S961, a biosynthetic insulin receptor antagonist, downregulates insulin receptor expression & suppresses the growth of breast cancer cells

Abstract

Background & objectives:Insulin resistance associated with hyperinsulinaemia and overexpression of insulin receptors (IRs) have been intricately linked to the pathogenesis and treatment outcomes of the breast carcinoma. Studies have revealed that upregulated expression of IRs in breast cancer pathogenesis regulates several aspects of the malignant phenotype, including cell proliferation and metastasis. This study was aimed to investigate the pivotal role of an IR antagonist S961 on IR signalling and other biological parameters in MCF-7, MDA-MB-231 and T47D cell lines.Methods:The effect of human insulin and S961 on growth, proliferation rate and clonogenic potential of breast cancer cells was evaluated by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide] assay and clonogenic assay. The mRNA expression of IR isoforms (IR-A and IR-B) was measured in the breast carcinoma cells using quantitative PCR.Results:The study revealed that breast cancer cells predominantly expressed IR-A isoform and showed extensive growth and proliferation owing to IR overexpression. It was found that S961 downregulated the IRs (IR-A and IR-B) with nanomolar dose and efficiently blocked expression of IRs even in the presence of insulin. IR mRNA expression levels were significantly downregulated in the continued presence of S961. S961 also inhibited cellular proliferation and colony formation in breast tumour cells.Interpretation & conclusions:IR antagonist, S961 showed distinct antagonism in vitro and appeared to be a powerful therapeutic modality that might provide insight into the pathogenesis of impaired IR signalling.

Expression of Insulin Receptor and c-MET Is Associated with Clinicopathologic Characteristics and Molecular Subtypes in Premenopausal Breast Cancer Patients

“…Activation of IR phosphorylates IR substrate (IRS) which, in turn, activates multiple downstream signal transduction effectors such as phosphoinositide 3-kinase (PI3K)/AKT and ERK pathways [38,39]. As a result, IR regulates several fundamental cellular processes such as cell proliferation, differentiation, cell cycle, and migration [17]. Insulin-like growth factor 1 receptor (IGF-1R) is a common dimerization partner of IR [5,7].…”

“…IR had received less attention as a therapeutic target in cancer because of the potential impact on glucose homeostasis [7]. Nevertheless, recent evidence from in vitro and in vivo studies had indicated that inhibitors of IR have potent antitumor activity [17,[57][58][59][60]. Sharma et al showed that IR antagonist S961 suppressed growth and downregulated IR expression in breast cancer cells [17].…”

“…Nevertheless, recent evidence from in vitro and in vivo studies had indicated that inhibitors of IR have potent antitumor activity [17,[57][58][59][60]. Sharma et al showed that IR antagonist S961 suppressed growth and downregulated IR expression in breast cancer cells [17]. KW-2450 (Kyowa Kirin Pharmaceutical Development, Inc., Princeton, NJ, USA) is an orally active multi-targeted tyrosine kinase inhibitor with both IGF-1R and IR inhibitory activity [58].…”

“…In line with this, conditions associated with insulin resistance such as type II diabetes mellitus, obesity, and metabolic syndrome are now recognized as important risk factors for the development and progression of a variety of malignancies including breast cancer [5,13,16]. Aberrant IR expression has been shown to mediate cancer resistance to both conventional and targeted therapies [17]. Measures to improve insulin resistance and obesity reduce the risk of epithelial cancers.…”