CYP3A5, one of the cytochrome P450 superfamily members, is involved in the metabolism of drugs, carcinogens, and endogenous molecules. Previous studies mainly focused on the role of CYP3A5 polymorphism or altered enzyme activity during carcinogenesis. However, the potential physiological function of CYP3A5 in tumor progression remains largely unknown. In our present study, the expression of CYP3A5 was firstly reported frequently down-regulated in not only 159 clinical HCC samples but also 4 external HCC cohort(n = 695). Tumors with reduced level of CYP3A5 were more likely to have aggressive characteristics (vascular invasion and poor differentiation), together with the worse overall survival time and time to disease recurrence. The exogenous expression of CYP3A5 was associated with the induction of TIMP1/2 and dysfunction of MMP2/9, which suppressed HCC migration and invasion in vitro and in vivo mechanically through inhibiting AKT signaling. Strikingly, the selective inhibition of AKT phosphorylation at Ser473(instead of Thr308) residue was found in CYP3A5-stable cells with an mTORC2-dependent manner. Co-immunoprecipitation and kinase assay further confirmed that mTORC2 kinase activity rather than Rictor/mTOR complex integrity was necessary for the inhibition of p-AKT(S473). Importantly, CYP3A5-induced ROS accumulation was identified as the key factor for the regulation of mTORC2 activity, in line with the decreased GSH/GSSG contents in most clinical HCC samples with relatively lower metastatic capacity. Together, these findings highlighted the novel function of CYP3A5 in the regulation of tumor metastasis via enhancing ROS level and in turn arresting mTORC2/p-AKT(S473) signaling, which may serve as a potential prognostic biomarker and therapeutic target for HCC.

Citation Format: lei chen, hongyang Wang. Cytochrome p450 3a5 manipulates the progression of hepatocellular carcinoma via selectively targeting ros/mtorc2/p-akt (s473) signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3261. doi:10.1158/1538-7445.AM2015-3261

©2015 American Association for Cancer Research.
2015