title: Stimulation of hERG1 channel activity promotes a calcium-dependent degradation of cyclin E2, but not cyclin E1, in breast cancer cells.
abstract: Cyclin E2 gene amplification, but not cyclin E1, has been recently defined as marker for poor prognosis in breast cancer, and appears to play a major role in proliferation and therapeutic resistance in several breast cancer cells. Our laboratory has previously reported that stimulation of the hERG1 potassium channel with selective activators led to down-regulation of cyclin E2 in breast cancer cells. In this work, we demonstrate that stimulation of hERG1 promotes an ubiquitin-proteasome-dependent degradation of cyclin E2 in multiple breast cancer cell lines representing Luminal A, HER2+ and Trastuzumab-resistant breast cancer cells. In addition we have also reveal that hERG1 stimulation induces an increase in intracellular calcium that is required for cyclin E2 degradation. This novel function for hERG1 activity was specific for cyclin E2, as cyclins A, B, D E1 were unaltered by the treatment. Our results reveal a novel mechanism by which hERG1 activation impacts the tumor marker cyclin E2 that is independent of cyclin E1, and suggest a potential therapeutic use for hERG1 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 Pharmacology, Northwestern University, Chicago, IL, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Shum
authors.affiliation: Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, IL, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Cuevas
authors.affiliation: Department of Pharmacology, Northwestern University, Chicago, IL, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Miller
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: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D019927:Cyclin E / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D005260:Female; D006801:Humans; D015513:Oncogene Proteins / Q000378:metabolism*
chemical_list: C475820:CCNE1 protein, human; C503688:CCNE2 protein, human; D019927:Cyclin E; D016213:Cyclins; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D015513:Oncogene Proteins; D002118:Calcium