title: Mechanism of autophagy to apoptosis switch triggered in prostate cancer cells by antitumor cytokine melanoma differentiation-associated gene 7/interleukin-24.
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.
authors.affiliation: Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA.
authors.forename: Sujit K
authors.initials: SK
authors.lastname: Bhutia
authors.forename: Rupesh
authors.initials: R
authors.lastname: Dash
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.forename: Belal
authors.initials: B
authors.lastname: Azab
authors.forename: Zhao-Zhong
authors.initials: ZZ
authors.lastname: Su
authors.forename: Seok-Geun
authors.initials: SG
authors.lastname: Lee
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Adly
authors.initials: A
authors.lastname: Yacoub
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: 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
chemical_list: 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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