IL-24 Promotes Apoptosis through cAMP-Dependent PKA Pathways in Human Breast Cancer Cells
AbstractInterleukin 24 (IL-24) is a tumor-suppressing protein, which inhibits angiogenesis and induces cancer cell-specific apoptosis. We have shown that IL-24 regulates apoptosis through phosphorylated eukaryotic initiation factor 2 alpha (eIF2α) during endoplasmic reticulum (ER) stress in cancer. Although multiple stresses converge on eIF2α phosphorylation, the cellular outcome is not always the same. In particular, ER stress-induced apoptosis is primarily regulated through the extent of eIF2α phosphorylation and activating transcription factor 4 (ATF4) action. Our studies show for the first time that cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) activation is required for IL-24-induced cell death in a variety of breast cancer cell lines and this event increases ATF4 activity. We demonstrate an undocumented role for PKA in regulating IL-24-induced cell death, whereby PKA stimulates phosphorylation of p38 mitogen-activated protein kinase and upregulates extrinsic apoptotic factors of the Fas/FasL signaling pathway and death receptor 4 expression. We also demonstrate that phosphorylation and nuclear import of tumor suppressor TP53 occurs downstream of IL-24-mediated PKA activation. These discoveries provide the first mechanistic insights into the function of PKA as a key regulator of the extrinsic pathway, ER stress, and TP53 activation triggered by IL-24. View Full-Text
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Persaud, L.; Mighty, J.; Zhong, X.; Francis, A.; Mendez, M.; Muharam, H.; Redenti, S.M.; Das, D.; Aktas, B.H.; Sauane, M. IL-24 Promotes Apoptosis through cAMP-Dependent PKA Pathways in Human Breast Cancer Cells. Int. J. Mol. Sci. 2018, 19, 3561.
Persaud L, Mighty J, Zhong X, Francis A, Mendez M, Muharam H, Redenti SM, Das D, Aktas BH, Sauane M. IL-24 Promotes Apoptosis through cAMP-Dependent PKA Pathways in Human Breast Cancer Cells. International Journal of Molecular Sciences. 2018; 19(11):3561.Chicago/Turabian Style
Persaud, Leah; Mighty, Jason; Zhong, Xuelin; Francis, Ashleigh; Mendez, Marifer; Muharam, Hilal; Redenti, Stephen M.; Das, Dibash; Aktas, Bertal H.; Sauane, Moira. 2018. "IL-24 Promotes Apoptosis through cAMP-Dependent PKA Pathways in Human Breast Cancer Cells." Int. J. Mol. Sci. 19, no. 11: 3561.
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