Eukaryotic Translation Initiation Factor 4A Down-Regulation Mediates Interleukin-24-Induced Apoptosis through Inhibition of Translation

Xuelin Zhong; Leah Persaud; Hilal Muharam; Ashleigh Francis; Dibash Das; Bertal Huseyin Aktas; Moira Sauane

doi:10.3390/cancers10050153

Eukaryotic Translation Initiation Factor 4A Down-Regulation Mediates Interleukin-24-Induced Apoptosis through Inhibition of Translation

Cancers (Basel). 2018 May 22;10(5):153. doi: 10.3390/cancers10050153.

Authors

Xuelin Zhong^{1

2}, Leah Persaud^{3

4}, Hilal Muharam⁵, Ashleigh Francis⁶, Dibash Das^{7

8}, Bertal Huseyin Aktas^{9

10}, Moira Sauane^{11

12}

Affiliations

¹ Department of Biological Sciences, Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, USA. xzhong@gradcenter.cuny.edu.
² Department of Biology, The Graduate Center, City University of New York, 365 Fifth Avenue, Room 4315, New York, NY 10016, USA. xzhong@gradcenter.cuny.edu.
³ Department of Biological Sciences, Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, USA. LEAH.PERSAUD@lehman.cuny.edu.
⁴ Department of Biology, The Graduate Center, City University of New York, 365 Fifth Avenue, Room 4315, New York, NY 10016, USA. LEAH.PERSAUD@lehman.cuny.edu.
⁵ Department of Biological Sciences, Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, USA. HILAL.MUHARAM@lc.cuny.edu.
⁶ Department of Biological Sciences, Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, USA. ashleighfrancis64@gmail.com.
⁷ Department of Biological Sciences, Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, USA. dd791@hunter.cuny.edu.
⁸ Department of Biology, The Graduate Center, City University of New York, 365 Fifth Avenue, Room 4315, New York, NY 10016, USA. dd791@hunter.cuny.edu.
⁹ Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. huseyin_aktas@hms.harvard.edu.
¹⁰ Harvard Medical School, Laboratory for Translational Research, One Kendall Square, Building 600, 3rd Floor, Cambridge, MA 02139, USA. huseyin_aktas@hms.harvard.edu.
¹¹ Department of Biological Sciences, Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, USA. moira.sauane@lehman.cuny.edu.
¹² Department of Biology, The Graduate Center, City University of New York, 365 Fifth Avenue, Room 4315, New York, NY 10016, USA. moira.sauane@lehman.cuny.edu.

Abstract

Dysregulated activity of helicase eIF4A drives transformation to and maintenance of cancer cell phenotype by reprogramming cellular translation. Interleukin 24 (IL-24) is a tumor-suppressing protein, which has the ability to inhibit angiogenesis, sensitize cancer cells to chemotherapy, and induce cancer cell-specific apoptosis. In this study, we found that eIF4A is inhibited by IL-24. Consequently, selective reduction of translation was observed for mRNAs harboring strong secondary structures in their 5'-untranslated regions (5'UTRs). These mRNAs encode proteins, which function in cell survival and proliferation. Consistently, overexpression of eIF4A conferred cancer cells with resistance to IL-24-induced cell death. It has been established that inhibition of eIF4A triggers mitochondrial-mediated apoptosis. We showed that IL-24 induces eIF4A-dependent mitochondrial depolarization. We also showed that IL-24 induces Sigma 1 Receptor-dependent eIF4A down-regulation and mitochondrial depolarization. Thus, the progress of apoptosis triggered by IL-24 is characterized by a complex program of changes in regulation of several initiation factors, including the eIF4A.

Keywords: Interleukin 24; Sigma 1 receptor; apoptosis; eukaryotic initiation factor 4A; eukaryotic initiation factor 4F complex; translation regulation.

Grants and funding

SC1 CA200518/CA/NCI NIH HHS/United States