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

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

doi:10.3390/cancers10050153

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.

Highlights

Cancer cells lose the physiologic restraints on the cellular translational machinery, leading to increase in both global protein synthesis and translation of specific mRNAs that promote tumor cell survival [1]
We show that eIF4A is required for Interleukin 24 (IL-24)-induced apoptosis, whereby it acts by selective reduction of translation was observed for mRNAs harboring strong to moderate secondary structures in their 50 -untranslated regions (50 UTRs), including mRNAs encoding proliferation- and survival-promoting proteins
Two major events are rate-limiting in translation initiation: the formation of the ternary complex binds the 40S ribosomal subunit, and the assembly of the eukaryotic initiation factor 4F (eIF4F) complex on the mRNA cap [4]

Summary

Introduction

Cancer cells lose the physiologic restraints on the cellular translational machinery, leading to increase in both global protein synthesis and translation of specific mRNAs that promote tumor cell survival [1]. Translation initiation plays a critical role in the physiological regulation of cell proliferation, differentiation and apoptosis. Unrestricted translation initiation critically contributes to the maintenance and progression of cancers and causes malignant transformation [2,3]. Two major rate-limiting steps in translation initiation regulation are the assembly of ternary complex (TC) and eIF4F complexes [4]. Targeting translational control in general and in particular, the eIF4F translation complex, is currently at the forefront of the development a promising therapeutic strategy [5,6].

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Results

Conclusion