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

Abstract

BACKGROUND:

Insulin receptor substrate 4 (IRS-4) is an adaptor protein for which new evidence suggests plays a role in tumour promotion.

METHODS:

We described nuclear IRS-4 in RKO colon cancer cell lines in biopsies of patients with colorectal cancer (CRC) (n = 20) and in matched adjacent normal colorectal (MANC) tissue (n = 20).

RESULTS:

Treatment with physiological doses of IGF-1 promoted nuclear influx of IRS-4 from cellular cytosol in RKO cells. When exogenous IRS-4 was overexpressed in RKO cells, there was an increase in cyclin D1, cyclin E, E2F1, pRB Ser 809/811 and pRB Ser 705 levels compared with the empty vector-transfected cells. Some of these changes returned to control values after wortmannin treatment. Subcellular fractionation showed an overexpression of IRS-4 in the cytoplasm, membrane, and nuclei of tumour samples, whereas the levels of the protein were barely detectable in the three compartments of normal samples. Immunohistochemical studies showed positive nuclear IRS-4 staining in over 74% of the tumour cells. IRS-4 was strongly overexpressed in tumoural tissues from CRC patients compared to MANC tissues. The up-regulation of IRS-4 in CRC samples correlated significantly with the increase of several G1 checkpoint proteins including cyclin D1 (r = 0.6662), Rb (r = 0.7779), pRb Serine 809/811 (r = 0.6864), pRb serine 705 (r = 0.6261) and E2F1 (r = 0.8702).

CONCLUSIONS:

Taken together, our findings suggest that IRS-4 promotes retinoblastoma-cyclin-dependent kinase activation and it may serve as a pharmacological target since its expression is very low in normal tissue, including colonic epithelium.

• Authors: Patricia Sanmartín-Salinas, María Del Val Toledo Lobo, Fernando Noguerales-Fraguas, Miguel Toro Londoño, Antonio Jiménez-Ruiz, Luis Gonzalez Guijarro
• Journal: Journal of gastroenterology (J Gastroenterol) Vol. 53 Issue 8 Pg. 932-944 (Aug 2018) ISSN: 1435-5922 [Electronic] Japan
• PMID: 29353348 (Publication Type: Journal Article)

Chemical References

• E2F1 Transcription Factor
• E2F1 protein, human
• Insulin Receptor Substrate Proteins
• Proliferating Cell Nuclear Antigen
• Retinoblastoma Protein
• Cyclin D1
• Insulin-Like Growth Factor I

Topics

• Adenocarcinoma (metabolism)
• Adenoma (metabolism)
• Aged
• Aged, 80 and over
• Carcinoma, Hepatocellular (metabolism)
• Cell Line, Tumor
• Cell Membrane (metabolism)
• Cell Nucleus (metabolism)
• Cell Proliferation (genetics)
• Colon (metabolism)
• Colorectal Neoplasms (metabolism, pathology)
• Cyclin D1 (metabolism)
• Cytoplasm (metabolism)
• E2F1 Transcription Factor (metabolism)
• Female
• Humans
• Insulin Receptor Substrate Proteins (genetics, metabolism)
• Insulin-Like Growth Factor I (pharmacology)
• Liver Neoplasms (metabolism)
• Male
• Middle Aged
• Neoplasm Grading
• Neoplasm Staging
• Proliferating Cell Nuclear Antigen (metabolism)
• Protein Transport (drug effects)
• Rectum (metabolism)
• Retinoblastoma Protein (metabolism)
• Signal Transduction
• Up-Regulation