دورية أكاديمية
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: | Wu CE; Northern Institute for Cancer Research, School of Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. jiaoen@gmail.com.; Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan 333, Taiwan. jiaoen@gmail.com., Koay TS; Northern Institute for Cancer Research, School of Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. T.S.Koay2@newcastle.ac.uk., Esfandiari A; Northern Institute for Cancer Research, School of Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. a.esfandiari@ucl.ac.uk.; Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, Paul O'Gorman Building, University College London, London WC1E 6BT, UK. a.esfandiari@ucl.ac.uk., Ho YH; Northern Institute for Cancer Research, School of Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. yhho9196@gmail.com., Lovat P; Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. penny.lovat@newcastle.ac.uk., Lunec J; Northern Institute for Cancer Research, School of Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. john.lunec@ncl.ac.uk. |
| المصدر: | Cancers [Cancers (Basel)] 2018 Dec 20; Vol. 11 (1). Date of Electronic Publication: 2018 Dec 20. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: MDPI Country of Publication: Switzerland NLM ID: 101526829 Publication Model: Electronic Cited Medium: Print ISSN: 2072-6694 (Print) Linking ISSN: 20726694 NLM ISO Abbreviation: Cancers (Basel) Subsets: PubMed not MEDLINE |
| أسماء مطبوعة: | Original Publication: Basel, Switzerland : MDPI |
| مستخلص: | MAPK and p14 ARF ⁻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 BRAF V600E and p53 WT 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 BRAF V600E and p53 WT 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. |
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| فهرسة مساهمة: | Keywords: ATM; DUSP6; HDM201; MDM2; RG7388; melanoma; nutlin-3; p53; trametinib |
| تواريخ الأحداث: | Date Created: 20181223 Latest Revision: 20201001 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC6356368 |
| DOI: | 10.3390/cancers11010003 |
| PMID: | 30577494 |
| قاعدة البيانات: | MEDLINE |
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