title: Inhibition of TRPC6 reduces non-small cell lung cancer cell proliferation and invasion.
abstract: 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.
authors.affiliation: Department of Radiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.|Molecular Imaging Research Center of Harbin Medical University, Harbin, Heilongjiang, China.|Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Yang
authors.affiliation: Department of Radiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.|Molecular Imaging Research Center of Harbin Medical University, Harbin, Heilongjiang, China.|Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Bing-Chen
authors.initials: BC
authors.lastname: Liu
authors.affiliation: Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Lu
authors.affiliation: Department of Radiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.|Molecular Imaging Research Center of Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Radiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.|Molecular Imaging Research Center of Harbin Medical University, Harbin, Heilongjiang, China.|Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Yu-Jia
authors.initials: YJ
authors.lastname: Zhai
authors.affiliation: Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Bao
authors.affiliation: Department of Radiation Oncology, and Biochemistry and Winship Cancer Institute of Emory University, Atlanta, Georgia, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Doetsch
authors.affiliation: Department of Radiation Oncology, and Biochemistry and Winship Cancer Institute of Emory University, Atlanta, Georgia, USA.
authors.forename: Xingming
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, USA.|Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Thai
authors.affiliation: Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, USA.|Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Abdel A
authors.initials: AA
authors.lastname: Alli
authors.affiliation: Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, USA.|Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Eaton
authors.affiliation: Department of Radiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.|Molecular Imaging Research Center of Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Bao-Zhong
authors.initials: BZ
authors.lastname: Shen
authors.affiliation: Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, USA.|Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: He-Ping
authors.initials: HP
authors.lastname: Ma
mesh_terms: D000072283:A549 Cells; D002118:Calcium / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005353:Fibronectins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering / Q000494:pharmacology*; D000074287:TRPC6 Cation Channel / Q000037:antagonists & inhibitors*; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D005353:Fibronectins; D007093:Imidazoles; D034741:RNA, Small Interfering; C569042:TJP1 protein, human; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; D062826:Zonula Occludens-1 Protein; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D002118:Calcium
keywords: anti-cancer drugs; cell cycle; confocal microscopy; intracellular calcium; metastasis