title: Transient Receptor Potential Canonical 1 (TRPC1) Channels as Regulators of Sphingolipid and VEGF Receptor Expression: IMPLICATIONS FOR THYROID CANCER CELL MIGRATION AND PROLIFERATION.
abstract: The identity of calcium channels in the thyroid is unclear. In human follicular thyroid ML-1 cancer cells, sphingolipid sphingosine 1-phosphate (S1P), through S1P receptors 1 and 3 (S1P1/S1P3), and VEGF receptor 2 (VEGFR2) stimulates migration. We show that human thyroid cells express several forms of transient receptor potential canonical (TRPC) channels, including TRPC1. In TRPC1 knockdown (TRPC1-KD) ML-1 cells, the basal and S1P-evoked invasion and migration was attenuated. Furthermore, the expression of S1P3 and VEGFR2 was significantly down-regulated. Transfecting wild-type ML-1 cells with a nonconducting TRPC1 mutant decreased S1P3 and VEGFR2 expression. In TRPC1-KD cells, receptor-operated calcium entry was decreased. To investigate whether the decreased receptor expression was due to attenuated calcium entry, cells were incubated with the calcium chelator BAPTA-AM (1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid). In these cells, and in cells where calmodulin and calmodulin-dependent kinase were blocked pharmacologically, S1P3 and VEGFR2 expression was decreased. In TRPC1-KD cells, both hypoxia-inducible factor 1α expression and the secretion and activity of MMP2 and MMP9 were attenuated, and proliferation was decreased in TRPC1-KD cells. This was due to a prolonged G1 phase of the cell cycle, a significant increase in the expression of the cyclin-dependent kinase inhibitors p21 and p27, and a decrease in the expression of cyclin D2, cyclin D3, and CDK6. Transfecting TRPC1 to TRPC1-KD cells rescued receptor expression, migration, and proliferation. Thus, the expression of S1P3 and VEGFR2 is mediated by a calcium-dependent mechanism. TRPC1 has a crucial role in this process. This regulation is important for the invasion, migration, and proliferation of thyroid cancer cells.
authors.affiliation: From the Department of Biosciences, Åbo Akademi University, 20520 Turku, Finland.
authors.forename: Muhammad Yasir
authors.initials: MY
authors.lastname: Asghar
authors.affiliation: From the Department of Biosciences, Åbo Akademi University, 20520 Turku, Finland.
authors.forename: Melissa
authors.initials: M
authors.lastname: Magnusson
authors.affiliation: From the Department of Biosciences, Åbo Akademi University, 20520 Turku, Finland.
authors.forename: Kati
authors.initials: K
authors.lastname: Kemppainen
authors.affiliation: the Department of Biochemistry and Molecular Biology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58201.
authors.forename: Pramod
authors.initials: P
authors.lastname: Sukumaran
authors.affiliation: Department of Physiology, Institute of Biomedicine, University of Turku, 20520 Turku, Finland, and.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Löf
authors.affiliation: From the Department of Biosciences, Åbo Akademi University, 20520 Turku, Finland.
authors.forename: Ilari
authors.initials: I
authors.lastname: Pulli
authors.affiliation: From the Department of Biosciences, Åbo Akademi University, 20520 Turku, Finland, the Minerva Foundation Institute for Medical Research, Biomedicum Helsinki, 00270 Helsinki, Finland.
authors.forename: Veronica
authors.initials: V
authors.lastname: Kalhori
authors.affiliation: From the Department of Biosciences, Åbo Akademi University, 20520 Turku, Finland, the Minerva Foundation Institute for Medical Research, Biomedicum Helsinki, 00270 Helsinki, Finland ktornqvi@abo.fi.
authors.forename: Kid
authors.initials: K
authors.lastname: Törnquist
mesh_terms: D002465:Cell Movement; D049109:Cell Proliferation; D056742:Cyclin D2 / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D049349:Receptors, Lysosphingolipid / Q000235:genetics* / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics* / Q000378:metabolism; D013107:Sphingolipids / Q000378:metabolism; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D056742:Cyclin D2; D049349:Receptors, Lysosphingolipid; D013107:Sphingolipids; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; C000588866:KDR protein, human; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; D018844:Cyclin-Dependent Kinases
keywords: cancer; receptor; sphingosine-1-phosphate (S1P); thyroid; transient receptor potential channels (TRP channels); vascular endothelial growth factor (VEGF)