Abstract 51: The eukaryotic translation initiation factor 4H regulates proliferation, migration, and invasion in cancer cells

Abstract

Abstract Background: Dysregulated translation during protein synthesis is a hallmark of multiple human cancers. However, the precise mechanisms remain to be understood. Protein translation of oncogenic mRNAs is highly upregulated in cancer cells and these cells are very sensitive to therapeutic strategies/agents targeting translation inhibition. In this study we investigated the role of translation initiation factor eIF4H in proliferation and survival of cancer cells. Methods: We selected the breast cancer cell line MDA-MB 231 and the CML cell line K562 for our study. We silenced eIF4H by shRNA and cell proliferation were analyzed by MTT assay and flowcytometry. Expression of antiapoptotic and proproliferative proteins were analyzed by Western blotting and for analysis of mRNA expression real-time PCR was used. Effect of eIF4H silencing on cell migration and invasion was analyzed by migration and invasion assays, respectively. Results: Using 2D Gel based proteomics we targeted the translational machinery in chronic myeloid leukemia cell line K562 and identified eIF4H as a critical regulator of carcinogenesis. The eIF4H expression was found to be overexpressed in a variety of cancer cell line vis-à-vis the normal nontransformed cells. Similarly, the real-time PCR analysis showed eIF4H overexpression in chronic myeloid leukemia clinical samples compared to that of the healthy controls. The pharmacologic inhibition of eIF4H induced downregulation of its regulatory proteins cMYC, cyclin D1, and antiapoptotic proteins in breast cancer cell line MDAMB-231 and CML cell line K562 cells. The genomic inhibition of eIF4H decreased cell migration and invasion in vitro in MDA-MB 231 cell line and it also inhibits proliferation of both cell lines. Furthermore, the p65-dependent transcriptional activation of eIF4H was observed to be associated with this process. Conclusion: Our results demonstrate that eIF4H plays an important role in the proliferation, migration, and invasion of cancer cells. Silencing of eIF4H markedly decreased expression of antiapoptotic and proproliferative proteins. Collectively, our findings suggest that eIF4H may have translational relevance as a therapeutic target in cancer therapy. Citation Format: Manohar Singh, Rachana Trivedi, Durga Prasad Mishra. The eukaryotic translation initiation factor 4H regulates proliferation, migration, and invasion in cancer cells [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 51.