IRS1/β‐Catenin Axis Is Activated and Induces MYC Expression in Acute Lymphoblastic Leukemia Cells

Abstract

Insulin-like growth factor 1 (IGF1) and its receptor IGF1R regulate normal cell growth and contribute to cell transformation through activation of downstream signaling pathways. In fibroblast cells, insulin receptor substrate 1 (IRS1), through IGF1 signaling, was found to be the key protein for nuclear translocation of β-catenin and MYC transcription activation. We herein investigated the IRS1/β-catenin axis in acute lymphoblastic leukemia (ALL) cells. Samples were obtained from 45 patients with ALL and 13 healthy donors. ALL cell lines were used. Gene expression was measured by quantitative PCR. Protein expression, associations, and cellular localization were evaluated by immunoprecipitation, subcellular fractionation, and confocal microscopy. Cells were submitted to IGF1 stimulation and/or IGF1R pharmacological inhibition (OSI-906). IRS1, β-catenin, and MYC mRNA expression were significantly elevated in ALL patients, compared to normal controls. MYC mRNA expression positively correlated with β-catenin and IRS1. Increased age and MYC expression negatively affected overall survival by univariate analysis. Total and phospho-IGF1R and IRS1, MYC and β-catenin protein expression were higher in ALL cells, compared to normal peripheral blood mononuclear cells (PBMC). IRS1 and β-catenin were found to be colocalized in the nuclei and the cytoplasm of ALL cell lines, whereas both proteins were only slightly detected in the cytoplasm of normal PBMC. In Jurkat cells, a constitutive IRS1 and β-catenin protein interaction were observed; OSI-906 treatment decreased IGF1R tyrosine phosphorylation, IRS1 expression and phosphorylation, nuclear translocation of β-catenin, IRS1 and β-catenin association, and MYC protein expression. In conclusion, the IRS1/β-catenin axis is activated in ALL cells. J. Cell. Biochem. 118: 1774-1781, 2017. © 2016 Wiley Periodicals, Inc.

Targeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐cell acute lymphoblastic leukemia

“…An aberrant increase in the levels of β-catenin exerts oncogenic effects via the activation of downstream gene expression programs in colorectal cancer (Morin et al, 1997;Rahmani, Avan, Hashemy, & Hassanian, 2018;Vermeulen et al, 2010), endometrial cancer (Giannakis et al, 2014;Liu, Chang, Lu, & Xiang, 2019), breast cancer (Gao et al, 2019;Khramtsov et al, 2010;Mohammadi-Yeganeh, Hosseini, & Paryan, 2019;Rahmani et al, 2019), prostate cancer (Pashirzad et al, 2019), bladder cancer (Xie et al, 2019), lung cancer (Wang, Zhou, Xu, & Hu, 2018b), glioblastoma (He et al, 2019) as well as in blood malignancies (Staal & Sen, 2008;Zhao et al, 2007). More specifically, ≥85% of pediatric T-ALL patients display increased β-catenin expression and upregulation of the Wnt target genes AXIN2, C-MYC, TCFL, and LEF (Arensman et al, 2014;Fernandes et al, 2017;Ng et al, 2014). Furthermore, about 30% of adult T-ALL patients displayed high expression of lymphoid enhancer-binding Factor 1 (LEF1) messenger RNA (mRNA; Guo et al, 2015).…”

Construction of Gene Network in Type 2 Diabetes with Genome-Wide Association Study

“…To obtain the target genes are selected from 2007 up to now in the research of GWAS in type 2 diabetes with significant genes, a total of 65, according to the cause of diabetes mellitus, can be divided into impaired beta cell function (such as TCF7L2, HHEX, SLC30A8 and CDKN2A) [3], insulin resistance (such as IRS1, ADAMTS9, PTPRD and SPRY2) [4]and the function is no clear genes (such as ADCY5, HMGA2, DUSP9, AP3S2, PEPD and ANK1) [5]. Genetic and biological pathway data from KEGG (Kyoto Encyclopedia of Genes and Genomes, KEGG) database [6] (http://www.kegg.com/jp) and Genecards database [7] (http://www.genecards.org), path number and gene mapping to the KEGG database for.…”

Revisiting β‐Catenin Signaling in T‐Cell Development and T‐Cell Acute Lymphoblastic Leukemia

“…For example, FOXM1 has been reported to enhance the nuclear translocation of β‐catenin in BCR‐ABL1 derived myeloid leukemia . Moreover, studies are showing that the IGF1R can participate in the nuclear translocation of β‐catenin and IRS1, a member of the same pathway that has been recently shown to interact with β‐catenin both in the cytoplasm and nuclei of T‐ALL cell lines …”