TASK-3 Downregulation Triggers Cellular Senescence and Growth Inhibition in Breast Cancer Cell Lines.

Rafael Zúñiga,Nelson Brown,Leandro Zúñiga,Claudio Valenzuela,Guierdy Concha

doi:10.3390/ijms19041033

Rafael Zúñiga, Nelson Brown + Show 3 more

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https://doi.org/10.3390/ijms19041033

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Abstract

TASK-3 potassium channels are believed to promote proliferation and survival of cancer cells, in part, by augmenting their resistance to both hypoxia and serum deprivation. While overexpression of TASK-3 is frequently observed in cancers, the understanding of its role and regulation during tumorigenesis remains incomplete. Here, we evaluated the effect of reducing the expression of TASK-3 in MDA-MB-231 and MCF-10F human mammary epithelial cell lines through small hairpin RNA (shRNA)-mediated knockdown. Our results show that knocking down TASK-3 in fully transformed MDA-MB-231 cells reduces proliferation, which was accompanied by an induction of cellular senescence and cell cycle arrest, with an upregulation of cyclin-dependent kinase (CDK) inhibitors p21 and p27. In non-tumorigenic MCF-10F cells, however, TASK-3 downregulation did not lead to senescence induction, although cell proliferation was impaired and an upregulation of CDK inhibitors was also evident. Our observations implicate TASK-3 as a critical factor in cell cycle progression and corroborate its potential as a therapeutic target in breast cancer treatment.

Highlights

Breast cancer is one of the most prevalent types of cancer affecting women [1] and remains a leading cause of cancer-related mortality worldwide [2]
In agreement with the immunofluorescence results, TASK-3 was detectable at the mRNA level in both cell lines, expression was clearly higher in MCF-10F cells (Supplementary Figure S1)
We examined the expression of several cell cycle regulators involved in the G1/S cell cycle transition, in an attempt to explore the potential mechanisms involved in the implementation of senescence in TASK-3-deficient MDA-MB-231 cells, and cell cycle arrest observed in MCF-10F cells, following small hairpin RNA (shRNA)-mediated knockdown of TASK-3

Summary

Introduction

Breast cancer is one of the most prevalent types of cancer affecting women [1] and remains a leading cause of cancer-related mortality worldwide [2]. In spite of their common tissue of origin, breast tumors display an extensive heterogeneity, which is reflected by a diverse array of molecular and histological subtypes [3]. K+ channels have been associated to several hallmarks of cancer, such as sustained proliferation, migration, invasion, angiogenesis, and metastasis [6,9,10,11,12,13,14]

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