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Functional role of inositol‐1,4,5‐trisphosphate‐3‐kinase‐A for motility of malignant transformed cells
Author(s) -
Windhorst Sabine,
Kalinina Tatyana,
Schmid Katharina,
Blechner Christine,
Kriebitzsch Neele,
Hinsch Robin,
Chang Lydia,
Herich Lena,
Schumacher Udo,
Mayr Georg W.
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25782
Subject(s) - cell migration , motility , biology , actin , metastasis , cancer research , adenocarcinoma , microbiology and biotechnology , cell , tumor progression , cancer , biochemistry , genetics
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.