Abstract
Intracellular Ca2+ levels are important regulators of cell cycle and proliferation. We, and others, have previously reported the role of KCa3.1 (KCNN4) channels in regulating the membrane potential and the Ca2+ entry in association with cell proliferation. However, the relevance of KC3.1 channels in cancer prognosis as well as the molecular mechanism of Ca2+ entry triggered by their activation remain undetermined. Here, we show that RNAi-mediated knockdown of KCa3.1 and/or TRPC1 leads to a significant decrease in cell proliferation due to cell cycle arrest in the G1 phase. These results are consistent with the observed upregulation of both channels in synchronized cells at the end of G1 phase. Additionally, knockdown of TRPC1 suppressed the Ca2+ entry induced by 1-EBIO-mediated KCa3.1 activation, suggesting a functional cooperation between TRPC1 and KCa3.1 in the regulation of Ca2+ entry, possibly within lipid raft microdomains where these two channels seem to co-localize. We also show significant correlations between KCa3.1 mRNA expression and poor patient prognosis and unfavorable clinical breast cancer parameters by mining large datasets in the public domain. Together, these results highlight the importance of KCa3.1 in regulating the proliferative mechanisms in breast cancer cells as well as in providing a promising novel target in prognosis and therapy.
Highlights
Breast cancer is one of the most frequent malignancies in women worldwide
We have previously reported that hyperpolarization induced by KCa3.1 activation is a key element for cell cycle progression in MCF-7 breast cancer cells [14]
We measured the effect of TRPC1 and KCa3.1 silencing on MCF-7 cell proliferation using a Trypan Blue assay
Summary
Breast cancer is one of the most frequent malignancies in women worldwide. There have been striking advances in breast cancer therapy over the last decade. KCa3.1 expression level has been correlated with breast www.impactjournals.com/oncotarget tumor grade These findings suggest that KCa3.1 channels are important for cancer cell proliferation, and that their blockade might prove useful as therapy in patients with up-regulated KCa3.1 tumor expression. In this context, we have previously investigated the role and functional expression of KCa3.1 channels in controlling breast cancer cell cycle progression [14]. We have shown that KCa3.1 channels are involved in cell proliferation by regulating G1/S transition Both KCa3.1 mRNA expression and channel activity increased during G1 phase progression, concomitant with increased Ca2+ entry. The molecular mechanisms involved in this Ca2+ entry remain unknown
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