A novel pathway involving melanoma differentiation associated gene-7/interleukin-24 mediates nonsteroidal anti-inflammatory drug-induced apoptosis and growth arrest of cancer cells.
Numerous studies show that nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in chemoprevention or treatment of cancer. Nevertheless, the mechanisms underlying these antineoplastic effects remain poorly understood. Here, we report that induction of the cancer-specific proapoptotic cytokine melanoma differentiation associated gene-7/interleukin-24 (MDA-7/IL-24) by several NSAIDs is an essential step for induction of apoptosis and G(2)-M growth arrest in cancer cells in vitro and inhibition of tumor growth in vivo. We also show that MDA-7/IL-24-dependent up-regulation of growth arrest and DNA damage inducible 45 alpha (GADD45alpha) and GADD45gamma gene expression is sufficient for cancer cell apoptosis via c-Jun NH(2)-terminal kinase (JNK) activation and growth arrest induction through inhibition of Cdc2-cyclin B checkpoint kinase. Knockdown of GADD45alpha and GADD45gamma transcription by small interfering RNA abrogates apoptosis and growth arrest induction by the NSAID treatment, blocks JNK activation, and restores Cdc2-cyclin B kinase activity. Our results establish MDA-7/IL-24 and GADD45alpha and GADD45gamma as critical mediators of apoptosis and growth arrest in response to NSAIDs in cancer cells.
Zerbini
Luiz F
LF
BIDMC Genomics Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.
Czibere
Akos
A
Wang
Yihong
Y
Correa
Ricardo G
RG
Otu
Hasan
H
Joseph
Marie
M
Takayasu
Yuko
Y
Silver
Moriah
M
Gu
Xuesong
X
Ruchusatsawat
Kriangsak
K
Li
Linglin
L
Sarkar
Devanand
D
Zhou
Jin-Rong
JR
Fisher
Paul B
PB
Libermann
Towia A
TA
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D003470:Culture Media; D004249:DNA Damage; D006801:Humans; D007378:Interleukins / Q000235:genetics* / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D014158:Transcription, Genetic; D000097642:GADD45 Proteins; D000099180:Interleukin-24
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018797:Cell Cycle Proteins; D003470:Culture Media; D007378:Interleukins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D000097642:GADD45 Proteins; D000099180:Interleukin-24; C439070:GADD45A protein, human