Targeted inhibition of metastatic melanoma through interference with Pin1-FOXM1 signaling
| Autor: | N J F van den Broek, Judith Campisi, D Putavet, D C van Gent, Boudewijn M.T. Burgering, P L J de Keizer, J.H.J. Hoeijmakers, M P Baar, Arjan B. Brenkman, K.A.T. Naipal, Flore Kruiswijk, Renuka Sivapatham, P.J. van der Spek, Wim H. J. Kruit, Sebastian C. Hasenfuss |
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| Přispěvatelé: | Molecular Genetics, Medical Oncology, Pathology |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Indoles medicine.medical_treatment Molecular Targeted Therapy Neoplasm Metastasis Vemurafenib Non-U.S. Gov't Melanoma Sulfonamides Tumor Research Support Non-U.S. Gov't Cell cycle 3. Good health Gene Expression Regulation Neoplastic Original Article medicine.drug Signal Transduction Proto-Oncogene Proteins B-raf Biology Research Support Cell Line N.I.H 03 medical and health sciences Research Support N.I.H. Extramural SDG 3 - Good Health and Well-being Cell Line Tumor medicine Journal Article Genetics Humans Protein Kinase Inhibitors Molecular Biology neoplasms Neoplastic Oncogene Forkhead Box Protein M1 Extramural Immunotherapy medicine.disease NIMA-Interacting Peptidylprolyl Isomerase 030104 developmental biology Gene Expression Regulation Immunology Mutation FOXM1 Cancer research Skin cancer V600E |
| Zdroj: | Oncogene, 35(17), 2166-2177. Nature Publishing Group Oncogene Oncogene, 35(17), 2166. Nature Publishing Group |
| ISSN: | 0950-9232 |
| Popis: | Melanoma is the most lethal form of skin cancer and successful treatment of metastatic melanoma remains challenging. BRAF/MEK inhibitors only show a temporary benefit due to rapid occurrence of resistance, whereas immunotherapy is mainly effective in selected subsets of patients. Thus, there is a need to identify new targets to improve treatment of metastatic melanoma. To this extent, we searched for markers that are elevated in melanoma and are under regulation of potentially druggable enzymes. Here, we show that the pro-proliferative transcription factor FOXM1 is elevated and activated in malignant melanoma. FOXM1 activity correlated with expression of the enzyme Pin1, which we found to be indicative of a poor prognosis. In functional experiments, Pin1 proved to be a main regulator of FOXM1 activity through MEK-dependent physical regulation during the cell cycle. The Pin1-FOXM1 interaction was enhanced by BRAFV600E, the driver oncogene in the majority of melanomas, and in extrapolation of the correlation data, interference with\ Pin1 in BRAFV600E-driven metastatic melanoma cells impaired both FOXM1 activity and cell survival. Importantly, cell-permeable Pin1-FOXM1-blocking peptides repressed the proliferation of melanoma cells in freshly isolated human metastatic melanoma ex vivo and in three-dimensional-cultured patient-derived melanoids. When combined with the BRAFV600E-inhibitor PLX4032 a robust repression in melanoid viability was obtained, establishing preclinical value of patient-derived melanoids for prognostic use of drug sensitivity and further underscoring the beneficial effect of Pin1-FOXM1 inhibitory peptides as anti-melanoma drugs. These proof-of-concept results provide a starting point for development of therapeutic Pin1-FOXM1 inhibitors to target metastatic melanoma.Oncogene advance online publication, 17 August 2015; doi:10.1038/onc.2015.282. |
| Databáze: | OpenAIRE |
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