1. ¹Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
2. ²Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
3. ³Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA
4. ⁴Institute of Biomedical Chemistry RAMS, Moscow, Russia
5. ⁵Department of Pathology, University of Michigan, Ann Arbor, MI, USA
6. ⁶Section of Hematology/Oncology, Children's Hospital of Pittsburgh, Rangos Research Center, Pittsburgh, PA, USA

Correspondence: Dr MA Nikiforov, Department of Cell Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Street, L3-317, Buffalo, NY 14263, USA. E-mail: mikhail.nikiforov@roswellpark.org

⁷These authors contributed equally to this paper.

Received 6 March 2008; Revised 29 May 2008; Accepted 19 June 2008; Published online 4 August 2008.

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.