Next Article in Journal
Transcriptome Analysis Provides Insights into the Markers of Resting and LPS-Activated Macrophages in Grass Carp (Ctenopharyngodon idella)
Next Article in Special Issue
The Interleukin-17 Family of Cytokines in Breast Cancer
Previous Article in Journal
Special Issue on Mechanisms of Mesothelioma Heterogeneity: Highlights and Open Questions
Previous Article in Special Issue
The Two-Faced Cytokine IL-6 in Host Defense and Diseases
Article Menu
Issue 11 (November) cover image

Export Article

Open AccessArticle
Int. J. Mol. Sci. 2018, 19(11), 3561; https://doi.org/10.3390/ijms19113561

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

1
Department of Biological Sciences, Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, USA
2
Biological Sciences Doctoral Program, The Graduate Center, City University of New York, 365 Fifth Avenue, Room 4315, New York, NY 10016, USA
3
Department of Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA
4
Harvard Medical School, and Brigham and Women’s Hospital, Division of Hematology, 75 Francis Street, Boston, MA 02115, USA
*
Authors to whom correspondence should be addressed.
Received: 21 September 2018 / Revised: 4 November 2018 / Accepted: 8 November 2018 / Published: 12 November 2018
(This article belongs to the Special Issue The Interleukins in Health and Disease)
Full-Text   |   PDF [4033 KB, uploaded 12 November 2018]   |  

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. View Full-Text
Keywords: interleukin 24; melanoma differentiation associated gene 7; protein kinase A; apoptosis; p53; cytokine; ATF4; extrinsic apoptosis; translation initiation; cancer therapy; gene therapy interleukin 24; melanoma differentiation associated gene 7; protein kinase A; apoptosis; p53; cytokine; ATF4; extrinsic apoptosis; translation initiation; cancer therapy; gene therapy
Figures

Graphical abstract

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
SciFeed

Share & Cite This Article

MDPI and ACS Style

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.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top