, respectively, GABBR2 expression, and the effect of dihydrotestosterone was at least partially restored by an antiandrogen hydroxyflutamide. A chromatin immunoprecipitation assay further revealed the binding of AR to the promoter region of <i>GABBR2</i> in bladder cancer cells. Meanwhile, <i>GABBR2</i> expression was significantly elevated in a cisplatin-resistant bladder cancer subline, compared with control cells. In AR-positive bladder cancer cells, knockdown of GABBR2 or treatment with a selective GABA B receptor antagonist, CGP46381, considerably enhanced the cytotoxic activity of cisplatin. However, no additional effect of CGP46381 on cisplatin-induced growth suppression was seen in GABBR2-knockdown cells. Moreover, in the absence of cisplatin, CGP46381 treatment and GABBR2 knockdown showed no significant changes in cell proliferation or migration. These findings suggest that GABBR2 represents a key downstream effector of AR signaling in inducing resistance to cisplatin treatment. Accordingly, inhibition of GABBR2 has the potential of being a means of chemosensitization, especially in patients with AR/GABBR2-positive bladder cancer.https://www.mdpi.com/1422-0067/24/18/13733androgen receptorchemoresistancecisplatinGABBR2urothelial cancer |
| spellingShingle | Mohammad Amin Elahi Najafi Masato Yasui Yuki Teramoto Tomoyuki Tatenuma Guiyang Jiang Hiroshi Miyamoto GABBR2 as a Downstream Effector of the Androgen Receptor Induces Cisplatin Resistance in Bladder Cancer International Journal of Molecular Sciences androgen receptor chemoresistance cisplatin GABBR2 urothelial cancer |
| title | GABBR2 as a Downstream Effector of the Androgen Receptor Induces Cisplatin Resistance in Bladder Cancer |
| title_full | GABBR2 as a Downstream Effector of the Androgen Receptor Induces Cisplatin Resistance in Bladder Cancer |
| title_fullStr | GABBR2 as a Downstream Effector of the Androgen Receptor Induces Cisplatin Resistance in Bladder Cancer |
| title_full_unstemmed | GABBR2 as a Downstream Effector of the Androgen Receptor Induces Cisplatin Resistance in Bladder Cancer |
| title_short | GABBR2 as a Downstream Effector of the Androgen Receptor Induces Cisplatin Resistance in Bladder Cancer |
| title_sort | gabbr2 as a downstream effector of the androgen receptor induces cisplatin resistance in bladder cancer |
| topic | androgen receptor chemoresistance cisplatin GABBR2 urothelial cancer |
| url | https://www.mdpi.com/1422-0067/24/18/13733 |
| work_keys_str_mv | AT mohammadaminelahinajafi gabbr2asadownstreameffectoroftheandrogenreceptorinducescisplatinresistanceinbladdercancer AT masatoyasui gabbr2asadownstreameffectoroftheandrogenreceptorinducescisplatinresistanceinbladdercancer AT yukiteramoto gabbr2asadownstreameffectoroftheandrogenreceptorinducescisplatinresistanceinbladdercancer AT tomoyukitatenuma gabbr2asadownstreameffectoroftheandrogenreceptorinducescisplatinresistanceinbladdercancer AT guiyangjiang gabbr2asadownstreameffectoroftheandrogenreceptorinducescisplatinresistanceinbladdercancer AT hiroshimiyamoto gabbr2asadownstreameffectoroftheandrogenreceptorinducescisplatinresistanceinbladdercancer |