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.
Highlights
The survival rate has been improved since the introduction of third-generation anti-neoplastic agents and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, lung cancer is still the leading cause of cancer deaths in the world [1,2,3,4,5]
In lung squamous cell carcinoma sections, the squamous cells were strongly stained with anti-TRPC1, anti-TRPC3, antiTRPC4 and anti-TRPC6 antibodies
We have shown that TRPC1, TRPC3, TRPC4 and TRPC6 exist in human lung cancer including the adenocarcinoma, squamous cell carcinoma and the adenocarcinomaderived cell line A549
Summary
The survival rate has been improved since the introduction of third-generation anti-neoplastic agents and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, lung cancer is still the leading cause of cancer deaths in the world [1,2,3,4,5]. The transient receptor potential (TRP) ion channel family has been implicated in the regulation of cancer growth and progression via the modulation of Ca2+ influx and the downstream signals including gene transcription [6,7,8]. Evidences from in vitro experiments have shown that overexpression of TRPC channels or silence of gene expression with siRNA can regulate cell proliferation or cell survival, suggesting these genes are important in cancer biology [6,9,20]
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