Mechanism of autophagy to apoptosis switch triggered in prostate cancer cells by antitumor cytokine melanoma differentiation-associated gene 7/interleukin-24

Sujit K. Bhutia, Rupesh Dash, Swadesh K. Das, Belal Azab, Zhao Zhong Su, Seok Geun Lee, Steven Grant, Adly Yacoub, Paul Dent, David T. Curiel, Devanand Sarkar, Paul B. Fisher

Research output: Contribution to journalArticle

93 Scopus citations

Abstract

Melanoma 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.

Original languageEnglish
Pages (from-to)3667-3676
Number of pages10
JournalCancer research
Volume70
Issue number9
DOIs
StatePublished - May 1 2010
Externally publishedYes

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    Bhutia, S. K., Dash, R., Das, S. K., Azab, B., Su, Z. Z., Lee, S. G., Grant, S., Yacoub, A., Dent, P., Curiel, D. T., Sarkar, D., & Fisher, P. B. (2010). Mechanism of autophagy to apoptosis switch triggered in prostate cancer cells by antitumor cytokine melanoma differentiation-associated gene 7/interleukin-24. Cancer research, 70(9), 3667-3676. https://doi.org/10.1158/0008-5472.CAN-09-3647