title: Evidence for Ca(2+)-regulated ATP release in gastrointestinal stromal tumors.
abstract: Gastrointestinal stromal tumors (GISTs) are thought to originate from the electrically active pacemaker cells of the gastrointestinal tract. Despite the presence of synaptic-like vesicles and proteins involved in cell secretion it remains unclear whether GIST cells possess regulated release mechanisms. The GIST tumor cell line GIST882 was used as a model cell system, and stimulus-release coupling was investigated by confocal microscopy of cytoplasmic free Ca(2+) concentration ([Ca(2+)]i), flow cytometry, and luminometric measurements of extracellular ATP. We demonstrate that GIST cells have an intact intracellular Ca(2+)-signaling pathway that regulates ATP release. Cell viability and cell membrane integrity was preserved, excluding ATP leakage due to cell death and suggesting active ATP release. The stimulus-secretion signal transduction is at least partly dependent on Ca(2+) influx since exclusion of extracellular Ca(2+) diminishes the ATP release. We conclude that measurements of ATP release in GISTs may be a useful tool for dissecting the signal transduction pathway, mapping exocytotic components, and possibly for the development and evaluation of drugs. Additionally, release of ATP from GISTs may have importance for tumor tissue homeostasis and immune surveillance escape.
authors.affiliation: Section for Endocrine and Sarcoma Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden. erik.berglund@ki.se
authors.forename: Erik
authors.initials: E
authors.lastname: Berglund
authors.forename: David
authors.initials: D
authors.lastname: Berglund
authors.forename: Pinar
authors.initials: P
authors.lastname: Akcakaya
authors.forename: Mehran
authors.initials: M
authors.lastname: Ghaderi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Daré
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.forename: Martin
authors.initials: M
authors.lastname: Köhler
authors.forename: Craig A
authors.initials: CA
authors.lastname: Aspinwall
authors.forename: Weng-Onn
authors.initials: WO
authors.lastname: Lui
authors.forename: Jan
authors.initials: J
authors.lastname: Zedenius
authors.forename: Catharina
authors.initials: C
authors.lastname: Larsson
authors.forename: Robert
authors.initials: R
authors.lastname: Bränström
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D002412:Cations / Q000494:pharmacology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D004252:DNA Mutational Analysis; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism; D051379:Mice; D010641:Phenotype; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics
chemical_list: D002412:Cations; D007328:Insulin; D000255:Adenosine Triphosphate; D019009:Proto-Oncogene Proteins c-kit; D002118:Calcium