A novel pathway involving melanoma differentiation associated gene-7/interleukin-24 mediates nonsteroidal anti-inflammatory drug-induced apoptosis and growth arrest of cancer cells

Luiz F. Zerbini, Akos Czibere, Yihong Wang, Ricardo G. Correa, Hasan Otu, Marie Joseph, Yuko Takayasu, Moriah Silver, Xuesong Gu, Kriangsak Ruchusatsawat, Linglin Li, Devanand Sarkar, Jin Rong Zhou, Paul B. Fisher, Towia A. Libermann

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

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 α (GADD45α) and GADD45γ 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 GADD45α and GADD45γ 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 GADD45α and GADD45γ as critical mediators of apoptosis and growth arrest in response to NSAIDs in cancer cells.

Original languageEnglish (US)
Pages (from-to)11922-11931
Number of pages10
JournalCancer Research
Volume66
Issue number24
DOIs
StatePublished - Dec 15 2006

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Zerbini, L. F., Czibere, A., Wang, Y., Correa, R. G., Otu, H., Joseph, M., Takayasu, Y., Silver, M., Gu, X., Ruchusatsawat, K., Li, L., Sarkar, D., Zhou, J. R., Fisher, P. B., & Libermann, T. A. (2006). A novel pathway involving melanoma differentiation associated gene-7/interleukin-24 mediates nonsteroidal anti-inflammatory drug-induced apoptosis and growth arrest of cancer cells. Cancer Research, 66(24), 11922-11931. https://doi.org/10.1158/0008-5472.CAN-06-2068