Insulin receptor substrate-4 is overexpressed in colorectal cancer and promotes retinoblastoma–cyclin-dependent kinase activation

2018 ◽  
Vol 53 (8) ◽  
pp. 932-944 ◽  
Author(s):  
Patricia Sanmartín-Salinas ◽  
María del Val Toledo Lobo ◽  
Fernando Noguerales-Fraguas ◽  
Miguel Toro Londoño ◽  
Antonio Jiménez-Ruiz ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Insulin Receptor ◽  
Insulin Receptor Substrate ◽  
Cyclin Dependent Kinase ◽  
Kinase Activation

scholarly journals Gly972Arg Variant of Insulin Receptor Substrate 1 Gene and Colorectal Cancer Risk in Overweight/Obese Subjects

2016 ◽  
Vol 31 (1) ◽  
pp. 68-72 ◽  
Author(s):  
Touraj Mahmoudi ◽  
Keivan Majidzadeh-A ◽  
Khatoon Karimi ◽  
Hamid Farahani ◽  
Reza Dabiri ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Insulin Receptor ◽  
Case Control Study ◽  
Insulin Receptor Substrate ◽  
Protective Effects ◽  
Insulin Receptor Substrate 1 ◽  
Pcr Rflp ◽  
Obese Subjects ◽  
Control Study

Background Given the major role of obesity and insulin resistance (IR) in colorectal cancer (CRC), we investigated whether genetic variants in ghrelin ( GHRL), resistin ( RETN) and insulin receptor substrate 1 ( IRS1) were associated with CRC risk. Methods This study was conducted as a case-control study, and 750 subjects, including 438 controls and 312 patients with CRC, were enrolled and genotyped using the PCR-RFLP method. Results No significant differences were observed for GHRL (rs696217), RETN (rs3745367) and IRS1 (rs1801278, Gly972Arg or G972R) gene variants between the cases and controls. However, the IRS1 G972R R allele compared with the G allele and the G972R RR+GR genotype compared with the GG genotype appeared to be markers of decreased CRC susceptibility in the overweight/obese subjects (p = 0.024; odds ratio [OR] = 0.42, 95% confidence interval [95% CI], 0.20-0.91; and p = 0.048; OR = 0.42, 95% CI, 0.17-0.99, respectively). Furthermore, the R allele and RR+GR genotype were also associated with decreased risks for obesity in the patients with CRC (p = 0.007; OR = 0.35, 95% CI, 0.15-0.77; and p = 0.015; OR = 0.35, 95% CI, 0.15-0.72, respectively). Conclusions In accordance with previous studies, our findings suggest that the IRS1 G972R R allele and RR+GR genotype have protective effects for CRC in overweight/obese patients and for obesity in patients with CRC. Nevertheless, further studies are required to confirm these findings.

scholarly journals Overexpression of IRS-4 Correlates with Procaspase 3 Levels in Tumoural Tissue of Patients with Colorectal Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-14
Author(s):  
Patricia Sanmartín-Salinas ◽  
Luis G. Guijarro
Keyword(s):  
Colorectal Cancer ◽  
Caspase 3 ◽  
Cultured Cells ◽  
Cyclin Dependent Kinase ◽  
Kinase Activation ◽  
Tnm System ◽  
Protein Levels ◽  
Receptor Signalling ◽  
T Values

We reported that insulin receptor substrate 4 (IRS-4) levels increased in tissue from colorectal cancer (CRC) patients and promoted retinoblastoma-cyclin-dependent kinase activation. The aim of the present study was to evaluate the effect of IRS-4 on IGF-1 receptor pathway and its impact on procaspase 3 and PARP expression in RKO and HepG2 cancer cell lines. The results obtained in vitro were compared with those obtained from biopsies of patients with CRC (n = 18), tubulovillous adenomas (TA) (n = 2) and in matched adjacent normal colorectal (MANC) tissue (n = 20). IRS-4 overexpression in cultured cells induced the overactivation of IGF-1/BRK/AKT/GSK-3/β-catenin/cyclin D1 pathways, which led to increased expression of procaspase 3 and PARP protein levels. Studies carried out on CRC and TA tissues revealed the overactivation of the IGF-1 receptor signalling pathway, as well as the overexpression of procaspase 3 and PARP in tumoural tissue with respect to MANC tissue. The upregulation of IRS-4 in tumoural samples correlated significantly with the increase in pIGF-1 receptor (Tyr 1165/1166) (r = 0.84; p < 0.0001), procaspase 3 (r = 0. 77; p < 0. 0005) and PARP (r = 0. 89; p < 0. 0005). Similarly, we observed an increase in the proteolysis of procaspase 3 in tumoural tissue with respect to MANC tissue, which correlated significantly with the degradation of PARP (r = 0.86; p < 0.0001), p53 (r = 0.84; p < 0.0001), and GSK-3 (r = 0.78; p < 0.0001). The stratification of patient samples using the TNM system revealed that procaspase 3 and caspase 3 increased gradually with T values, which suggests their involvement in the size and local invasion of primary tumours. Taken together, our findings suggest that IRS-4 overexpression promotes the activation of the IGF-1 receptor pathway, which leads to the increase in procaspase 3 levels in CRC.

Overexpression of insulin receptor substrate-4 is correlated with clinical staging in colorectal cancer patients

2017 ◽  
Vol 49 (1) ◽  
pp. 39-49 ◽  
Author(s):  
Patricia Sanmartín-Salinas ◽  
M. Val Toledo-Lobo ◽  
Fernando Noguerales-Fraguas ◽  
María-Encarnación Fernández-Contreras ◽  
Luis G. Guijarro
Keyword(s):  
Colorectal Cancer ◽  
Insulin Receptor ◽  
Cancer Patients ◽  
Clinical Staging ◽  
Insulin Receptor Substrate ◽  
Colorectal Cancer Patients

Sa1919 Regulation of G1/S Checkpoint by Insulin Receptor Substrate-4 in Colon Cancer Cells and Its Possible Involvement in Colorectal Cancer

2015 ◽  
Vol 148 (4) ◽  
pp. S-354-S-355
Author(s):  
Patricia Sanmartín-Salinas ◽  
Miguel A. Toro ◽  
Maria Chaparro ◽  
Borja Hernandez-Breijo ◽  
D. Cano-Martínez ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Insulin Receptor ◽  
Cancer Cells ◽  
Insulin Receptor Substrate ◽  
Colon Cancer Cells

scholarly journals Insulin Receptor Substrate Is a Mediator of Phosphoinositide 3-Kinase Activation in Quiescent Pancreatic Cancer Cells

2005 ◽  
Vol 65 (20) ◽  
pp. 9164-9168 ◽  
Author(s):  
Takayuki Asano ◽  
Yixin Yao ◽  
Sonyo Shin ◽  
James McCubrey ◽  
James L. Abbruzzese ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Insulin Receptor ◽  
Cancer Cells ◽  
Insulin Receptor Substrate ◽  
Kinase Activation ◽  
Pancreatic Cancer Cells ◽  
Phosphoinositide 3 Kinase

scholarly journals Insulin signalling and insulin actions in the muscles and livers of insulin-resistant, insulin receptor substrate 1-deficient mice.

1996 ◽  
Vol 16 (6) ◽  
pp. 3074-3084 ◽  
Author(s):  
T Yamauchi ◽  
K Tobe ◽  
H Tamemoto ◽  
K Ueki ◽  
Y Kaburagi ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Map Kinase ◽  
Insulin Receptor ◽  
Glucose Transport ◽  
Pi3 Kinase ◽  
Insulin Receptor Substrate ◽  
Wild Type ◽  
Insulin Receptor Substrate 1 ◽  
Kinase Activation ◽  
Deficient Mice

We and others recently generated mice with a targeted disruption of the insulin receptor substrate 1 (IRS-1) gene and demonstrated that they exhibited growth retardation and had resistance to the glucose-lowering effect of insulin. Insulin initiates its biological effects by activating at least two major signalling pathways, one involving phosphatidylinositol 3-kinase (PI3-kinase) and the other involving a ras/mitogen-activated protein kinase (MAP kinase) cascade. In this study, we investigated the roles of IRS-1 and IRS-2 in the biological action in the physiological target organs of insulin by comparing the effects of insulin in wild-type and IRS-1-deficient mice. In muscles from IRS-1-deficient mice, the responses to insulin-induced PI3-kinase activation, glucose transport, p70 S6 kinase and MAP kinase activation, mRNA translation, and protein synthesis were significantly impaired compared with those in wild-type mice. Insulin-induced protein synthesis was both wortmannin sensitive and insensitive in wild-type and IRS-1 deficient mice. However, in another target organ, the liver, the responses to insulin-induced PI3-kinase and MAP kinase activation were not significantly reduced. The amount of tyrosine-phosphorylated IRS-2 (in IRS-1-deficient mice) was roughly equal to that of IRS-1 (in wild-type mice) in the liver, whereas it only 20 to 30% of that of IRS-1 in the muscles. In conclusion, (i) IRS-1 plays central roles in two major biological actions of insulin in muscles, glucose transport and protein synthesis; (ii) the insulin resistance of IRS-1-deficient mice is mainly due to resistance in the muscles; and (iii) the degree of compensation for IRS-1 deficiency appears to be correlated with the amount of tyrosine-phosphorylated IRS-2 (in IRS-1-deficient mice) relative to that of IRS-1 (in wild-type mice).

Sign in / Sign up

Export Citation Format

Share Document