AMPK activators inhibit the proliferation of human melanomas bearing the activated MAPK pathway.

Melanoma Research
Carlotta PettiAndrea Anichini

Abstract

Raf/MEK/ERK signaling can inhibit the liver kinase B1-AMP-activated protein kinase (LKB1-AMPK) pathway, thus rendering melanoma cells resistant to energy stress conditions. We evaluated whether pharmacological reactivation of the AMPK function could exert antitumor effects on melanoma cells bearing this pathway constitutively active because of a mutation in NRAS or BRAF genes. Nine melanoma cell lines were treated with the AMPK activators 5-aminoimidazole-4-carboxamide-ribonucleoside (AICAR) and phenformin. The activation of AMPK enzymatic activity, phosphorylation of AMPK and acetyl-CoA carboxylase kinase, in-vitro proliferation, cell cycle, and in-vivo growth of xenografts in nude mice were evaluated. AICAR and phenformin promoted phosphorylation and enzymatic activity of AMPK, as well as phosphorylation of the AMPK downstream target acetyl-CoA carboxylase. Drug treatment of either BRAF-mutant or NRAS-mutant melanomas, at doses not inducing cell death, was accompanied by a dose-dependent decrease in melanoma cell proliferation because of cell cycle arrest in either the G0/G1 or the S phase, associated with an increased expression of the p21 cell cycle inhibitor. Melanomas isolated from subcutaneously implanted mice, 25 days f...Continue Reading

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Citations

Oct 9, 2015·Journal of Enzyme Inhibition and Medicinal Chemistry·Olga ScudieroGennaro Piccialli
Aug 7, 2013·The Journal of Pain : Official Journal of the American Pain Society·Otto Quintus RusseEllen Niederberger
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Sep 7, 2018·Frontiers in Endocrinology·Emilie Jaune, Stéphane Rocchi

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