Abstract
Transient receptor potential channels convey signaling information from a number of stimuli to a wide variety of cellular functions, mainly by inducing changes in cytosolic Ca2+ concentration. Different members of the TRPC, TRPM and TRPV subfamilies have been reported to play a role in tumorigenesis. Here we show that the estrogen receptor positive and triple negative breast cancer cell lines, MCF7 and MDA-MB-231, respectively, exhibit enhanced expression of the TRPC6 channel as compared to the non-tumoral MCF10A cell line. In vitro TRPC6 knockdown using shRNA impaired MCF7 and MDA-MB-231 cell proliferation, migration and invasion detected by BrdU incorporation, wound healing and Boyden chamber assays, respectively. Using RNAi-mediated TRPC6 silencing as well as overexpression of the pore-dead dominant-negative TRPC6 mutant we have found that TRPC6 plays a relevant role in the activation of store-operated Ca2+ entry in the breast cancer cell lines but not in non-tumoral breast cells. Finally, we have found that TRPC6 interacts with Orai1 and Orai3 in MCF7 and MDA-MB-231 cells and is required for the translocation of Orai1 and Orai3 to the plasma membrane in MDA-MB-231 and MCF7 cells, respectively, upon Ca2+ store depletion. These findings introduce a novel mechanism for the modulation of Ca2+ influx and the development of different cancer hallmarks in breast cancer cells.
Highlights
Breast cancer is among the leading causes of cancer death in women worldwide, accounting for about 25% of all diagnosed female cancers [1]
We have further explored the involvement of TRPC6 in the ability of MCF10A, MCF7 and MDA-MB-231 to proliferate
These findings indicate that the interaction of TRPC6 with Orai1 and Orai3 is constitutive and not modified
Summary
Breast cancer is among the leading causes of cancer death in women worldwide, accounting for about 25% of all diagnosed female cancers [1]. Breast cancer cells are characterized by a high proliferation rate, resistance to programmed cell death, and increased capability to migrate and invade surrounding tissues [2]. These hallmarks can develop through different mechanisms that lead to the onset and progression of breast cancer, among them the alteration in the PI3K pathway [3], abnormal activation of the MAPK signaling [4] or anomalous intracellular Ca2+ signaling [5]. Cancers 2018, 10, 331 channels, in the mechanisms underlying cell growth and proliferation, migration, apoptosis resistance and angiogenesis in cancer cells. The information concerning the Orai homologs Orai and Orai is rather scarce but Orai has been found to be overexpressed in parathyroid adenoma [15] and acute myeloid leukemia cells [16], while Orai is overexpressed in estrogen receptor-expressing (ER+ ) breast cancer cell lines [17] and in prostate cancer tissue specimens obtained from resection surgeries as compared to noncancerous tissue [18]
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