Unbalancing p53/Mdm2/IGF-1R axis by Mdm2 activation restrains the IGF-1-dependent invasive phenotype of skin melanoma

Abstract

Melanoma tumors usually retain wild-type p53; however, its tumor-suppressor activity is functionally disabled, most commonly through an inactivating interaction with mouse double-minute 2 homolog (Mdm2), indicating p53 release from this complex as a potential therapeutic approach. P53 and the tumor-promoter insulin-like growth factor type 1 receptor (IGF-1R) compete as substrates for the E3 ubiquitin ligase Mdm2, making their relative abundance intricately linked. Hence we investigated the effects of pharmacological Mdm2 release from the Mdm2/p53 complex on the expression and function of the IGF-1R. Nutlin-3 treatment increased IGF-1R/Mdm2 association with enhanced IGF-1R ubiquitination and a dual functional outcome: receptor downregulation and selective downstream signaling activation confined to the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. This Nutlin-3 functional selectivity translated into IGF-1-mediated bioactivities with biphasic effects on the proliferative and metastatic phenotype: an early increase and late decrease in the number of proliferative and migratory cells, while the invasiveness was completely inhibited following Nutlin-3 treatment through an impaired IGF-1-mediated matrix metalloproteinases type 2 activation mechanism. Taken together, these experiments reveal the biased agonistic properties of Nutlin-3 for the mitogen-activated protein kinase pathway, mediated by Mdm2 through IGF-1R ubiquitination and provide fundamental insights into destabilizing p53/Mdm2/IGF-1R circuitry that could be developed for therapeutic gain.

Metabolic strategies of melanoma cells: Mechanisms, interactions with the tumor microenvironment, and therapeutic implications

“…By preventing the unregulated degradation of p53, nutlin-3 restores p53 levels in human melanoma cell lines, regardless of p53 mutational status (Ji et al, 2012;Worrall et al, 2017). However, nutlin-3 selectively decreases the viability of cells with wild-type p53 (Ji et al, 2012;Worrall et al, 2017). Interestingly, nutlin-3 treatment increases cellular levels of MDM2, resulting in ubiquitination and degradation of insulin-like growth factor type 1 receptor (IGF-1R) (Worrall et al, 2017).…”

“…However, nutlin-3 selectively decreases the viability of cells with wild-type p53 (Ji et al, 2012;Worrall et al, 2017). Interestingly, nutlin-3 treatment increases cellular levels of MDM2, resulting in ubiquitination and degradation of insulin-like growth factor type 1 receptor (IGF-1R) (Worrall et al, 2017). The disruption of the IGF-1R signaling axis causes an initial increase in melanoma cell proliferation but ultimately suppresses proliferation and inhibits migration (Worrall et al, 2017).…”

Non-Coding RNAs in IGF-1R Signaling Regulation: The Underlying Pathophysiological Link between Diabetes and Cancer

“…Likewise, the IGF-1R could activate downstream non-kinase signaling pathways in a kinase-independent manner by employing the signal transduction machinery traditionally known to be used by the GPCR (e.g., the GRK/β-arrestin system and G-proteins) [32,33]. Equally important, components of these non-canonical, kinase-independent pathways orchestrate feedback mechanisms controlling the IGF-1R expression, trafficking, and signaling [34][35][36].…”

Fucoidan downregulates insulin-like growth factor-I receptor levels in HT-29 human colon cancer cells

“…In particular, it has been suggested that fucoidan is able to enhance p21 expression at transcriptional level in a p53-independent manner (50). IGF-I signaling is strongly associated with cell growth and has a significant role in ribosome biogenesis by regulating the expression of proteins directly involved in the processing of ribosomal subunits and p53-mediated regulation of cell cycle progression (51). In particular, IGF-I activates the murine double minute 2 (MDM2) protein which is a component crucial regulator of cell proliferation and apoptosis and acts in association to some ribosomal proteins by inhibiting the p53 tumor suppressor (51).…”

“…IGF-I signaling is strongly associated with cell growth and has a significant role in ribosome biogenesis by regulating the expression of proteins directly involved in the processing of ribosomal subunits and p53-mediated regulation of cell cycle progression (51). In particular, IGF-I activates the murine double minute 2 (MDM2) protein which is a component crucial regulator of cell proliferation and apoptosis and acts in association to some ribosomal proteins by inhibiting the p53 tumor suppressor (51). It has been demonstrated that fucoidan is able to synergize with standard anticancer agents as 5-FU and reduce its toxicity (52,53).…”