Abstract
The insulin receptor (IR) mediates both metabolic and mitogenic effects especially when overexpressed or in clinical conditions with compensatory hyperinsulinemia, due to the metabolic pathway resistance, as obesity diabetes. In many cancers, IR is overexpressed preferentially as IR-A isoform, derived by alternative splicing of exon 11. The IR-A overexpression, and the increased IR-A:IR-B ratio, are mechanisms that promote the mitogenic response of cancer cells to insulin and IGF-2, which is produced locally by both epithelial and stromal cancer cells. In cancer IR-A, isoform predominance may occur for dysregulation at both mRNA transcription and post-transcription levels, including splicing factors, non-coding RNAs and protein degradation. The mechanisms that regulate IR isoform expression are complex and not fully understood. The IR isoform overexpression may play a role in cancer cell stemness, in tumor progression and in resistance to target therapies. From a clinical point of view, the IR-A overexpression in cancer may be a determinant factor for the resistance to IGF-1R target therapies for this issue. IR isoform expression in cancers may have the meaning of a predictive biomarker and co-targeting IGF-1R and IR-A may represent a new more efficacious treatment strategy.
Highlights
The insulin receptor (IR), a tyrosine kinase protein physiologically present in all mammalian tissues, is a heterotetramer composed of two extracellular α-subunits and two transmembrane β-subunits bound together by disulfide bonds [1,2].The α-subunits present two different binding sites for the ligands, site 1 and site2 [3,4,5,6]
The activated IGF-2/IR-A loop is associated with de-differentiation and stem-like phenotype and in epithelial mesenchymal transition (EMT) [121] and other stem-like features [47], which play a key role in cancer development and recurrence
IR, can mediate primary resistance to IGF-1R targeted therapy and can be used as a potential biomarker for patient selection. These findings provide a rationale for co-targeting IGF-1R and IR in cancer treatment
Summary
The insulin receptor (IR), a tyrosine kinase protein physiologically present in all mammalian tissues, is a heterotetramer composed of two extracellular α-subunits and two transmembrane β-subunits bound together by disulfide bonds [1,2]. The binding affinity of hybrid receptors for the three ligands of unlabeled ligand) to insulin and IGF-2 for the IR isoforms and for IR-A/IR-B. Several studies have highlighted the role of the abnormal expression of IR isoforms in cell proliferation and cancer [14,16,17,26]. The abnormal IR transcript splicing causing an increased IR-A:IR-B ratio is a mechanism that potentiates the mitogenic response of cancer cells to circulating insulin and IGFs favoring tumor growth and progression [13]. We will summarize general data and the very recent studies on the role of the IR isoforms in many cancer types, and the possible mechanisms favoring the overexpression of IR-A isoform in malignant cells
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