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, 178 (1), 26-31

Insulin-like Growth Factor System and Sporadic Malignant Melanoma


Insulin-like Growth Factor System and Sporadic Malignant Melanoma

Ettore Capoluongo. Am J Pathol.


Insulin and insulin-like growth factors (IGFs) are important regulators of energy metabolism and growth. Several findings have outlined an important role played by this family of molecules in both tumor maintenance and development. Despite the established contribution of the IGF system in carcinogenesis, little and contrasting data have been reported concerning the intertwined relationships between melanoma and this family of molecules. The present minireview aims to summarize the main topics and evidence concerning this malignant skin cancer, with a focus on the following: i) melanoma and cell proliferation effects induced by the IGF system, ii) in vitro and in vivo experimental data, and iii) targeting studies. Because of consistent findings regarding the role of the IGF-1 receptor in the modulation of IGF-1 activity, possible therapeutic strategies combining the use of antisense oligonucleotides against IGF-1 receptor mRNA could be applied in the future.


Figure 1
Figure 1
The biological actions of IGF-1 are mediated by IGF-1R and modulated by IGFBPs. Insulin-like growth factors 1 and 2 bind the extracellular domain of IGF-1R and induce the autophosphorylation of the tyrosine kinase (TK) receptor domain. The major IGFBP circulating in the serum is IGFBP-3; it circulates as a ternary complex formed by the BP-3 itself, the IGFs, and an acid-labile subunit. This complex protects IGFs from proteolysis, prolonging their half-lives in the bloodstream. The affinity of the IGFBPs for IGFs is generally higher than that of IGF-IR. The free IGF/BP-bound IGF ratio is crucial for the determination of the effectiveness of this growth factor. After IGF-1R activation, the insulin receptor substrates (IRSs) (eg, IRS-1) become phosphorylated, determining the activation of two main cascades (Ras/Raf–mitogen-activated protein kinase [MAPK] and phosphatidylinositol-3 kinase [PI3K]–PDK1[3′–phosphoinositide–dependent kinase–1]–antiapoptotic protein family/PKB [Protein Kinase B] pathways). In particular, one component of IGF-1 mitogenic signaling is mediated by TK through the association between the adapter protein Shc, growth factor receptor–binding (Grb) protein-2, and son of sevenless homolog (Sos)-1, which is capable of inducing both ras and MAPK cascades. The MAPK pathway modifies transcription activity at the nuclear level. Phosphorylation of IRS-1 and PI3K activation are also involved in IGF-1 signaling, similar to the action of insulin.

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