title: AMPK activation by GSK621 inhibits human melanoma cells in vitro and in vivo.
abstract: Recent studies suggest that forced activation of AMP-activated protein kinase (AMPK) could inhibit melanoma cell proliferation. In this report, we evaluated the anti-melanoma cell activity by a novel small-molecular AMPK activator, GSK621. Treatment of GSK621 decreased survival and proliferation of human melanoma cells (A375, WM-115 and SK-Mel-2 lines), which was accompanied by activation of caspase-3/-9 and apoptosis. Reversely, caspase inhibitors attenuated GSK621-induced cytotoxicity against melanoma cells. Significantly, GSK621 was more potent than other AMPK activators (A769662, Compound 13 and AICAR) in inhibiting melanoma cells. Intriguingly, same GSK621 treatment was non-cytotoxic or pro-apoptotic against human melanocytes. Molecularly, we showed that activation of AMPK mediated GSK621's activity against melanoma cells. AMPKα1 shRNA knockdown or dominant negative mutation (T172A) dramatically attenuated GSK621-induced melanoma cell lethality. Further studies revealed that MEK-ERK activation might be the primary resistance factor of GSK621. MEK-ERK inhibition, either genetically or pharmacologically, significantly sensitized melanoma cells to GSK-621. Remarkably, intraperitoneal (i.p.) injection of GSK621 inhibited A375 tumor growth in SCID mice. Co-administration of MEK-ERK inhibitor MEK162 further sensitized GSK621-induced anti-A375 tumor activity in vivo. Together, the results imply that targeted activation of AMPK by GSK621 inhibits melanoma cell survival and proliferation. MEK-ERK inhibition may further sensitize GSK621's anti-melanoma cell activity in vitro and in vivo.
authors.affiliation: Department of Plastic and Peripheral Vascular Surgery, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Lezi
authors.initials: L
authors.lastname: Chen
authors.affiliation: Guangzhou Institute of Dermatology, Guangzhou, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Plastic and Peripheral Vascular Surgery, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address: drdengguangzhou@126.com.
authors.forename: Guosan
authors.initials: G
authors.lastname: Deng
authors.affiliation: Department of Plastic and Peripheral Vascular Surgery, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address: shifengkuangsy@163.com.
authors.forename: Shifeng
authors.initials: S
authors.lastname: Kuang
authors.affiliation: Department of Plastic and Peripheral Vascular Surgery, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Jihong
authors.initials: J
authors.lastname: Lian
authors.affiliation: Department of Plastic and Peripheral Vascular Surgery, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Mian
authors.initials: M
authors.lastname: Wang
authors.affiliation: Guangzhou Institute of Dermatology, Guangzhou, China.
authors.forename: Huilan
authors.initials: H
authors.lastname: Zhu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D011744:Pyrimidinones / Q000494:pharmacology* / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C000606536:GSK621; D007093:Imidazoles; D011744:Pyrimidinones; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Apoptosis; GSK621; MEK-ERK; Melanoma