IL-24 Promotes Apoptosis through cAMP-Dependent PKA Pathways in Human Breast Cancer Cells.

Leah Persaud,Leah Persaud,Leah Persaud,Marifer Mendez,Jason Mighty,Jason Mighty,Jason Mighty,Xuelin Zhong,Xuelin Zhong,Xuelin Zhong,Moira Sauane,Moira Sauane,Moira Sauane,Dibash Das,Dibash Das,Dibash Das,Bertal Huseyin Aktas,Bertal Huseyin Aktas,Hilal Muharam,Hilal Muharam,Stephen M Redenti,Stephen M Redenti,Stephen M Redenti,Ashleigh Francis,Ashleigh Francis

doi:10.3390/ijms19113561

Abstract

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 (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.

Highlights

Interleukin-24 (IL-24) is a member of the IL-10 protein family and it displays broad cancer-specific suppressor effects [1,2,3,4,5,6,7,8]
We have recently demonstrated that IL-24 activates protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), one of three canonical ER-stress response pathways
We have recently shown that IL-24 inhibits translation initiation by phosphorylating eIF2α during ER stress [14]

Summary

Introduction

Interleukin-24 (IL-24) is a member of the IL-10 protein family and it displays broad cancer-specific suppressor effects [1,2,3,4,5,6,7,8]. The tumor suppressor activities of IL-24 include the inhibition of angiogenesis, invasion, and metastasis, sensitization to chemotherapy, and the induction of cancer-specific apoptosis [1,2,3,4,5,6,7,8]. We have shown that overexpression of IL-24 is implicated in endoplasmic reticulum (ER) stress-mediated apoptosis in cancer cells [10]. We have recently demonstrated that IL-24 activates protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), one of three canonical ER-stress response pathways. Previous studies have shown that protein kinase A (PKA) can induce ATF4 expression, leading to apoptosis in human liver carcinoma cells after treatment with palmitate, a saturated fatty acid, implicated in ER stress [11]

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Discussion

Conclusion