Cytochrome P450 1B1 inhibition suppresses tumorigenicity of prostate cancer via caspase-1 activation

Inik Chang, Yozo Mitsui, Seul Ki Kim, Ji Su Sun, Hye Sook Jeon, Jung Yun Kang, Nam Ju Kang, Shinichiro Fukuhara, Ankurpreet Gill, Varahram Shahryari, Z. Laura Tabatabai, Kirsten L. Greene, Rajvir Dahiya, Dong Min Shin, Yuichiro Tanaka

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)39087-39100
Number of pages14
JournalOncotarget
Volume8
Issue number24
DOIs
Publication statusPublished - 2017

Bibliographical note

Funding Information:
We thank Dr. Roger Erickson for helpful discussion and comments about the manuscript. This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and future Planning (NRF-2016R1A5A2008630 and-2016R1C1B2014926 to Inik Chang) and the Veterans Affairs Merit Review and Program Project Awards (to Yuichiro Tanaka). The funding body had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Publisher Copyright:
© Chang et al.

All Science Journal Classification (ASJC) codes

  • Oncology

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