Isoform- and Paralog-Switching in IR-Signaling: When Diabetes Opens the Gates to Cancer

• Main Authors: Pierluigi Scalia, Antonio Giordano, Caroline Martini, Stephen J. Williams
• Format: Article
• Language: English
• Published: MDPI AG 2020-11-01
• Series: Biomolecules
• Subjects: <i>IR</i>: insulin receptor; <i>IGF</i>: insulin-like growth factor; <i>HIF:</i> hypoxia-inducible factor; <i>Isoform:</i> for the scope of this review, the term isoform is restricted to products of alternatively spliced coding genes; <i>Paralog</i>: the product of gene variants with high sequence similarity encoded by duplicated genes in the genome; MAPK-ERK: Mitogen-activated protein Kinase-Extracellular-signal-regulated Kinase
• Online Access: https://www.mdpi.com/2218-273X/10/12/1617

Insulin receptor (IR) and IR-related signaling defects have been shown to trigger insulin-resistance in insulin-dependent cells and ultimately to give rise to type 2 diabetes in mammalian organisms. IR expression is ubiquitous in mammalian tissues, and its over-expression is also a common finding in cancerous cells. This latter finding has been shown to associate with both a relative and absolute increase in IR isoform-A (IR-A) expression, missing 12 aa in its EC subunit corresponding to exon 11. Since IR-A is a high-affinity transducer of Insulin-like Growth Factor-II (IGF-II) signals, a growth factor is often secreted by cancer cells; such event offers a direct molecular link between IR-A/IR-B increased ratio in insulin resistance states (obesity and type 2 diabetes) and the malignant advantage provided by IGF-II to solid tumors. Nonetheless, recent findings on the biological role of isoforms for cellular signaling components suggest that the preferential expression of IR isoform-A may be part of a wider contextual isoform-expression switch in downstream regulatory factors, potentially enhancing IR-dependent oncogenic effects. The present review focuses on the role of isoform- and paralog-dependent variability in the IR and downstream cellular components playing a potential role in the modulation of the IR-A signaling related to the changes induced by insulin-resistance-linked conditions as well as to their relationship with the benign versus malignant transition in underlying solid tumors.