In previous works, we have shown that insulin\like growth factor\binding protein\3 (IGFBP\3), a tissue and circulating protein able to bind to IGFs, decreases drastically in the blood serum of patients with diffuse metastatic melanoma. signaling. Once it has entered the cell, IGFBP\3 binds the Wnt signalosome interacting specifically with its component GSK\3. As a consequence, the \catenin destruction complex dissociates from the LRP6 Wnt receptor and GSK\3 is activated through dephosphorylation, becoming free to target cytoplasmic \catenin which is degraded by the proteasomal pathway. Altogether, the results suggest that IGFBP\3 is a novel and effective inhibitor of Wnt signaling. As IGFBP\3 is a SAR131675 IC50 physiological protein which has no detectable toxic effects either on cultured cells or live mice, it might qualify as an interesting new therapeutic agent in melanoma, and potentially many other cancers with a hyperactive Wnt signaling. ? 2016 The Authors. Published by Wiley Periodicals, Inc. have been observed in approximately 50% of malignant melanomas 2. However, mutations alone are insufficient to cause malignant transformation and other triggering events are needed for melanomagenesis. Since melanoma is a highly malignant cancer with a potent capacity to metastasize distantly, an approach that decreases its metastatic ability may facilitate the development of an effective strategy for its treatment and/or prevention. Although the molecular mechanisms underlying the progression of melanoma remain unresolved, several studies have implicated constitutively active Wnt/\catenin signaling in melanoma progression and metastasis 3. Non\phosphorylated \catenin accumulates in the cytoplasm; when activated, it enters the nucleus and interacts with T\cell transcription factors to control various target genes that are involved in cellular proliferation and migration. Nuclear \catenin accumulation has been correlated with late stages of tumor progression and metastasis. The presence of mutated \catenin is associated with aggressive tumor growth and regulates expression of various target genes that mediate cellular processes including proliferation (e.g., cyclins and c\myc), migration, and invasion (e.g., matrix metalloproteinases) 3, 4. In the canonical model of Wnt signaling, \catenin is phosphorylated at certain key residues by glycogen synthase kinase 3\ (GSK3\) and casein kinase 1 (CK1), leading to its ubiquitination and subsequent degradation 5, 6. Like cancers of other organs, the regulation of \catenin is lost in melanoma 7, 8, 9. \catenin is also an important component of cellCcell adhesion, where it forms a dynamic link between E\cadherin and cytoskeleton 10, 11. However, the SAR131675 IC50 breaking of cell\to\cell adhesion due to activation of \catenin and its nuclear accumulation may increase the migration potential of tumor cells. Thus, nuclear/cytoplasmic traffic of \catenin in the cells determines their migration potential 12, 13. The insulin\like growth factor (IGF/IGF\binding protein) axis has been shown to influence the proliferation and survival of various tumors 14. IGFBP\3 is reported to be SAR131675 IC50 a growth suppressor by virtue of its effect on multiple pathways 15. However, there is also evidence that IGFBP\3 can have stimulatory effects on the growth of MCM2 breast cancer cells 16, 17. In the IGF receptor\dependent pathways, IGFBP\3 binds to IGF/1\2 and suppresses their growth signal 14. In the IGF receptor\independent pathways, IGFBP\3 mediates a wide variety of SAR131675 IC50 growth\controlling signals such as TGF, retinoic acid, tumor suppressor protein p53, vitamin D, anti\estrogens, and tumor necrosis factor\ 14, 17. Several epidemiological studies have examined the relationship between the serum concentrations of IGF/IGFBPs and cancer incidence, emphasizing the evidence that insulin\like growth factors (IGFs) and insulin\like growth factor binding proteins (IGFBPs) may represent specific tumor markers 18, 19, 20. In previous studies, we have shown that a strong correlation exists between the serum concentration of IGFBP\3 and disease progression in melanoma patients 20. Moreover, a low concentration of IGFBP\3 was highly significantly correlated with survival and metastatic volume, indicating that a dearth of this protein in the blood accompanies, and perhaps favors, the metastatic dissemination of.