title: Ion channels in control of pancreatic stellate cell migration.
abstract: Pancreatic stellate cells (PSCs) play a critical role in the progression of pancreatic ductal adenocarcinoma (PDAC). Once activated, PSCs support proliferation and metastasis of carcinoma cells. PSCs even co-metastasise with carcinoma cells. This requires the ability of PSCs to migrate. In recent years, it has been established that almost all "hallmarks of cancer" such as proliferation or migration/invasion also rely on the expression and function of ion channels. So far, there is only very limited information about the function of ion channels in PSCs. Yet, there is growing evidence that ion channels in stromal cells also contribute to tumor progression. Here we investigated the function of KCa3.1 channels in PSCs. KCa3.1 channels are also found in many tumor cells of different origin. We revealed the functional expression of KCa3.1 channels by means of Western blot, immunofluorescence and patch clamp analysis. The impact of KCa3.1 channel activity on PSC function was determined with live-cell imaging and by measuring the intracellular Ca2+ concentration ([Ca2+]i). KCa3.1 channel blockade or knockout prevents the stimulation of PSC migration and chemotaxis by reducing the [Ca2+]i and calpain activity. KCa3.1 channels functionally cooperate with TRPC3 channels that are upregulated in PDAC stroma. Knockdown of TRPC3 channels largely abolishes the impact of KCa3.1 channels on PSC migration. In summary, our results clearly show that ion channels are crucial players in PSC physiology and pathophysiology.
authors.affiliation: Institut für Physiologie II, 48149 Münster, Gemany.
authors.forename: Hannah
authors.initials: H
authors.lastname: Storck
authors.affiliation: Institut für Physiologie II, 48149 Münster, Gemany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Hild
authors.affiliation: Institut für Physiologie II, 48149 Münster, Gemany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Schimmelpfennig
authors.affiliation: Institut für Physiologie II, 48149 Münster, Gemany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Sargin
authors.affiliation: Institut für Physiologie II, 48149 Münster, Gemany.
authors.forename: Nikolaj
authors.initials: N
authors.lastname: Nielsen
authors.affiliation: UKSH, Campus Kiel, Institut für Experimentelle Tumorforschung (IET), Sektion Molekulare Onkologie, D-24105 Kiel, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Zaccagnino
authors.affiliation: Institut für Physiologie I, 48149 Münster, Gemany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Budde
authors.affiliation: Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, DK 2100 Copenhagen, Denmark.
authors.forename: Ivana
authors.initials: I
authors.lastname: Novak
authors.affiliation: UKSH, Campus Kiel, Institut für Experimentelle Tumorforschung (IET), Sektion Molekulare Onkologie, D-24105 Kiel, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Kalthoff
authors.affiliation: Institut für Physiologie II, 48149 Münster, Gemany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Schwab
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002633:Chemotaxis / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms; D058954:Pancreatic Stellate Cells / Q000187:drug effects / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D007473:Ion Channels; D010982:Platelet-Derived Growth Factor; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D002118:Calcium
keywords: KCa3.1 channel; TRPC3 channel; migration; pancreatic stellate cell