Involvement of TRPC Channels in Lung Cancer Cell Differentiation and the Correlation Analysis in Human Non-Small Cell Lung Cancer

Abstract

The canonical transient receptor potential (TRPC) channels are Ca2+-permeable cationic channels controlling the Ca2+ influx evoked by G protein-coupled receptor activation and/or by Ca2+ store depletion. Here we investigate the involvement of TRPCs in the cell differentiation of lung cancer. The expression of TRPCs and the correlation to cancer differentiation grade in non-small cell lung cancer (NSCLC) were analyzed by real-time PCR and immunostaining using tissue microarrays from 28 patient lung cancer samples. The association of TRPCs with cell differentiation was also investigated in the lung cancer cell line A549 by PCR and Western blotting. The channel activity was monitored by Ca2+ imaging and patch recording after treatment with all-trans-retinoic acid (ATRA). The expression of TRPC1, 3, 4 and 6 was correlated to the differentiation grade of NSCLC in patients, but there was no correlation to age, sex, smoking history and lung cancer cell type. ATRA upregulated TRPC3, TRPC4 and TRPC6 expression and enhanced Ca2+ influx in A549 cells, however, ATRA showed no direct effect on TRPC channels. Inhibition of TRPC channels by pore-blocking antibodies decreased the cell mitosis, which was counteracted by chronic treatment with ATRA. Blockade of TRPC channels inhibited A549 cell proliferation, while overexpression of TRPCs increased the proliferation. We conclude that TRPC expression correlates to lung cancer differentiation. TRPCs mediate the pharmacological effect of ATRA and play important roles in regulating lung cancer cell differentiation and proliferation, which gives a new understanding of lung cancer biology and potential anti-cancer therapy.

A Reciprocal Shift in Transient Receptor Potential Channel 1 (TRPC1) and Stromal Interaction Molecule 2 (STIM2) Contributes to Ca2+ Remodeling and Cancer Hallmarks in Colorectal Carcinoma Cells

“…Accordingly, these changes could represent the most critical events underlying Ca 2ϩ remodeling and acquisition of cancer features. In support of this view, it has been reported that TRPC channels are overexpressed and regulate cell proliferation in human nonsmall cell lung, breast, liver, stomach, and glioma cancer (13,(51)(52)(53)(54) eration of tumor cells because one of its physiological roles is the modulation of the cell cycle progression through the regulation of cell volume (56). In addition, it has been reported recently that the interaction between STIM1 and TRPC1 is essential for cell migration after wounding in rat intestinal, epithelial cells (57).…”

Plasma membrane calcium channels in cancer: Alterations and consequences for cell proliferation and migration

“…Among the TRPC subfamily, the expression of TRPC1, TRPC3, TRPC4, and TRPC6 was correlated with differentiation grades in NSCLC [64]. The same study reported that the inhibition of TRPC channels decreased cell mitosis, by using the pore-blocking antibodies T1E3 and T367E3 to inhibit specifically TRPC1 and TRPC3/6 in A549 cells.…”

Functional cooperation between KCa3.1 and TRPC1 channels in human breast cancer: Role in cell proliferation and patient prognosis

“…We have also showed that the decrease of the extracellular Ca 2+ concentration [Ca 2+ ] o inhibits MCF-7 cell proliferation suggesting that Ca 2+ influx is essential for BC MCF-7 cell proliferation [40]. TRPC1 is an important Ca 2+ regulator in a variety of cell types including malignant gliomas [41], ovarian cancer [42], and lung cancer [43, 44]. In the MCF-7 breast cancer cell line, we previously demonstrated that TRPC1 provides a Ca 2+ entry that regulates cell proliferation via ERK1/2 phosphorylation [16].…”