Abstract
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 approximately 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)-alpha. 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-alpha and BRAF interaction because TNF-alpha 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-kappaB (NF-kappaB) transcription factor activity, which is strongly induced by TNF-alpha in these cells. These findings suggest that drugs that target the BRAF/MEK pathway could be combined with agents that target TNF-alpha and/or NF-kappaB signaling to provide exciting new therapeutic opportunities for the treatment of melanoma.
Highlights
Melanoma is a form of cancer that arises from melanocytes, the specialized pigmented cells found in the epidermis [1]
The tumor necrosis factor (TNF)-a-mediated survival seen when BRAF signaling is inhibited requires the transcription factor nuclear factor-nB (NF-nB) and, in at least one of the lines tested, the cell cycle regulator p21Cip1 is required. These results suggest that therapies based on inhibition of oncogenic BRAF may be ineffective in melanoma unless they are combined with agents that inhibit TNF-a or NF-nB signaling, providing exciting new strategies that could be used to treat this potentially devastating disease
We have examined the interaction between death receptor and BRAF signaling in melanoma
Summary
Melanoma is a form of cancer that arises from melanocytes, the specialized pigmented cells found in the epidermis [1]. Of particular note are cytokines of the tumor necrosis factor (TNF) family, which includes TNF-related apoptosis-inducing ligand (TRAIL), Fas ligand (FasL), and TNF-a [4], the latter two of which are secreted by cells of the immune system. When these ligands bind to their receptors [TRAIL receptor, Fas receptor, and TNF receptor (TNFR) 1/2], they induce receptor trimerization and thereby stimulate recruitment of several proteins which form a complex called the death-inducing signaling complex [5]. This complex dissociates from the receptors and binds to the adaptor molecule Fas-associated death domain, leading to activation of a caspase cascade and to cell death
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
