PKCα promotes generation of reactive oxygen species via DUOX2 in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains the second leading cause of cancer-related death worldwide, and elevated rates of reactive oxygen species (ROS) have long been considered as a hallmark of almost all types of cancer including HCC. Protein kinase C alpha (PKC alpha), a serine/threonine kinase among conventional PKC family, is recognized as a major player in signal transduction and tumor progression. Overexpression of PKC alpha is commonly observed in human HCC and associated with its poor prognosis. However, how PKC alpha is involved in hepatocellular carcinogenesis remains not fully understood. In this study, we found that among the members of conventional PKC family, PKC alpha, but not PKC beta I or beta II, promoted ROS production in HCC cells. PKC alpha stimulated generation of ROS by up-regulating DUOX2 at post-transcriptional level. Depletion of DUOX2 abrogated PKC alpha-induced activation of AKT/MAPK pathways as well as cell proliferation, migration and invasion in HCC cells. Moreover, the expression of DUOX2 and PKC alpha was well positively correlated in both HCC cell lines and patient samples. Collectively, our findings demonstrate that PKC alpha plays a critical role in HCC development by inducing DUOX2 expression and ROS generation, and propose a strategy to target PKC alpha/DUOX2 as a potential adjuvant therapy for HCC treatment. (C) 2015 Elsevier Inc. All rights reserved.