title: Cytochrome P450 1B1 inhibition suppresses tumorigenicity of prostate cancer via caspase-1 activation.
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.
authors.affiliation: Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea.
authors.forename: Inik
authors.initials: I
authors.lastname: Chang
authors.affiliation: Department of Surgery and Division of Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America.|Department of Urology, University of California, San Francisco, California, United States of America.
authors.forename: Yozo
authors.initials: Y
authors.lastname: Mitsui
authors.affiliation: Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea.|BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, South Korea.
authors.forename: Seul Ki
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea.|BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, South Korea.
authors.forename: Ji Su
authors.initials: JS
authors.lastname: Sun
authors.affiliation: Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea.
authors.forename: Hye Sook
authors.initials: HS
authors.lastname: Jeon
authors.affiliation: Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea.|BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, South Korea.
authors.forename: Jung Yun
authors.initials: JY
authors.lastname: Kang
authors.affiliation: Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea.|BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, South Korea.
authors.forename: Nam Ju
authors.initials: NJ
authors.lastname: Kang
authors.affiliation: Department of Surgery and Division of Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America.|Department of Urology, University of California, San Francisco, California, United States of America.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Fukuhara
authors.affiliation: Department of Surgery and Division of Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America.
authors.forename: Ankurpreet
authors.initials: A
authors.lastname: Gill
authors.affiliation: Department of Surgery and Division of Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America.
authors.forename: Varahram
authors.initials: V
authors.lastname: Shahryari
authors.affiliation: Department of Pathology, Veterans Affairs Medical Center and University of California, San Francisco, California, United States of America.
authors.forename: Z Laura
authors.initials: ZL
authors.lastname: Tabatabai
authors.affiliation: Department of Pathology, Veterans Affairs Medical Center and University of California, San Francisco, California, United States of America.
authors.forename: Kirsten L
authors.initials: KL
authors.lastname: Greene
authors.affiliation: Department of Surgery and Division of Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America.|Department of Urology, University of California, San Francisco, California, United States of America.
authors.forename: Rajvir
authors.initials: R
authors.lastname: Dahiya
authors.affiliation: Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea.|BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, South Korea.
authors.forename: Dong Min
authors.initials: DM
authors.lastname: Shin
authors.affiliation: Department of Surgery and Division of Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America.|Department of Urology, University of California, San Francisco, California, United States of America.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D065633:Cytochrome P-450 CYP1B1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D034741:RNA, Small Interfering; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1; D020170:Caspase 1
keywords: CYP1B1; caspase-1; prostate cancer; shRNA; tumorigenicity