Inhibition of TRPC6 reduces non-small cell lung cancer cell proliferation and invasion
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Li-Li Yang1,2,3,*, Bing-Chen Liu1,2,3,*, Xiao-Yu Lu3, Yan Yan1,2, Yu-Jia Zhai1,2,3, Qing Bao3, Paul W. Doetsch4, Xingming Deng4, Tiffany L. Thai3,5, Abdel A. Alli3,5, Douglas C. Eaton3,5, Bao-Zhong Shen1,2, He-Ping Ma3,5
1Department of Radiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
2Molecular Imaging Research Center of Harbin Medical University, Harbin, Heilongjiang, China
3Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, USA
4Department of Radiation Oncology, and Biochemistry and Winship Cancer Institute of Emory University, Atlanta, Georgia, USA
5Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia, USA
*These authors have contributed equally to this work
Bao-Zhong Shen, email: [email protected]
He-Ping Ma, email: [email protected]
Keywords: anti-cancer drugs, cell cycle, metastasis, intracellular calcium, confocal microscopy
Received: November 12, 2015 Accepted: November 11, 2016 Published: December 20, 2016
Recent studies indicate that the transient receptor potential canonical 6 (TRPC6) channel is highly expressed in several types of cancer cells. However, it remains unclear whether TRPC6 contributes to the malignancy of human non-small cell lung cancer (NSCLC). We used a human NSCLC A549 cell line as a model and found that pharmacological blockade or molecular knockdown of TRPC6 channel inhibited A549 cell proliferation by arresting cell cycle at the S-G2M phase and caused a significant portion of cells detached and rounded-up, but did not induce any types of cell death. Western blot and cell cycle analysis show that the detached round cells at the S-G2M phase expressed more TRPC6 than the still attached polygon cells at the G1 phase. Patch-clamp data also show that TRPC whole-cell currents in the detached cells were significantly higher than in the still attached cells. Inhibition of Ca2+-permeable TRPC6 channels significantly reduced intracellular Ca2+ in A549 cells. Interestingly, either blockade or knockdown of TRPC6 strongly reduced the invasion of this NSCLC cell line and decreased the expression of an adherent protein, fibronectin, and a tight junction protein, zonula occluden protein-1 (ZO-1). These data suggest that TRPC6-mediated elevation of intracellular Ca2+ stimulates NSCLC cell proliferation by promoting cell cycle progression and that inhibition of TRPC6 attenuates cell proliferation and invasion. Therefore, further in vivo studies may lead to a consideration of using a specific TRPC6 blocker as a complement to treat NSCLC.
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