title: hERG1/Kv11.1 activation stimulates transcription of p21waf/cip in breast cancer cells via a calcineurin-dependent mechanism.
abstract: The function of Kv11.1 is emerging in breast cancer biology, as a growing body of evidence indicates that the hERG1/Kv11.1 potassium channel is aberrantly expressed in several cancer types including breast cancers.The biological effects of Kv11.1 channel blockers and their associated side effects are very well known but the potential use of Kv11.1 activators as an anticancer strategy are still unexplored. In our previous work, we have established that stimulation of the Kv11.1 potassium channel activates a senescent-like program that is characterized by a significant increase in tumor suppressor protein levels, such as p21waf/cip and p16INK4A. In this study we investigated the mechanism linking Kv11.1 stimulation to augmentation of p21waf/cip protein level. We have demonstrated that the Kv11.1 channel activator NS1643 activates a calcineurin-dependent transcription of p21waf/cip and that this event is fundamental for the inhibitory effect of NS1643 on cell proliferation. Our results reveal a novel mechanism by which stimulation of Kv11.1 channel leads to transcription of a potent tumor suppressor and suggest a potential therapeutic use for Kv11.1 channel activators.
authors.affiliation: Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, IL, USA.
authors.forename: Mathew
authors.initials: M
authors.lastname: Perez-Neut
authors.affiliation: Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, IL, USA.
authors.forename: Vidhya R
authors.initials: VR
authors.lastname: Rao
authors.affiliation: Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, IL, USA.
authors.forename: Saverio
authors.initials: S
authors.lastname: Gentile
mesh_terms: D001054:Apolipoproteins A / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D003408:Cresols / Q000494:pharmacology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D001054:Apolipoproteins A; C493956:CDKN1A protein, human; D003408:Cresols; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; C534296:KV11 peptide, human; D010446:Peptide Fragments; D010671:Phenylurea Compounds; C507624:1,3-bis(2-hydroxy-5-trifluoromethylphenyl)urea; D019703:Calcineurin
keywords: Ca2+-dependent transcription; breast cancer; calmodulin; hERG1/Kv11.1; p21waf/cip