LMP1 and 2A Induce the Expression of Nrf2 Through Akt Signaling Pathway in Epstein-Barr Virus–Transformed B Cells

Abstract The transcription factor Nrf2, which regulates the expression of antioxidant and cytoprotectiveenzymes, contributes to cell proliferation and resistance to chemotherapy. Nrf2 is also dysregulated in many cancers such as lung, head and neck, and breast cancers, but its role in Epstein-Barr virus (EBV)–transformed B cellsis still not understood. Here, we investigated EBV infection-induced Nrf2 activation in B cellsby analyzing translocation of Nrf2 from the cytosol to the nucleus. In addition, we confirmed expression of the target genes in response to increased Nrf2 activation in EBV-transformed B cells. We demonstrated that knockdown of LMP1 and 2A blocks the translocation of Nrf2 to the nucleus and reduces ROS production in EBV-transformed B cells. Further, we showed that inhibition of Akt prevents Nrf2 activation. Moreover, knockdown of Nrf2 induces apoptotic cell death in EBV-transformed B cells. In conclusion, our study demonstrates that Nrf2 promotes proliferation of EBV-transformed B cellsthrough the EBV-related proteins LMP1 and 2A and Akt signaling, implicating Nrf2 as a potential molecular target for EBV-associated disease.