title: 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.
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Worrall
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: N
authors.initials: N
authors.lastname: Suleymanova
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: C
authors.identifier: 0000-0002-7786-112X
authors.initials: C
authors.lastname: Crudden
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.|Dermatology Department, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: I
authors.initials: I
authors.lastname: Trocoli Drakensjö
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.|Department of Dermatology, University of Medicine and Pharmacy 'Iuliu Hatieganu' Cluj-Napoca, Romania.
authors.forename: E
authors.initials: E
authors.lastname: Candrea
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Nedelcu
authors.affiliation: Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: S-I
authors.initials: SI
authors.lastname: Takahashi
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: L
authors.identifier: 0000-0003-0280-9500
authors.initials: L
authors.lastname: Girnita
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.|Dermatology Department, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Girnita
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D049109:Cell Proliferation; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D010641:Phenotype; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D007334:Insulin-Like Growth Factor I; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D017526:Receptor, IGF Type 1