Mechanism of autophagy to apoptosis switch triggered in prostate cancer cells by antitumor cytokine melanoma differentiation-associated gene 7/interleukin-24.
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.
Bhutia
Sujit K
SK
Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA.
Dash
Rupesh
R
Das
Swadesh K
SK
Azab
Belal
B
Su
Zhao-Zhong
ZZ
Lee
Seok-Geun
SG
Grant
Steven
S
Yacoub
Adly
A
Dent
Paul
P
Curiel
David T
DT
Sarkar
Devanand
D
Fisher
Paul B
PB
D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D002154:Calpain / Q000378:metabolism; D045744:Cell Line, Tumor; D002518:Ceramides / Q000096:biosynthesis; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D007378:Interleukins / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000099180:Interleukin-24
D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D002154:Calpain; D002518:Ceramides; D007378:Interleukins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D000099180:Interleukin-24; C502778:ATG5 protein, human; C491997:BECN1 protein, human
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