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

Sanmartín-Salinas, Patricia; Lobo, María del Val Toledo; Noguerales-Fraguas, Fernando; Londoño, Miguel Toro; Jiménez-Ruı́z, Antonio; Guijarro, Luis

doi:10.1007/s00535-018-1432-8

Cited by 14 publications

(22 citation statements)

References 37 publications

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“…The tyrosine phosphorylation of IGF-1 receptor has been associated with the resistance of CRC patients to conventional therapies and targeted therapeutic agents [ 26 , 27 ]. This phenomenon may be caused by the increase in IRS-4 levels in CRC tissue [ 23 ]. In the present study, we observed that IRS-4 overexpression in HepG2 and RKO cancer cells is associated with the activation of IGF-1 receptor signalling pathways in the absence of extracellular ligand.…”

Section: Discussionmentioning

confidence: 99%

“…The stimulation of this pathway was associated with the increase in anchorage-independent survival of mammary epithelial cells in culture [ 29 ] and possibly in metastatic dissemination [ 29 ]. Previously, we demonstrated that IRS-4 increased HepG2 [ 10 ] and RKO [ 23 ] proliferation by a Rb-CDK pathway. In addition we showed that overexpression of IRS-4 correlated with clinical staging in colorectal cancer patients [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…PARP is a coactivator of the β -catenin /TCF-4 complex [ 37 ]. In this respect, we observed the increase in β -catenin and the surrogate marker cyclin D1 in cells overexpressing IRS-4, which has been positively associated with the increase in G1 checkpoint cell cycle proteins in CRC samples [ 23 ]. Based on these observations, we propose that the regulatory role of IRS-4 on procaspase 3, PARP and cyclin D1 levels may be of some importance in the progression of CRC.…”

Section: Discussionmentioning

confidence: 99%

“…Cells overexpressing IRS-4 were obtained as previously described [ 23 ] with minor modifications. Briefly, DNA was isolated from RKO cells using DNeasy Blood & Tissue kit (Qiagen).…”

Section: Methodsmentioning

confidence: 99%

“…Uncontrolled tumour cell proliferation is often characterized by aberrant activity of cell cycle proteins. We recently demonstrated that IRS-4 is involved in retinoblastoma-cyclin-dependent kinase (Rb-CDK) pathway activation in human CRC [ 23 ]. However, the signalling mechanism of IRS-4 in CRC remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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

Sanmartín-Salinas

Guijarro

2018

Journal of Oncology

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Cells overexpressing IRS-4 were obtained as previously described [ 23 ] with minor modifications. Briefly, DNA was isolated from RKO cells using DNeasy Blood & Tissue kit (Qiagen).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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