Functional role of inositol-1,4,5-trisphosphate-3-kinase-A for motility of malignant transformed cells.

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 is ectopically expressed in tumor cells and critically involved in migration. Down-regulation of expression in transformed cell-lines with ectopic expression of ITduanyu1529 significantly decreased migration and the number of linear and branched cell protrusion. Conversely, up-regulation of ITduanyu1529 in tumor cell lines with low endogenous ITduanyu1529 expression increased migration and formation of cell processes. In vitro, ITduanyu1529 alone induced the formation of linear actin filaments, whereas ITduanyu1529 mediated formation of branched protrusions seems to result from interaction between ITduanyu1529 and the F-actin cross-linking protein filamin C. Based on these actin-modulating and migration-promoting effects of ITduanyu1529 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 ITduanyu1529 expression rate was found, this tumor entity was examined in more detail. ITduanyu1529 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 ITduanyu1529 increases motility of tumor cells we conclude that the observed expression of ITduanyu1529 early in tumor development increases the metastatic potential of lung adenocarcinoma cells. Therefore, we suggest that ITduanyu1529 may be a promising therapeutic molecular target for anti metastatic therapy of lung cancer.

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