Activation of hERG3 channel stimulates autophagy and promotes cellular senescence in melanoma
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Mathew Perez-Neut1, Lauren Haar1, Vidhya Rao1, Sreevidya Santha1, Katherine Lansu1, Basabi Rana1, Walter K. Jones1, Saverio Gentile1
1Department of Molecular Pharmacology & Therapeutics, Loyola University, Chicago, IL-60153, USA
Saverio Gentile, e-mail: [email protected]
Keywords: potassium channels, autophagy, hERG, senescence, melanoma
Received: January 12, 2016 Accepted: February 15, 2016 Published: March 01, 2016
Ion channels play a major factor in maintaining cellular homeostasis but very little is known about the role of these proteins in cancer biology. In this work we have discovered that, the Kv11.3 (hERG3) a plasma-membrane potassium channel plays a critical role in the regulation of autophagy in a cancer cell model. We have found that pharmacologic stimulation of the Kv11.3 channel with a small molecule activator, NS1643 induced autophagy via activation of an AMPK-dependent signaling pathway in melanoma cell line. In addition, we have found that NS1643 produced a strong inhibition of cell proliferation by activating a cellular senescence program. Furthermore, inhibition of autophagy via siRNA targeting AMPK or treatment with hydroxychloroquine an autophagy inhibitor activates apoptosis in NS1643-treated cells. Thus, we propose that, Kv11.3 is a novel mediator of autophagy, autophagy can be a survival mechanism contributing to cellular senescence, and that use of a combinatorial pharmacologic approach of Kv11.3 activator with inhibitors of autophagy represents a novel therapeutic approach against melanoma.
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