Journal
ONCOGENE
Volume 33, Issue 9, Pages 1158-1166Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2013.45
Keywords
MAPK; B-RAF; STAT3; Mcl-1; anoikis
Funding
- National Health and Medical Research Council of Australia (NHMRC) [633004]
- Cancer Institute New South Wales [10/TPG/1-02]
- Health Department of NSW through Sydney West Area Health Service
- Australian Cancer Research Foundation
- Cancer Institute New South Wales, Research Fellowship
- NHMRC Senior Research Fellowship
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Approximately 50% of melanomas depend on mutant B-RAF for proliferation, metastasis and survival. The inhibition of oncogenic B-RAF with highly targeted compounds has produced remarkable albeit short-lived clinical responses in B-RAF mutant melanoma patients. Reactivation of signaling downstream of B-RAF is frequently associated with acquired resistance to B-RAF inhibitors, and the identification of B-RAF targets may provide new strategies for managing melanoma. Oncogenic B-RAF(V600E) is known to promote the stabilizing phosphorylation of the anti-apoptotic protein Mcl-1, implicated in melanoma survival and chemoresistance. We now show that B-RAFV600E signaling also induces the transcription of Mcl-1 in melanocytes and melanoma. We demonstrate that activation of STAT3 serine-727 and tyrosine-705 phosphorylations is promoted by B-RAF(V600E) activity and that the Mcl-1 promoter is dependent on a STAT consensus-site for B-RAF-mediated activation. Consequently, suppression of STAT3 activity disrupted B-RAF(V600E)-mediated induction of Mcl-1 and reduced melanoma cell survival. We propose that STAT3 has a central role in the survival and contributes to chemoresistance of B-RAF(V600E) melanoma.
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