Mechanism by which Mcl-1 regulates cancer-specific apoptosis triggered by mda-7/IL-24, an IL-10-related cytokine.
Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24), a cytokine belonging to the IL-10 family, selectively induces apoptosis in cancer cells without harming normal cells by promoting an endoplasmic reticulum (ER) stress response. The precise molecular mechanism by which the ER stress response culminates in cell death requires further clarification. The present study shows that in prostate carcinoma cells, the mda-7/IL-24-induced ER stress response causes apoptosis by translational inhibition of the antiapoptotic protein myeloid cell leukemia-1 (Mcl-1). Forced expression of Mcl-1 blocked mda-7/IL-24 lethality, whereas RNA interference or gene knockout of Mcl-1 markedly sensitized transformed cells to mda-7/IL-24. Mcl-1 downregulation by mda-7/IL-24 relieved its association with the proapoptotic protein Bak, causing oligomerization of Bak and leading to cell death. These observations show the profound role of the Bcl-2 protein family member Mcl-1 in regulating cancer-specific apoptosis induced by this cytokine. Thus, our studies provide further insights into the molecular mechanism of ER stress-induced cancer-selective apoptosis by mda-7/IL-24. As Mcl-1 is overexpressed in the majority of prostate cancers, mda-7/IL-24 might provide an effective therapeutic for this disease.
Dash
Rupesh
R
Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia 23298, USA.
Richards
Joanna E
JE
Su
Zhao-Zhong
ZZ
Bhutia
Sujit K
SK
Azab
Belal
B
Rahmani
Mohamed
M
Dasmahapatra
Girija
G
Yacoub
Adly
A
Dent
Paul
P
Dmitriev
Igor P
IP
Curiel
David T
DT
Grant
Steven
S
Pellecchia
Maurizio
M
Reed
John C
JC
Sarkar
Devanand
D
Fisher
Paul B
PB
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D016753:Interleukin-10; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000099180:Interleukin-24
D016753:Interleukin-10; D007378:Interleukins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D000099180:Interleukin-24; C508609:IL10 protein, human; C579094:Mcl1 protein, mouse