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.
Highlights
The cytochrome P450 (CYP) superfamily is involved in the metabolism of a diverse range of xenobiotics and endogenous compounds
Since Cytochrome P450 1B1 (CYP1B1) is implicated as an important factor in the development of various cancers, understanding the precise mechanisms of CYP1B1-mediated cancer progression is required in the development of new strategies for cancer treatment
Exogenous expression of CASP1 markedly reduced the growth of renal cancer cells in vitro and in vivo, and silencing CASP1 activity resulted in the establishment of solid tumors [30]
Summary
The cytochrome P450 (CYP) superfamily is involved in the metabolism of a diverse range of xenobiotics and endogenous compounds. Saini et al showed that CYP1B1 knockdown inhibits endometrial carcinogenesis by affecting cellular proliferation, cell cycle and invasive potential through the regulation of cyclin E1, Skp, and TRAIL [3]. In squamous cell carcinoma of the head and neck, CYP1B1 knockdown reduced the migration and proliferation of premalignant cells and CYP1B1mediated estrogen metabolism is essential for cancer development [4]. We reported that CYP1B1 expression is regulated by miR-200c and high CYP1B1 levels contribute to resistance of renal cell carcinoma (RCC) to docetaxel [5]. CYP1B1 reduction altered expression of CDC20 and DAPK1 and resulted in the disturbance of cell cycle and apoptosis in RCC [6]. Kwon et al suggested that CYP1B1-mediated Sp1 induction was critical for epithelialmesenchymal transition and Wnt/β-catenin signaling in breast cancer [7]
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