title: Molecular mechanisms underlying Ca2+-mediated motility of human pancreatic duct cells.
abstract: We recently reported that transforming growth factor-β (TGF-β) induces an increase in cytosolic Ca(2+) ([Ca(2+)](cyt)) in pancreatic cancer cells, but the mechanisms by which TGF-β mediates [Ca(2+)](cyt) homeostasis in these cells are currently unknown. Transient receptor potential (TRP) channels and Na(+)/Ca(2+) exchangers (NCX) are plasma membrane proteins that play prominent roles in controlling [Ca(2+)](cyt) homeostasis in normal mammalian cells, but little is known regarding their roles in the regulation of [Ca(2+)](cyt) in pancreatic cancer cells and pancreatic cancer development. Expression and function of NCX1 and TRPC1 proteins were characterized in BxPc3 pancreatic cancer cells. TGF-β induced both intracellular Ca(2+) release and extracellular Ca(2+) entry in these cells; however, 2-aminoethoxydiphenyl borate [2-APB; a blocker for both inositol 1,4,5-trisphosphate (IP(3)) receptor and TRPC], LaCl(3) (a selective TRPC blocker), or KB-R7943 (a selective inhibitor for the Ca(2+) entry mode of NCX) markedly inhibited the TGF-β-induced increase in [Ca(2+)](cyt). 2-APB or KB-R7943 treatment was able to dose-dependently reverse membrane translocation of PKCα induced by TGF-β. Transfection with small interfering RNA (siRNA) against NCX1 almost completely abolished NCX1 expression in BxPc3 cells and also inhibited PKCα serine phosphorylation induced by TGF-β. Knockdown of NCX1 or TRPC1 by specific siRNA transfection reversed TGF-β-induced pancreatic cancer cell motility. Therefore, TGF-β induces Ca(2+) entry likely via TRPC1 and NCX1 and raises [Ca(2+)](cyt) in pancreatic cancer cells, which is essential for PKCα activation and subsequent tumor cell invasion. Our data suggest that TRPC1 and NCX1 may be among the potential therapeutic targets for pancreatic cancer.
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of California, San Diego CA 92093-0063, USA. jcarethe@umich.edu
authors.forename: Hui
authors.initials: H
authors.lastname: Dong
authors.forename: Ki-Nam
authors.initials: KN
authors.lastname: Shim
authors.forename: Jenny M J
authors.initials: JM
authors.lastname: Li
authors.forename: Christine
authors.initials: C
authors.lastname: Estrema
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Ornelas
authors.forename: Flang
authors.initials: F
authors.lastname: Nguyen
authors.forename: Shanglei
authors.initials: S
authors.lastname: Liu
authors.forename: Sonia L
authors.initials: SL
authors.lastname: Ramamoorthy
authors.forename: Samuel
authors.initials: S
authors.lastname: Ho
authors.forename: John M
authors.initials: JM
authors.lastname: Carethers
authors.forename: Jimmy Y C
authors.initials: JY
authors.lastname: Chow
mesh_terms: D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000032:analysis / Q000502:physiology*; D002227:Carbazoles / Q000494:pharmacology; D002460:Cell Line; D002465:Cell Movement; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors; D010183:Pancreatic Ducts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000032:analysis / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000502:physiology; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D001896:Boron Compounds; D002227:Carbazoles; D004791:Enzyme Inhibitors; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019831:Sodium-Calcium Exchanger; D016212:Transforming Growth Factor beta; D050051:Transient Receptor Potential Channels; C110374:sodium-calcium exchanger 1; C081021:Go 6976; C109986:2-aminoethoxydiphenyl borate; D051571:Protein Kinase C-alpha; D013890:Thiourea; D002118:Calcium