title: Insulin Receptor Isoform Variations in Prostate Cancer Cells.
abstract: Men who develop prostate cancer (PCa) increasingly have one of the co-morbidities associated with a Western lifestyle that are characterized by hyperinsulinemia, hyperglycemia and increased expression of insulin-like growth factors-I (IGF-I) and IGF-II. Each have been associated with poor prognosis and more aggressive cancers that exhibit increased metabolism and increased glucose uptake. The insulin receptor (IR) has two splice isoforms IR-A and IR-B: IR-A has a higher affinity for IGF-II comparable to that for insulin, whereas the IR-B isoform predominantly just binds to insulin. In this study, we assessed alterations in the IR-A and IR-B isoform ratio and associated changes in cell proliferation and migration of PCa cell lines following exposure to altered concentrations of glucose and treatment with IGF-II and insulin. We observed that where IR-B predominated insulin had a greater effect on migration than IGF-II and IGF-II was more effective when IR-A was the main isoform. With regard to proliferation IGF-II was more effective than insulin regardless of which isoform was dominant. We assessed the abundance of the IR isoforms bothin vivoandin vitroand observed that the majority of the tissue samples and cell lines expressed more IR-A than IR-B. Alterations in the isoforms in response to changes in their hormonal milieu could have a profound impact on how malignant cells behave and play a role in promoting carcinogenesis. A greater understanding of the mechanisms underlying changes in alternative splicing of the IR may provide additional targets for future cancer therapies.
authors.affiliation: IGFs and Metabolic Endocrinology Group, School of Clinical Sciences, Southmead Hospital, University of Bristol , Bristol , UK.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Perks
authors.affiliation: IGFs and Metabolic Endocrinology Group, School of Clinical Sciences, Southmead Hospital, University of Bristol , Bristol , UK.
authors.forename: H A
authors.initials: HA
authors.lastname: Zielinska
authors.affiliation: IGFs and Metabolic Endocrinology Group, School of Clinical Sciences, Southmead Hospital, University of Bristol , Bristol , UK.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: IGFs and Metabolic Endocrinology Group, School of Clinical Sciences, Southmead Hospital, University of Bristol , Bristol , UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Jarrett
authors.affiliation: IGFs and Metabolic Endocrinology Group, School of Clinical Sciences, Southmead Hospital, University of Bristol , Bristol , UK.
authors.forename: A
authors.initials: A
authors.lastname: Frankow
authors.affiliation: Department of Biological, Biomedical and Analytical Sciences, Faculty of Health and Applied Sciences, University of the West of England , Bristol , UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Ladomery
authors.affiliation: Department of Clinical Oncology, Bristol Haematology and Oncology Centre, University Hospitals Bristol , Bristol , UK.
authors.forename: Amit
authors.initials: A
authors.lastname: Bahl
authors.affiliation: Department of Pathology, Faculty of Medicine, University of Malaya , Kuala Lumpur , Malaysia.
authors.forename: Anthony
authors.initials: A
authors.lastname: Rhodes
authors.affiliation: Department of Cellular Histopathology, North Bristol NHS Trust , Bristol , UK.
authors.forename: Jon
authors.initials: J
authors.lastname: Oxley
authors.affiliation: IGFs and Metabolic Endocrinology Group, School of Clinical Sciences, Southmead Hospital, University of Bristol , Bristol , UK.
authors.forename: Jeff M P
authors.initials: JM
authors.lastname: Holly
keywords: IGF-II; insulin; insulin receptor; prostate cancer; splicing variants