Abstract
Lung cancer is the leading cause of cancer-related death, and NSCLC constitutes nearly 85%–90% of all cases. The IRS proteins function as adaptors and transmit signals from multiple receptors. Upon binding of insulin to the insulin receptor (IR), IRS1 is phosphorylated at several YXXM motifs creating docking sites for the binding of PI3Kp85, which activates AKT kinase. Therefore, we thought that gain of function mutantions of IRS1 could be related to development of lung cancer. In line with this, we wanted determine whether the IRS1 gene was mutated in the coding regions surrounding YXXM motifs. We sequenced the coding regions surrounding YXXM motifs of IRS1 using tumor samples of 42 NSCLC patients and 40 matching controls and found heterozygote p.S668T mutation in nine of 42 samples and four of nine also had the p.D674H mutation. We generated IRS1 expression vectors harboring p.S668T, p.D674H and double mutants. Expression of the mutants differentially affected insulin-induced phosphorylation of IRS1, AKT, ERK, and STAT3. Also, our mutants induced proliferation, glucose uptake, inhibited the migration of 293T cells and affected the responsiveness of the cells to cisplatin and radiation. Our results suggest that these novel mutations play a role in the phenotype of lung cancer.
Highlights
Lung cancer is divided into two major groups: non small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)
Since we hypothesized that mutations at or around the YXXM motifs of IRS1 may impact insulin signaling and the phenotype of lung cancer, we isolated the genomic DNA from 42 tumor and 40 normal lung tissues of NSCLC patients and sequenced the coding region of IRS1
The level for the D674H mutant of IRS1 was higher in cells treated with insulin for 30 min, fold induction of tyrosine phosphorylation dropped from 120 to 40 fold. These results indicate that the D674H mutation destabilizes IRS1, and this was reversed by S668T (Figure 1)
Summary
Lung cancer is divided into two major groups: non small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). In addition to binding to the insulin receptor, IRS1 binds to and transmits signals from the receptors of prolactin, growth hormone (GH), leptin, vascular endothelial growth factor (VEGF), tropomyosin receptor kinase B (TrkB), anaplastic lymphoma kinase (ALK), insulin like growth factor (IGF1), and integrins (Vuori and Ruoslathi, 1994; Senthil et al, 2002; Gibson et al, 2007; Chan and Lee, 2008; Porter et al, 2012) Since these receptors induce cell proliferation, survival and migration, it was suggested that IRS1 may be involved in the development of cancer and metastasis. The expression and phosphorylation of IRS1 has been determined in numerous cell lines, and trends toward increased expression or phosphorylation of IRS1 have been reported in many cancers (Bergman et al, 1996; Rocha et al, 1997; Schnarr et al, 2000; Hoang et al, 2004; Koda et al, 2005; Han et al, 2006; Ravikumar et al, 2007; Sisci et al, 2007)
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