Melanoma differentiation associated gene−7(mda−7) encodes IL−24, a cytokine that can selectively trigger apoptosis in transformed cells. Recombinant mda−7 adenovirus (Ad.mda−7) effectively kills glioma cells, offering a novel gene therapy strategy to address deadly brain tumors. In this study, we defined the proximal mechanisms by which Ad−mda−7 kills glioma cells. Key factors implicated included activation of the endoplasmic reticulum stress kinase protein kinase R−like endoplasmic reticulum kinase (PERK), Ca(++) elevation, ceramide generation and reactive oxygen species (ROS) production. PERK inhibition blocked ceramide or dihydroceramide generation, which were critical for Ca(++) induction and subsequent ROS formation. Activation of autophagy and cell death relied upon ROS formation, the inhibition of which ablated Ad.mda−7−killing activity. In contrast, inhibiting TRX induced by Ad.MDA−7 enhanced tumor cytotoxicity and improved animal survival in an orthotopic tumor model. Our findings indicate that mda−7/IL−24 induces an endoplasmic reticulum stress response that triggers production of ceramide, Ca(2+), and ROS, which in turn promote glioma cell autophagy and cell death.

PMID: 20103619 [PubMed − in process] Source: National Library of Medicine.