title: Functional role of inositol-1,4,5-trisphosphate-3-kinase-A for motility of malignant transformed cells.
abstract: Cell migration is one of the hallmarks of metastatic disease and thus identification of migration promoting proteins is crucial for the understanding of metastasis formation. Here we show that the neuron-specific, F-actin bundling inositol-1,4,5-trisphosphate-3-kinase-A (ITPKA) is ectopically expressed in tumor cells and critically involved in migration. Down-regulation of ITPKA expression in transformed cell-lines with ectopic expression of ITPKA significantly decreased migration and the number of linear and branched cell protrusion. Conversely, up-regulation of ITPKA in tumor cell lines with low endogenous ITPKA expression increased migration and formation of cell processes. In vitro, ITPKA alone induced the formation of linear actin filaments, whereas ITPKA mediated formation of branched protrusions seems to result from interaction between ITPKA and the F-actin cross-linking protein filamin C. Based on these actin-modulating and migration-promoting effects of ITPKA we examined its expression in clinical samples of different tumor entities, starting with the analysis of multiple tumor tissue arrays. As in lung adenocarcinoma specimens, the highest ITPKA expression rate was found, this tumor entity was examined in more detail. ITPKA was expressed early in adenocarcinoma progression (pN0) and was largely maintained in invasive and metastatic tumor cell populations (pN1/2, lymph node metastases). Together with our result that high expression of ITPKA increases motility of tumor cells we conclude that the observed expression of ITPKA early in tumor development increases the metastatic potential of lung adenocarcinoma cells. Therefore, we suggest that ITPKA may be a promising therapeutic molecular target for anti metastatic therapy of lung cancer.
authors.affiliation: Institut für Biochemie und Molekularbiologie I: Zelluläre Signaltransduktion, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany. s.windhorst@uke.uni-hamburg.de
authors.forename: Sabine
authors.initials: S
authors.lastname: Windhorst
authors.forename: Tatyana
authors.initials: T
authors.lastname: Kalinina
authors.forename: Katharina
authors.initials: K
authors.lastname: Schmid
authors.forename: Christine
authors.initials: C
authors.lastname: Blechner
authors.forename: Neele
authors.initials: N
authors.lastname: Kriebitzsch
authors.forename: Robin
authors.initials: R
authors.lastname: Hinsch
authors.forename: Lydia
authors.initials: L
authors.lastname: Chang
authors.forename: Lena
authors.initials: L
authors.lastname: Herich
authors.forename: Udo
authors.initials: U
authors.lastname: Schumacher
authors.forename: Georg W
authors.initials: GW
authors.lastname: Mayr
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology; D000077192:Adenocarcinoma of Lung; D045744:Cell Line, Tumor; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic; D003285:Contractile Proteins / Q000378:metabolism; D005260:Female; D064448:Filamins; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology; D008840:Microfilament Proteins / Q000378:metabolism; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism / Q000502:physiology*
chemical_list: D003285:Contractile Proteins; D064448:Filamins; D008840:Microfilament Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C051038:Inositol 1,4,5-trisphosphate 3-kinase