Article ; Online: Mechanism of autophagy to apoptosis switch triggered in prostate cancer cells by antitumor cytokine melanoma differentiation-associated gene 7/interleukin-24.
2010 Volume 70, Issue 9, Page(s) 3667–3676
Abstract: Melanoma differentiation-associated gene 7 (mda-7)/interleukin-24 (IL-24) is a unique member ... apoptosis in prostate cancer cells that underlie the cytotoxic action of mda-7/IL-24, possibly providing new ... we report that Ad.mda-7-induced ER stress and ceramide production trigger autophagy in human prostate cancer ...
| 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. |
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| MeSH term(s) | Apoptosis/physiology ; Apoptosis Regulatory Proteins/metabolism ; Autophagy/physiology ; Autophagy-Related Protein 5 ; Beclin-1 ; Calpain/metabolism ; Cell Line, Tumor ; Ceramides/biosynthesis ; Endoplasmic Reticulum/metabolism ; Humans ; Interleukins/metabolism ; Male ; Membrane Proteins/metabolism ; Microtubule-Associated Proteins/metabolism ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology | |||||
| Chemical Substances | ATG5 protein, human ; Apoptosis Regulatory Proteins ; Autophagy-Related Protein 5 ; BECN1 protein, human ; Beclin-1 ; Ceramides ; Interleukins ; Membrane Proteins ; Microtubule-Associated Proteins ; interleukin-24 ; Calpain (EC 3.4.22.-) | |||||
| Language | English | |||||
| Publishing date | 2010-04-20 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 1432-1 | |||||
| ISSN | 1538-7445 ; 0008-5472 | |||||
| ISSN (online) | 1538-7445 | |||||
| ISSN | 0008-5472 | |||||
| DOI | 10.1158/0008-5472.CAN-09-3647 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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