title: Two-Pore Channel Function Is Crucial for the Migration of Invasive Cancer Cells.
abstract: Metastatic invasion is the major cause of cancer-related deaths. In this study, we introduce two-pore channels (TPC), a recently described class of NAADP- and PI(3,5)P2-sensitive Ca2+-permeable cation channels in the endolysosomal system of cells, as candidate targets for the treatment of invasive cancers. Inhibition of the channel abrogated migration of metastatic cancer cellsin vitroSilencing or pharmacologic inhibition of the two-pore channel TPC2 reduced lung metastasis of mammary mouse cancer cells. Disrupting TPC function halted trafficking of β1-integrin, leading to its accumulation in EEA1-positive early endosomes. As a consequence, invasive cancer cells were no longer able to form leading edges, which are required for adequate migration. Our findings link TPC to cancer cell migration and provide a preclinical proof of concept for their candidacy as targets to treat metastatic cancers.Cancer Res; 77(6); 1427-38. ©2017 AACR.
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Ong Nam Phuong
authors.initials: ON
authors.lastname: Nguyen
authors.affiliation: Department of Pharmacy, Center for Drug Research and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Grimm
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Lina S
authors.initials: LS
authors.lastname: Schneider
authors.affiliation: Department of Pharmacy, Center for Drug Research and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Yu-Kai
authors.initials: YK
authors.lastname: Chao
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Atzberger
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Bartel
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Watermann
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Ulrich
authors.affiliation: Pathological Institute, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Mayr
authors.affiliation: Department of Pharmacy, Center for Drug Research and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Wahl-Schott
authors.affiliation: Department of Pharmacy, Center for Drug Research and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-University Munich, Munich, Germany. angelika.vollmar@cup.uni-muenchen.de martin.biel@cup.uni-muenchen.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Biel
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, Munich, Germany. angelika.vollmar@cup.uni-muenchen.de martin.biel@cup.uni-muenchen.de.
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D044182:Benzylisoquinolines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002243:Carbolines / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D011992:Endosomes / Q000378:metabolism; D005260:Female; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D008247:Lysosomes / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009249:NADP / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D009361:Neoplasm Invasiveness; D010879:Piperazines / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D044182:Benzylisoquinolines; D015220:Calcium Channels; D002243:Carbolines; C000614918:Ned-19 compound; D010879:Piperazines; C546785:TPCN2 protein, mouse; C009438:tetrandrine; D009249:NADP; C024376:NAADP; D002118:Calcium