Mechanism by which Mcl-1 regulates cancer-specific apoptosis triggered by mda-7/IL-24, an IL-10-related cytokine

Rupesh Dash, Joanna E. Richards, Zhao Zhong Su, Sujit K. Bhutia, Belal Azab, Mohamed Rahmani, Girija Dasmahapatra, Adly Yacoub, Paul Dent, Igor P. Dmitriev, David T. Curiel, Steven Grant, Maurizio Pellecchia, John C. Reed, Devanand Sarkar, Paul B. Fisher

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)5034-5045
Number of pages12
JournalCancer research
Volume70
Issue number12
DOIs
StatePublished - Jun 15 2010

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