Down-modulation of c-myc expression by phorbol ester protects CEM T leukaemia cells from starvation-induced apoptosis: Role of ornithine decarboxylase and polyamines

Abstract

Myc is a transcriptional activator whose deregulated expression not only promotes proliferation but also induces or sensitizes cells to apoptosis. Here we demonstrate that c-myc plays a role in triggering apoptosis in CEM T leukaemia cells exposed to progressive medium exhaustion. Indeed starved cells undergo apoptosis in the presence of constitutively elevated c-myc expression and the phorbol ester, phorbol 12-miristate 13-acetate (PMA), which rescues cells from apoptosis, induces complete c-myc down-regulation. We also investigate the hypothesis that ornithine decarboxylase (ODC), a transcriptional target of c-myc, is a down-stream mediator of c-myc driven apoptosis. We demonstrate that PMA induces in starved cells an earlier and larger decrease in ODC expression (mRNA and activity) and intracellular polyamine content, compared to untreated starved cells. Moreover we show that α-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC enzymatic activity, effectively reduces, while exogenous added polyamines enhance apoptosis in starved cells. All these data indicate that ODC and polyamines may act as facilitating factors in triggering apoptosis induced by growth/survival factors withdrawal.