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Review
. 2018 Nov 16;19(11):3615.
doi: 10.3390/ijms19113615.

Insulin Receptor Isoforms in Cancer

Veronica Vella  1   2 , Agostino Milluzzo  3 , Nunzio Massimo Scalisi  4 , Paolo Vigneri  5 , Laura Sciacca  6
Affiliations
Review

Insulin Receptor Isoforms in Cancer

Veronica Vella et al. Int J Mol Sci. .

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.

Keywords: IGF-1R; IGF-2; cancer; hybrid receptors; insulin; insulin receptor; insulin receptor isoforms; splicing factors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the insulin receptor (IR) isoforms. Homodimerization of the αβ subunits A or B produces IR-A and IR-B. Heterodimerization of one A and one B αβ subunit forms the hybrid IR. The isoforms are generated by alternative splicing of exon 11 that encoded a 12-amino acid segment in the C-terminus of the α subunit, present in IR-B, but not in IR-A and this difference cause the difference in structure/function. The table indicates the affinity binding (expressed as EC50 of unlabeled ligand) to insulin and IGF-2 for the IR isoforms and for IR-A/IR-B.
Figure 2
Figure 2
Schematic representation of mechanisms regulating the expression of IR isoforms. The figure summarizes the principal phases determining the level of the total cellular IR content and the relative IR isoform expression. (1) Transcription regulation: The balance between stimulatory and inhibitory transcription factors plays an important role in regulating IR gene transcription in chromosome 19; (2) Alternative splicing: At post-transcriptional level alternative splicing of the IR mRNA transcript (including or excluding exon 11) regulates the IR isoform relative abundance. Different modulators, such as splicing factors, miRNAs and lnRNAs are involved; (3) mRNA turnover and translation: The stability of IR mRNAs and its translation into the IR protein by ribosomes is regulated by the RNA binding proteins (RBPs); (4) Internalization and degradation: IR isoforms undergo internalization and protein degradation by ubiquitination at a different rate, through a process that facilitates endocytosis and endosomal degradation. The ligand binding feature is an important determinant of this process.
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