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

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.

Eukaryotic initiation Factor 4AIII facilitates hepatocellular carcinoma cell proliferation, migration, and epithelial‐mesenchymal transition process via antagonistically binding to WD repeat domain 66 with miRNA‐2113

“…Among all candidate mRNAs, WDR66 has been reported as a human disease‐associated gene (Kim et al, 2012). More important, WDR66 has been uncovered to be a novel oncogene in gastric cancer and involved in the EMT process of esophageal squamous cell carcinoma cells (Wang et al, 2013; Zhong et al, 2018). The present research confirmed that eIF4AIII interacted with WDR66 and further stabilized its mRNA.…”

“…They are implicated in certain cellular activities referring to alteration of RNA secondary structure, such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. The functional roles of eIF4A family in cancers are exposed in a few studies, for instances, eukaryotic translation initiation Factor 4A silence mediates interleukin‐24‐caused apoptosis by inhibition of translation (Zhong et al, 2018); miR‐133a serves as a tumor suppressor role in colorectal cancer through targeting eIF4A1 (W. Li et al, 2017b); Sanguinarine inhibits the progression of epithelial ovarian cancer by regulating long noncoding RNA (lncRNA) CASC2‐EIF4A3 pathway and/or inhibiting PI3K/AKT/mTOR or nuclear factor kappa B (NF‐κB) signaling pathway (Zhang et al, 2018). The precise function of eIF4AIII in HCC has never been elaborated.…”

Clinical Significance of the Interleukin 24 mRNA Level in Head and Neck Squamous Cell Carcinoma and Its Subgroups: An In Silico Investigation

“…IL24 mRNA is known to have an apoptotic effect on cancer cells but not on noncancer cells [ 22 , 23 ]. IL24 mRNA could induce autophagy as a protective mechanism, while 3-methyladenine (3-MA) inhibition of autophagy significantly enhanced the anticancer effect of IL24 in OSCC [ 18 ].…”

Integrative resource for network-based investigation of COVID-19 combinatorial drug repositioning and mechanism of action

“…34 LY2275796 inhibits the eIF4E complex and its activating kinases, MNK1/2, and is currently in phase 1 development as the second antisense anticancer drug. 35 Inhibition of eIF4A 36 or eIF4F, 37 the catalytic subunits of eIF4F, is shown to lead to apoptosis in selected cancer models. EIF4E, F, and G proteins are involved in tumor progression, angiogenesis, and metastases.…”