Abstract 1038: Defining the mechanism by which melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24)-induced autophagy switches to apoptosis in prostate cancer cells

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Abstract Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24), a unique member of the IL-10 gene family, displays a broad range of antitumor properties including cancer-specific induction of apoptosis, inhibition of tumor angiogenesis, and modulation of an anti-tumor immune response. Apoptosis induction by mda-7/IL-24, when delivered by an adenovirus (Ad. mda-7), involves an endoplasmic reticulum (ER) stress response and generation of ceramides. Additionally, Ad. mda-7 promotes autophagy in certain cancer cell types. In the present study, we document that Ad-mda-7-induced ER stress and ceramide generation result in induction of autophagy in prostate cancer cells, without affecting normal human prostate epithelial cells, via the canonical autophagic pathway, involving Beclin-1, atg5 and hVps34. Autophagy is evident until 24 h post Ad. mda-7-infection and then switches to apoptosis at 48 h. Inhibition of autophagy by 3-methyladenosine (3-MA) significantly increases Ad. mda-7-induced apoptosis suggesting that autophagy might first be initiated as a cytoprotective mechanism in prostate cancer cells. Inhibition of apoptosis by overexpression of anti-apoptotic proteins Bcl-2 or Bcl-xL increases autophagy upon Ad. mda-7 infection. During the apoptotic phase, MDA-7/IL-24 protein physically interacts with Beclin-1 and this interaction might inhibit Beclin-1 function culminating in apoptosis. Conversely, Ad. mda-7 infection leads to calpain-mediated cleavage of ATG5 protein that might also facilitate a biochemical switch from autophagy to apoptosis. Our present studies reveal novel aspects of interplay between autophagy and apoptosis that underlie the cytotoxic action of mda-7/IL-24 in prostate cancer cells. These new insights into mda-7/IL-24 action provide interesting leads for developing innovative combinatorial approaches for prostate cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1038.