AMPK activation by GSK621 inhibits human melanoma cells in vitro and in vivo

Journal Article · Fri Nov 25 04:00:00 EST 2016 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2016.10.040· OSTI ID:22696704

Chen, Lezi ^[1]; Chen, Quan ^[2]; Deng, Guosan ^[1]; Kuang, Shifeng ^[1]; Lian, Jihong; Wang, Mian ^[1]; Zhu, Huilan ^[2]

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1. Department of Plastic and Peripheral Vascular Surgery, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou (China)
2. Guangzhou Institute of Dermatology, Guangzhou (China)

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. - Highlights: • The novel AMPK activator GSK621 inhibits melanoma cell survival and proliferation. • GSK621 provokes caspase-dependent apoptotic death in melanoma cells. • GSK621 is more efficient other AMPK activators in inhibiting melanoma cells. • AMPKα silence or mutation attenuates GSK621's cytotoxicity in melanoma cells. • MEK-ERK inhibition sensitizes GSK621's anti-melanoma cell activity in vitro and in vivo.

• OSTI ID: 22696704
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 4 Vol. 480; ISSN 0006-291X; ISSN BBRCA9
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANIMAL CELLS
CELL PROLIFERATION
DOMINANT MUTATIONS
IN VIVO
INHIBITION
MELANOMAS
PLANT GROWTH