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Tumor Necrosis Factor- Blocks Apoptosis in Melanoma Cells when BRAF Signaling Is Inhibited

¹ Signal Transduction Team, Cancer Research UK Centre of Cell and Molecular Biology, The Institute of Cancer Research, London, United Kingdom and ² University of Massachusetts Medical School, Worcester, Massachusetts

Requests for reprints: Richard Marais, Signal Transduction Team, Cancer Research UK Centre of Cell and Molecular Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, United Kingdom. Phone: 44-20-7153-5171; Fax: 44-20-7153-5171; E-mail: richard.marais{at}icr.ac.uk.

The protein kinase BRAF, a component of the RAS/RAF/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling pathway, regulates cell fate in response to extracellular signals. Activating mutations in BRAF occur in 70% of human melanomas. The active proteins stimulate constitutive pathway signaling, proliferation, and survival. Thus, inhibition of BRAF signaling in melanoma cells causes cell cycle arrest and induces cell death through apoptosis, validating BRAF as an important therapeutic target. Here, we show that the apoptosis induced by inhibition of BRAF signaling in melanoma cells can be prevented if the cells are treated with tumor necrosis factor (TNF)-. This allows the cells to recover from the inhibition of BRAF signaling and reenter the cell cycle. This effect occurs due to a specific TNF- and BRAF interaction because TNF- does not prevent cell death in the presence of cisplatin, nitrogen mustard or thapsigargin. Furthermore, the cytokines Fas ligand, TNF-related apoptosis-inducing ligand, interleukin (IL)-1, and IL-6 do not prevent cell death when BRAF signaling is inhibited. The survival mechanism requires nuclear factor-B (NF-B) transcription factor activity, which is strongly induced by TNF- in these cells. These findings suggest that drugs that target the BRAF/MEK pathway could be combined with agents that target TNF- and/or NF-B signaling to provide exciting new therapeutic opportunities for the treatment of melanoma. [Cancer Res 2007;67(1):122–9]

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