Interleukin 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 (eIF2a) during endoplasmic reticulum (ER)
stress in cancer. Although multiple stresses converge on eIF2a phosphorylation, the cellular outcome
is not always the same. In particular, ER stress-induced apoptosis is primarily regulated through
the extent of eIF2a 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.

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