Metformin accelerates the growth of BRAF V600E-driven melanoma by upregulating VEGF-A.
Affiliation
Division of Tumour Biology, The Institute of Cancer Research, London, United Kingdom.Issue Date
2012-04
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The antidiabetic drug metformin has antitumor activity in a variety of cancers because it blocks cell growth by inhibiting TORC1. Here, we show that melanoma cells that are driven by oncogenic BRAF are resistant to the growth-inhibitory effects of metformin because RSK sustains TORC1 activity even when AMP-activated protein kinase (AMPK) is activated. We further show that AMPK targets the dual-specificity protein phosphatase DUSP6 for degradation and this increases ERK activity, which then upregulates the VEGF-A protein. Critically, this drives angiogenesis and accelerates the growth of BRAF-driven tumors in mice. Unexpectedly, however, when VEGF signaling is inhibited, instead of accelerating tumor growth, metformin inhibits tumor growth. Thus, we show that BRAF-driven melanoma cells are resistant to the antigrowth effects of AMPK and that AMPK mediates cell-autonomous and cell-nonautonomous effects that accelerate the growth of these cells in vivo. Significance: Metformin inhibits the growth of most tumor cells, but BRAF-mutant melanoma cells are resistant to metformin in vitro, and metformin accelerates their growth in vivo. Unexpectedly, VEGF inhibitors and metformin synergize to suppress the growth of BRAF-mutant tumors, revealing a combination of drugs that may be effective in these patients.Citation
Metformin accelerates the growth of BRAF V600E-driven melanoma by upregulating VEGF-A. 2012, 2 (4):344-55 Cancer DiscovJournal
Cancer DiscoveryDOI
10.1158/2159-8290.CD-11-0280PubMed ID
22576211Type
ArticleLanguage
enISSN
2159-8290ae974a485f413a2113503eed53cd6c53
10.1158/2159-8290.CD-11-0280
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