Oncotarget

Research Papers:

Stimulation of hERG1 channel activity promotes a calcium-dependent degradation of cyclin E2, but not cyclin E1, in breast cancer cells

Mathew Perez-Neut _, Andrew Shum, Bruce D. Cuevas, Richard Miller and Saverio Gentile

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Oncotarget. 2015; 6:1631-1639. https://doi.org/10.18632/oncotarget.2829

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Abstract

Mathew Perez-Neut1, Andrew Shum2, Bruce D. Cuevas1, Richard Miller2, Saverio Gentile1

1Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, IL, USA

2Department of Pharmacology, Northwestern University, Chicago, IL, USA

Correspondence to:

Saverio Gentile, e-mail: sagentile@luc.edu

Keywords: Cyclin E2, hERG1, breast cancer, calcium-dependent degradation

Received: October 16, 2014     Accepted: November 27, 2014     Published: January 19, 2015

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.


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