Cytochrome P450 1B1 inhibition suppresses tumorigenicity of prostate cancer via caspase-1 activation
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Inik Chang1,*, Yozo Mitsui2,3,*, Seul Ki Kim1,4, Ji Su Sun1,4, Hye Sook Jeon1, Jung Yun Kang1,4, Nam Ju Kang1,4, Shinichiro Fukuhara2,3, Ankurpreet Gill2, Varahram Shahryari2, Z. Laura Tabatabai5, Kirsten L. Greene5, Rajvir Dahiya2,3, Dong Min Shin1,4 and Yuichiro Tanaka2,3
1Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea
2Department of Surgery and Division of Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America
3Department of Urology, University of California, San Francisco, California, United States of America
4BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, South Korea
5Department of Pathology, Veterans Affairs Medical Center and University of California, San Francisco, California, United States of America
*These authors have contributed equally to this work
Inik Chang, email: firstname.lastname@example.org
Yuichiro Tanaka, email: email@example.com
Keywords: CYP1B1, prostate cancer, tumorigenicity, shRNA, caspase-1
Received: December 29, 2016 Accepted: March 01, 2017 Published: September 25, 2018
Cytochrome P450 1B1 (CYP1B1) is recognized as a universal tumor biomarker and a feasible therapeutic target due to its specific overexpression in cancer tissues. Despite its up-regulation in prostate cancer (PCa), biological significance and clinicopathological features of CYP1B1 are still elusive. Here, we show that overexpression or hyperactivation of CYP1B1 stimulated proliferative, migratory and invasive potential of non-tumorigenic PCa cells. Attenuation of CYP1B1 with its specific small hairpin (sh) RNAs greatly reduced proliferation through apoptotic cell death and impaired migration and invasion in PCa cells. Intratumoral injection of CYP1B1 shRNA attenuated growth of pre-existing tumors. The antitumor effect of CYP1B1 shRNA was also observed in prostate tumor xenograft mouse models. Among the genes altered by CYP1B1 knockdown, reduction of caspase-1 (CASP1) activity attenuated the antitumor effect of CYP1B1 inhibition. Indeed, CYP1B1 regulates CASP1 expression or activity. Finally, CYP1B1 expression was increased in higher grades of PCa and overall survival was significantly reduced in patients with high levels of CYP1B1 protein. CYP1B1 expression was reversely associated with CASP1 expression in clinical tissue samples. Together, our results demonstrate that CYP1B1 regulates PCa tumorigenesis by inhibiting CASP1 activation. Thus, the CYP1B1-CASP1 axis may be useful as a potential biomarker and a therapeutic target for PCa.
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