Reduced expression and activity of the proapoptotic,
double-stranded RNA-dependent
protein kinase, PKR (
protein kinase R) is observed in breast, lung and various
leukemias, suggesting that loss of PKR potentiates transformation. Now we report that decreased PKR activity inhibits
chemotherapy-induced apoptosis of
leukemia cells both in vitro and in vivo. Inhibition of PKR expression or activity reduces
protein phosphatase 2A (PP2A) activity, a
B-cell lymphoma 2 (Bcl-2)
phosphatase, resulting in enhanced Bcl-2 phosphorylation. Thus, inhibition of PKR activity leads to hyperphosphorylation of Bcl-2, stabilization of Bcl-2/Bax interaction and decreased Bax insertion into the outer mitochondrial membrane. Treatment with the PP2A activator,
FTY720, restores Bcl-2 dephosphorylation and apoptosis in cells with reduced PKR expression following stress. Significantly, xenografts of REH leukemic cells with reduced PKR display significantly increased
tumor volume, increased resistance to
doxorubicin treatment and shorter survival. Importantly,
FTY720 treatment restores sensitivity to
chemotherapy and prolongs overall survival of these mice. Collectively, these findings suggest that PP2A activation is a downstream target of PKR and the PKR/PP2A signaling axis is required for rapid and potent stress-induced apoptosis. Importantly, loss of PKR promotes
leukemia progression and may serve as a
biomarker for predicting chemosensitivity.