PKC α mediates chemoresistance in acute lymphoblastic leukemia through effects on Bcl2 phosphorylation

Overexpression of protein kinase C α (PKC α) promotes Bcl2 phosphorylation and chemoresistance in human acute leukemia cells. The contribution of non-Bcl2 mechanisms in this process is currently unknown. In this report, overexpression of PKC α was found not to affect cell proliferation, cell cycle, or activation of mitogen-activated protein kinases. The failure of PKC a overexpression to activate non-Bcl2 survival pathways suggested that PKC α-mediated chemoresistance requires Bcl2. Supporting this notion, REH/PKC α transfectants were found to be as sensitive to HA14-1 (a drug that targets Bcl2 function) as parental cells. In addition, HA14-1 abrogated PKC α's ability to protect REH cells from etoposide. These findings suggested that Bcl2 is necessary for the protective function of PKC α in REH cells. Since Bcl2 phosphorylation status is negatively regulated by protein phosphatase 2A (PP2A) and PP2A regulates PKC α, we investigated whether PKC α can conversely regulate PP2A. Overexpression of PKC α was found to suppress mitochondrial PP2A activity by a mechanism that, at least in part, involves suppressed expression of the regulatory subunit comprising the Bcl2 phosphatase (ie the PP2A/B56 α subunit). The ability of PKC α to target both Bcl2 and the Bcl2 phosphatase represents a novel mechanism for chemoresistance.