Eukaryotic Initiation Factor-2, Gamma Subunit, Suppresses Proliferation and Regulates the Cell Cycle Via the MAPK/ERK Signaling Pathway in Acute Myeloid Leukemia

Overview

Journal J Cancer Res Clin Oncol

Specialty Oncology

Date 2021 Jul 7

PMID 34232382

Citations 5

Authors

Jielun Lu

Shuyi Chen

Huo Tan

Zhenqian Huang

Bo Li

Ling Liu

Yimin Chen

Xiaozhen Zeng

Yawei Zou

LiHua Xu

Affiliations

Soon will be listed here.

Abstract

Purpose: The expression of eukaryotic translation initiation factor-2 subunit 3 (EIF2S3) in patients with non-small cell lung and colorectal cancer is lower than that in healthy individuals. However, the functions of EIF2S3 remain unclear, and its study in leukemia has not been reported. The article aims to explore the role of EIF2S3 in AML (acute myeloid leukemia) and its underlying mechanism.

Methods: Reverse transcription-quantitative PCR was performed to evaluate the expression levels of EIF2S3, and its association with patient prognosis was determined. Inducible HEL-EIF2S3 and HL-60-EIF2S3 cell lines were established by retrovirus infection. Cellular proliferation and the cell cycle were analyzed using Cell Counting Kit-8 and flow cytometric analyses. Tumorigenic ability was evaluated using xenograft nude mouse model. Gene expression profiles were analyzed in HL-60-EIF2S3 cells by next-generation sequencing, and WB analysis was performed to detect the expression of related proteins.

Results: The expression of EIF2S3 in patients with AML was lower than that experiencing CR (P = 0.02). Furthermore, EIF2S3 overexpression inhibited cellular proliferation, halted G0/1 to S phase cell cycle progression, and inhibited tumorigenicity (P = 0.015). 479 differentially expressed genes were identified between HL60-EIF2S3 DOX (-) and HL60-EIF2S3 DOX ( +) cells via NGS and several of them involved in MAPK/ERK signaling pathway. The phosphorylation levels of ERK decreased when EIF2S3 was overexpressed (P < 0.050).

Conclusion: EIF2S3 overexpression may result in a decrease in cellular proliferation, cell cycle arrest, and tumorigenic inhibition via the MAPK/ERK signaling pathway in AML cells.

Citing Articles

A novel prognostic model based on pyroptosis signature in AML.

Zhang H, Zhu H, Sheng Y, Cheng Z, Peng H Heliyon. 2024; 10(17):e36624.

PMID: 39263179 PMC: 11387551. DOI: 10.1016/j.heliyon.2024.e36624.

Developmental programming: adverse sexually dimorphic transcriptional programming of gestational testosterone excess in cardiac left ventricle of fetal sheep.

Ramamoorthi Elangovan V, Saadat N, Ghnenis A, Padmanabhan V, Vyas A Sci Rep. 2023; 13(1):2682.

PMID: 36792653 PMC: 9932081. DOI: 10.1038/s41598-023-29212-9.

Gene-Function-Based Clusters Explore Intricate Networks of Gene Expression of Circulating Tumor Cells in Patients with Colorectal Cancer.

Huang C, Terng H, Hwang Y Biomedicines. 2023; 11(1).

PMID: 36672653 PMC: 9855519. DOI: 10.3390/biomedicines11010145.

Upregulation of NUAK2: A novel prognostic marker in breast cancer.

Chen B, Wang B, Xu X, Chen X, Yi W, Xu S Histol Histopathol. 2022; 38(7):811-822.

PMID: 36440828 DOI: 10.14670/HH-18-554.

Maintains Cancer Stemness and Promotes Erlotinib Resistance in Lung Adenocarcinoma.

Jiang S, Huang J, He H, Liu Y, Liang L, Sun X Cancers (Basel). 2022; 14(18).

PMID: 36139554 PMC: 9497119. DOI: 10.3390/cancers14184395.

References

Arber D, Orazi A, Hasserjian R, Thiele J, Borowitz M, Le Beau M . The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016; 127(20):2391-405. DOI: 10.1182/blood-2016-03-643544. View

Borck G, Shin B, Stiller B, Mimouni-Bloch A, Thiele H, Kim J . eIF2γ mutation that disrupts eIF2 complex integrity links intellectual disability to impaired translation initiation. Mol Cell. 2012; 48(4):641-6. PMC: 3513554. DOI: 10.1016/j.molcel.2012.09.005. View

Bose P, Vachhani P, Cortes J . Treatment of Relapsed/Refractory Acute Myeloid Leukemia. Curr Treat Options Oncol. 2017; 18(3):17. DOI: 10.1007/s11864-017-0456-2. View

Chang Y, Huang C, Yao C, Su S, Terng H, Chou H . Gene expression profile of peripheral blood in colorectal cancer. World J Gastroenterol. 2014; 20(39):14463-71. PMC: 4202375. DOI: 10.3748/wjg.v20.i39.14463. View

Chen W, Zheng R, Baade P, Zhang S, Zeng H, Bray F . Cancer statistics in China, 2015. CA Cancer J Clin. 2016; 66(2):115-32. DOI: 10.3322/caac.21338. View

Chian C, Hwang Y, Terng H, Lee S, Chao T, Chang H . Panels of tumor-derived RNA markers in peripheral blood of patients with non-small cell lung cancer: their dependence on age, gender and clinical stages. Oncotarget. 2016; 7(31):50582-50595. PMC: 5226605. DOI: 10.18632/oncotarget.10558. View

Coombs C, Tallman M, Levine R . Molecular therapy for acute myeloid leukaemia. Nat Rev Clin Oncol. 2015; 13(5):305-18. PMC: 5525060. DOI: 10.1038/nrclinonc.2015.210. View

Davila-Rodriguez M, Cortes-Gutierrez E, Hernandez-Valdes R, Guzman-Cortes K, De Leon-Cantu R, Cerda-Flores R . DNA damage in acute myeloid leukemia patients of Northern Mexico. Eur J Histochem. 2018; 61(4):2851. PMC: 5733396. DOI: 10.4081/ejh.2017.2851. View

Dohner H, Estey E, Amadori S, Appelbaum F, Buchner T, Burnett A . Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2009; 115(3):453-74. DOI: 10.1182/blood-2009-07-235358. View

10.

Grimwade D, Hills R, Moorman A, Walker H, Chatters S, Goldstone A . Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010; 116(3):354-65. DOI: 10.1182/blood-2009-11-254441. View

11.

Guo Y, Pan W, Liu S, Shen Z, Xu Y, Hu L . ERK/MAPK signalling pathway and tumorigenesis. Exp Ther Med. 2020; 19(3):1997-2007. PMC: 7027163. DOI: 10.3892/etm.2020.8454. View

12.

Hinnebusch A . Molecular mechanism of scanning and start codon selection in eukaryotes. Microbiol Mol Biol Rev. 2011; 75(3). PMC: 3165540. DOI: 10.1128/MMBR.00008-11. View

13.

Hinnebusch A . The scanning mechanism of eukaryotic translation initiation. Annu Rev Biochem. 2014; 83:779-812. DOI: 10.1146/annurev-biochem-060713-035802. View

14.

Hinnebusch A, Lorsch J . The mechanism of eukaryotic translation initiation: new insights and challenges. Cold Spring Harb Perspect Biol. 2012; 4(10). PMC: 3475172. DOI: 10.1101/cshperspect.a011544. View

15.

Lavoie H, Therrien M . Regulation of RAF protein kinases in ERK signalling. Nat Rev Mol Cell Biol. 2015; 16(5):281-98. DOI: 10.1038/nrm3979. View

16.

Lee Jr J, McCubrey J . The Raf/MEK/ERK signal transduction cascade as a target for chemotherapeutic intervention in leukemia. Leukemia. 2002; 16(4):486-507. DOI: 10.1038/sj.leu.2402460. View

17.

Lord C, Ashworth A . The DNA damage response and cancer therapy. Nature. 2012; 481(7381):287-94. DOI: 10.1038/nature10760. View

18.

Meloche S, Pouyssegur J . The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene. 2007; 26(22):3227-39. DOI: 10.1038/sj.onc.1210414. View

19.

Moortgat S, Desir J, Benoit V, Boulanger S, Pendeville H, Nassogne M . Two novel EIF2S3 mutations associated with syndromic intellectual disability with severe microcephaly, growth retardation, and epilepsy. Am J Med Genet A. 2016; 170(11):2927-2933. DOI: 10.1002/ajmg.a.37792. View

20.

Narayanan D, Weinberg O . How I investigate acute myeloid leukemia. Int J Lab Hematol. 2019; 42(1):3-15. DOI: 10.1111/ijlh.13135. View