title: Activation of hERG3 channel stimulates autophagy and promotes cellular senescence in melanoma.
abstract: 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.
authors.affiliation: Department of Molecular Pharmacology & Therapeutics, Loyola University, Chicago, IL-60153, USA.
authors.forename: Mathew
authors.initials: M
authors.lastname: Perez-Neut
authors.affiliation: Department of Molecular Pharmacology & Therapeutics, Loyola University, Chicago, IL-60153, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Haar
authors.affiliation: Department of Molecular Pharmacology & Therapeutics, Loyola University, Chicago, IL-60153, USA.
authors.forename: Vidhya
authors.initials: V
authors.lastname: Rao
authors.affiliation: Department of Molecular Pharmacology & Therapeutics, Loyola University, Chicago, IL-60153, USA.
authors.forename: Sreevidya
authors.initials: S
authors.lastname: Santha
authors.affiliation: Department of Molecular Pharmacology & Therapeutics, Loyola University, Chicago, IL-60153, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Lansu
authors.affiliation: Department of Molecular Pharmacology & Therapeutics, Loyola University, Chicago, IL-60153, USA.
authors.forename: Basabi
authors.initials: B
authors.lastname: Rana
authors.affiliation: Department of Molecular Pharmacology & Therapeutics, Loyola University, Chicago, IL-60153, USA.
authors.forename: Walter K
authors.initials: WK
authors.lastname: Jones
authors.affiliation: Department of Molecular Pharmacology & Therapeutics, Loyola University, Chicago, IL-60153, USA.
authors.forename: Saverio
authors.initials: S
authors.lastname: Gentile
mesh_terms: D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology*; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; C486376:KCNH7 protein, human
keywords: autophagy; hERG; melanoma; potassium channels; senescence