Hypoxia-induced down-modulation of PKCε promotes TRAIL-mediated apoptosis of tumor cells

Abstract

Tumor oxygen status is considered as a prognostic marker that impacts on malignant progression and outcome of tumor therapy. TNF-related apoptosis inducing ligand (TRAIL) plays a key role in cancer immunity, with potential applications in cancer therapy. Protein kinase C (PKC)ε, a transforming oncogene, has a role in the protection of cardiomyocytes and neurons from hypoxia-induced damage while, it can also modulate the susceptibility of tumor cells to TRAIL-induced cell death. Here we demonstrate that hypoxia induces a tumor cell phenotype highly sensitive to the cytotoxic effects of TRAIL. Based on the observation that: i) PKCε expression levels are impaired during hypoxia, ii) the overexpression of PKCε, but not of a kinase-inactive PKCε mutant, is able to revert the hypoxia-induced sensitivity to TRAIL, iii) the down-modulation of PKCε levels by RNA interference, on the contrary, induces the highly TRAIL-sensitive phenotype, iv) the inhibition of hypoxia-inducible transcription factor-1α (HIF-1α) by specific siRNA blocks both the hypoxia-induced down-modulation of PKCε and the induction of the highly TRAIL-sensitive phenotype; we conclude that the HIF-1α upregulation during hypoxia is associated to PKCε down-modulation that likely represents the key molecular event promoting the apoptogenic effects of TRAIL in hypoxic tumor cells.