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

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.

TASK-3 Gene Knockdown Dampens Invasion and Migration and Promotes Apoptosis in KATO III and MKN-45 Human Gastric Adenocarcinoma Cell Lines

“…In order to elucidate the mechanisms explaining the decrease in proliferation observed in TASK-3-depleted cells, cell cycle regulators and apoptosis were evaluated. No significant differences in the expression levels of different cell cycle regulators were detected, which is in contrast to the report by Zuniga et al [36]. In this work, a significant increase in the expression of the CDK inhibitors p21 and p27 was reported [36].…”

“…No significant differences in the expression levels of different cell cycle regulators were detected, which is in contrast to the report by Zuniga et al [36]. In this work, a significant increase in the expression of the CDK inhibitors p21 and p27 was reported [36]. This disagreement could be explained by differences in the cell lines used, implying that TASK-3 is modulated in a cell type-specific manner [46,47].…”

“…After confirming TASK-3 overexpression in KATO III and MKN-45 cells, knockdown experiments aimed to reduce its expression in these cells were carried out. For this, a shRNA construct, previously tested and validated, was used [36]. Our results confirmed that the knockdown was successful and specific, since the mRNA and protein levels of the TASK-1 channel were not altered.…”

“…However, it is worth noting that Lee et al [54] observed that an up-regulation of TASK-3 in MDA-MB-231 breast cancer cells led to a decrease in their migratory capabilities. Strikingly, our own studies showed that knocking down TASK-3 in MDA-MB-231 cells provoked a decrease in cell proliferation associated with an induction of cell cycle arrest [36], further attesting for the complexity and our lack of understanding of the function of these channels in cancer.…”

“…One hypothesis suggests that the control of K + ions and water movement could play a role [34,35]. Also, a recent study showed that knocking down TASK-3 in breast cancer cells resulted in the induction of cellular senescence and cell cycle arrest [36]. Likewise, it was demonstrated that the use of a dominant-negative form of TASK-3 (TASK-3 G95E) [37], or the use of a monoclonal antibody against its extracellular domain [38], led to a decrease in proliferation due to apoptosis induction in lung and breast carcinoma cells, respectively.…”