Role of mTOR and HIF-1α in LMP2A-mediated increase in ATP production

Abstract

Abstract Numerous studies indicate that latency proteins from Epstein-Barr virus contribute not only to the development, but also the survival of B cell lymphomas. Our laboratory has demonstrated that LMP2A promotes B cell lymphoma survival by inducing the activation of STAT3. More recently, pathways that link STAT3 activation with increased cellular metabolism suggested that LMP2A may increase B cell lymphoma ATP production via the mTOR-dependent activation of STAT3. Using LMP2A-negative and -positive B cell lymphoma cell lines, our data suggest that LMP2A increases ATP production in an mTOR-dependent pathway. However, the addition of the STAT3 inhibitor, STATTIC, did not impact the LMP2A-mediated increase in ATP production. Further investigation indicated that LMP2A-mediated activation of mTOR results in increases in HIF-1α protein, but not RNA, that are required for the enhancements in ATP production. Finally, our data demonstrate that LMP2A requires the activation of phosphorylated p70 ribosomal s6 kinase and 4E-BP1 to increase protein levels of HIF-1α that are required to increase ATP levels in LMP2A-expressing cell lines. Taken together, our data suggest that LMP2A gives lymphoma cells a competitive advantage to produce more ATP through increases in HIF-1α that are mTOR and p70s6K/4E-BP-1 dependent.