Tags

Type your tag names separated by a space and hit enter

Androgen dihydrotestosterone (DHT) promotes the bladder cancer nuclear AR-negative cell invasion via a newly identified membrane androgen receptor (mAR-SLC39A9)-mediated Gαi protein/MAPK/MMP9 intracellular signaling.
Oncogene 2019O

Abstract

While androgens may function via nuclear androgen receptor (nAR) to increase bladder cancer (BCa) progression, the impact of androgens on muscle invasive BCa, which contains nearly 80% nAR-negative cells, remains unclear. To dissect the androgens potential impacts on these nAR-negative muscle invasive BCa, we first found that the androgens, dihydrotestosterone (DHT) might function via a novel membrane AR (mAR-SLC39A9) to increase nAR-negative BCa cell migration and invasion. Mechanism dissection revealed that DHT/mAR-SLC39A9 might function by altering Gαi protein-mediated MAPK/MMP9 intracellular signaling to increase nAR-negative BCa cell migration and invasion. Preclinical studies using multiple in vitro nAR-negative BCa cell lines and an in vivo mouse model all demonstrated that targeting this newly identified DHT/mAR-SLC39A9/Gαi/MAPK/MMP9 signaling with small molecules mAR-SLC39A9-shRNA or Gαi-shRNA, and not the classic antiandrogens including enzalutamide, bicalutamide, or hydroxyflutamide, could suppress nAR-negative BCa cell invasion. Results from human clinical samples surveys also indicated the positive correlation of this newly identified DHT/mAR signaling with BCa progression and prognosis. Together, these results suggest that androgens may not only function via the classic nAR to increase the nAR-positive BCa cell invasion, they may also function via this newly identified mAR-SLC39A9 to increase the nAR-negative/mAR-positive BCa cell invasion.

Authors+Show Affiliations

Departments of Urology, Xiangya Hospital, Central South University, 410008, Changsha, China. George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Institute, Rochester, NY, USA.George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Institute, Rochester, NY, USA.George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Institute, Rochester, NY, USA.Departments of Urology, Xiangya Hospital, Central South University, 410008, Changsha, China. George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Institute, Rochester, NY, USA.Sex Hormone Research Center, Departments of Urology and Medical Technology, China Medical University/Hospital, 404, Taichung, Taiwan.Sex Hormone Research Center, Departments of Urology and Medical Technology, China Medical University/Hospital, 404, Taichung, Taiwan.George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Institute, Rochester, NY, USA.George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Institute, Rochester, NY, USA.George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Institute, Rochester, NY, USA.Departments of Urology, Xiangya Hospital, Central South University, 410008, Changsha, China. whzuxb@163.com.George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Institute, Rochester, NY, USA. chang@urmc.rochester.edu. Sex Hormone Research Center, Departments of Urology and Medical Technology, China Medical University/Hospital, 404, Taichung, Taiwan. chang@urmc.rochester.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31506605

Citation

Chen, Jinbo, et al. "Androgen Dihydrotestosterone (DHT) Promotes the Bladder Cancer Nuclear AR-negative Cell Invasion Via a Newly Identified Membrane Androgen Receptor (mAR-SLC39A9)-mediated Gαi protein/MAPK/MMP9 Intracellular Signaling." Oncogene, 2019.
Chen J, Chou F, Yeh S, et al. Androgen dihydrotestosterone (DHT) promotes the bladder cancer nuclear AR-negative cell invasion via a newly identified membrane androgen receptor (mAR-SLC39A9)-mediated Gαi protein/MAPK/MMP9 intracellular signaling. Oncogene. 2019.
Chen, J., Chou, F., Yeh, S., Ou, Z., Shyr, C., Huang, C., ... Chang, C. (2019). Androgen dihydrotestosterone (DHT) promotes the bladder cancer nuclear AR-negative cell invasion via a newly identified membrane androgen receptor (mAR-SLC39A9)-mediated Gαi protein/MAPK/MMP9 intracellular signaling. Oncogene, doi:10.1038/s41388-019-0964-6.
Chen J, et al. Androgen Dihydrotestosterone (DHT) Promotes the Bladder Cancer Nuclear AR-negative Cell Invasion Via a Newly Identified Membrane Androgen Receptor (mAR-SLC39A9)-mediated Gαi protein/MAPK/MMP9 Intracellular Signaling. Oncogene. 2019 Sep 10; PubMed PMID: 31506605.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Androgen dihydrotestosterone (DHT) promotes the bladder cancer nuclear AR-negative cell invasion via a newly identified membrane androgen receptor (mAR-SLC39A9)-mediated Gαi protein/MAPK/MMP9 intracellular signaling. AU - Chen,Jinbo, AU - Chou,Fuju, AU - Yeh,Shuyuan, AU - Ou,Zhenyu, AU - Shyr,Chihrong, AU - Huang,Chiping, AU - Xiang,Zhendong, AU - Sun,Yin, AU - Messing,Edward, AU - Zu,Xiongbing, AU - Chang,Chawnshang, Y1 - 2019/09/10/ PY - 2018/12/22/received PY - 2019/05/15/accepted PY - 2019/05/08/revised PY - 2019/9/12/entrez JF - Oncogene JO - Oncogene N2 - While androgens may function via nuclear androgen receptor (nAR) to increase bladder cancer (BCa) progression, the impact of androgens on muscle invasive BCa, which contains nearly 80% nAR-negative cells, remains unclear. To dissect the androgens potential impacts on these nAR-negative muscle invasive BCa, we first found that the androgens, dihydrotestosterone (DHT) might function via a novel membrane AR (mAR-SLC39A9) to increase nAR-negative BCa cell migration and invasion. Mechanism dissection revealed that DHT/mAR-SLC39A9 might function by altering Gαi protein-mediated MAPK/MMP9 intracellular signaling to increase nAR-negative BCa cell migration and invasion. Preclinical studies using multiple in vitro nAR-negative BCa cell lines and an in vivo mouse model all demonstrated that targeting this newly identified DHT/mAR-SLC39A9/Gαi/MAPK/MMP9 signaling with small molecules mAR-SLC39A9-shRNA or Gαi-shRNA, and not the classic antiandrogens including enzalutamide, bicalutamide, or hydroxyflutamide, could suppress nAR-negative BCa cell invasion. Results from human clinical samples surveys also indicated the positive correlation of this newly identified DHT/mAR signaling with BCa progression and prognosis. Together, these results suggest that androgens may not only function via the classic nAR to increase the nAR-positive BCa cell invasion, they may also function via this newly identified mAR-SLC39A9 to increase the nAR-negative/mAR-positive BCa cell invasion. SN - 1476-5594 UR - https://www.unboundmedicine.com/medline/citation/31506605/Androgen_dihydrotestosterone_(DHT)_promotes_the_bladder_cancer_nuclear_AR-negative_cell_invasion_via_a_newly_identified_membrane_androgen_receptor_(mAR-SLC39A9)-mediated_Gαi_protein/MAPK/MMP9_intracellular_signaling L2 - http://dx.doi.org/10.1038/s41388-019-0964-6 DB - PRIME DP - Unbound Medicine ER -