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Mechanism of autophagy to apoptosis switch triggered in prostate cancer cells by antitumor cytokine melanoma differentiation-associated gene 7/interleukin-24 Bhutia SK; Dash R; Das SK; Azab B; Su ZZ; Lee SG; Grant S; Yacoub A; Dent P; Curiel DT; Sarkar D; Fisher PBCancer Res 2010[May]; 70 (9): 3667-76Melanoma differentiation-associated gene 7 (mda-7)/interleukin-24 (IL-24) is a unique member of the IL-10 gene family, which displays a broad range of antitumor properties, including induction of cancer-specific apoptosis. Adenoviral-mediated delivery by Ad.mda-7 invokes an endoplasmic reticulum (ER) stress response that is associated with ceramide production and autophagy in some cancer cells. Here, we report that Ad.mda-7-induced ER stress and ceramide production trigger autophagy in human prostate cancer cells, but not in normal prostate epithelial cells, through a canonical signaling pathway that involves Beclin-1, atg5, and hVps34. Autophagy occurs in cancer cells at early times after Ad.mda-7 infection, but a switch to apoptosis occurs by 48 hours after infection. Inhibiting autophagy with 3-methyladenosine increases Ad.mda-7-induced apoptosis, suggesting that autophagy may be initiated first as a cytoprotective mechanism. Inhibiting apoptosis by overexpression of antiapoptotic proteins Bcl-2 or Bcl-xL increased autophagy after Ad.mda-7 infection. During the apoptotic phase, the MDA-7/IL-24 protein physically interacted with Beclin-1 in a manner that could inhibit Beclin-1 function culminating in apoptosis. Conversely, Ad.mda-7 infection elicited calpain-mediated cleavage of the autophagic protein ATG5 in a manner that could facilitate switch to apoptosis. Our findings reveal novel aspects of the interplay between autophagy and apoptosis in prostate cancer cells that underlie the cytotoxic action of mda-7/IL-24, possibly providing new insights in the development of combinatorial therapies for prostate cancer.|Apoptosis Regulatory Proteins/metabolism[MESH]|Apoptosis/*physiology[MESH]|Autophagy-Related Protein 5[MESH]|Autophagy/*physiology[MESH]|Beclin-1[MESH]|Calpain/metabolism[MESH]|Cell Line, Tumor[MESH]|Ceramides/biosynthesis[MESH]|Endoplasmic Reticulum/metabolism[MESH]|Humans[MESH]|Interleukins/*metabolism[MESH]|Male[MESH]|Membrane Proteins/metabolism[MESH]|Microtubule-Associated Proteins/metabolism[MESH]|Prostatic Neoplasms/genetics/*metabolism/*pathology[MESH] |
