C-MYC overexpression is required for continuous suppression of oncogene-induced senescence in melanoma cells.

Abstract

Malignant melanomas often harbor activating mutations in BRAF (V600E) or, less frequently, in NRAS (Q61R). Intriguingly, the same mutations have been detected at higher incidences in benign nevi, which are largely composed of senescent melanocytes. Overexpression of BRAF(V600E) or NRAS(Q61R) in human melanocytes in vitro has been shown to induce senescence, although via different mechanisms. How oncogene-induced senescence is overcome during melanoma progression remains unclear. Here, we report that in the majority of analysed BRAF(V600E)- or NRAS(Q61R)-expressing melanoma cells, C-MYC depletion induced different yet overlapping sets of senescence phenotypes that are characteristic of normal melanocytes undergoing senescence due to overexpression of BRAF(V600E) or NRAS(Q61R), respectively. These senescence phenotypes were p16(INK4A)- or p53-independent, however, several of them were suppressed by genetic or pharmacological inhibition of BRAF(V600E) or phosphoinositide 3-kinase pathways, including rapamycin-mediated inhibition of mTOR-raptor in NRAS(Q61R)-expressing melanoma cells. Reciprocally, overexpression of C-MYC in normal melanocytes suppressed BRAF(V600E)-induced senescence more efficiently than NRAS(Q61R)-induced senescence, which agrees with the generally higher rates of activating mutations in BRAF than NRAS gene in human cutaneous melanomas. Our data suggest that one of the major functions of C-MYC overexpression in melanoma progression is to continuous suppress BRAF(V600E)- or NRAS(Q61R)-dependent senescence programs.

• Authors: D Zhuang, S Mannava, V Grachtchouk, W-H Tang, S Patil, J A Wawrzyniak, A E Berman, T J Giordano, E V Prochownik, M S Soengas, M A Nikiforov
• Journal: Oncogene (Oncogene) Vol. 27 Issue 52 Pg. 6623-34 (Nov 06 2008) ISSN: 1476-5594 [Electronic] England
• PMID: 18679422 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclin-Dependent Kinase Inhibitor p16
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-myc
• Tumor Suppressor Protein p53
• Proto-Oncogene Proteins B-raf
• Mitogen-Activated Protein Kinase Kinases
• ras Proteins

Topics

• Cell Line, Tumor
• Cellular Senescence (drug effects)
• Cyclin-Dependent Kinase Inhibitor p16 (genetics, metabolism)
• Disease Progression
• Gene Deletion
• Gene Expression
• Humans
• Melanocytes (metabolism)
• Melanoma (enzymology, genetics, pathology)
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors, metabolism)
• Neoplasm Metastasis (genetics, pathology)
• Phenotype
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins B-raf (genetics, metabolism)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• ras Proteins (genetics, metabolism)