ATM Dependent DUSP6 Modulation of p53 Involved in Synergistic Targeting of MAPK and p53 Pathways with Trametinib and MDM2 Inhibitors in Cutaneous Melanoma
| العنوان: | ATM Dependent DUSP6 Modulation of p53 Involved in Synergistic Targeting of MAPK and p53 Pathways with Trametinib and MDM2 Inhibitors in Cutaneous Melanoma |
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| المؤلفون: | Tsin Shue Koay, Chiao-En Wu, John Lunec, Penny E. Lovat, Yi-Hsuan Ho, Arman Esfandiari |
| المصدر: | Cancers Cancers; Volume 11; Issue 1; Pages: 3 Cancers, Vol 11, Iss 1, p 3 (2018) |
| بيانات النشر: | MDPI, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, MAPK/ERK pathway, p53, Cancer Research, Cell cycle checkpoint, DUSP6, lcsh:RC254-282, Article, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, nutlin-3, MDM2, medicine, melanoma, RG7388, neoplasms, HDM201, Trametinib, trametinib, biology, Chemistry, Melanoma, MEK inhibitor, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, ATM, biology.protein, Cancer research, Mdm2 |
| الوصف: | MAPK and p14ARF⁻MDM2⁻p53 pathways are critical in cutaneous melanomas. Here, synergistic combination of the MEK inhibitor, trametinib, with MDM2 inhibitors, nutlin-3/RG7388/HDM201, and the mechanistic basis of responses, for BRAFV600E and p53WT melanoma cells, are reported. The combination treatments induced higher levels of p53 target gene transcripts and protein products, resulting in increased cell cycle arrest and apoptosis compared with MDM2 inhibitors alone, suggesting trametinib synergized with MDM2 inhibitors via upregulation of p53-dependent pathways. In addition, DUSP6 phosphatase involvement was indicated by downregulation of its mRNA and protein following pERK reduction by trametinib. Furthermore, suppression of DUSP6 by siRNA, or inhibition with the small molecule inhibitor, BCI, at a dose without cytotoxicity, potentiated the effect of MDM2 inhibitors through increased ATM-dependent p53 phosphorylation, as demonstrated by complete reversal with the ATM inhibitor, KU55933. Trametinib synergizes with MDM2 inhibitors through a novel DUSP6 mechanism in BRAFV600E and p53WT melanoma cells, in which DUSP6 regulation of p53 phosphorylation is mediated by ATM. This provides a new therapeutic rationale for combination treatments involving activation of the ATM/p53 pathway and MAPK pathway inhibition. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2072-6694 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1c0311d14b779824c9a879482d559e8b http://europepmc.org/articles/PMC6356368 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....1c0311d14b779824c9a879482d559e8b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20726694 |
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