Transforming Growth Factor β1 Alters Calcium Mobilizing Properties and Endogenous ATP Release in A549 Cells: Possible Implications for Cell Migration

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We examined the effects of transforming growth factor β1 (TGFβ1) on cellular functions in human lung cancer cell line A549. Treatment of A549 cells with 1 ng/ml TGFβ1 for more than 3 days altered their morphology from an epithelial cobblestone-like appearance to a fibroblast-like one, reduced the expression of E-cadherin mRNA and protein, and induced the formation of F-actin fibers. These hallmarks indicate that TGFβ1 induced the epithelial–mesenchymal transition in A549 cells. Migration of TGFβ1-treated A549 cells, which was quantified by the wound-healing assay, was markedly accelerated by 3 μM ATPγS, a non-hydrolyzable ATP analogue. ATPγS-induced migration of TGFβ1-treated A549 cells was reversed by the P2 antagonist suramin. In contrast, migration of control A549 cells was not altered by ATPγS. TGFβ1-treated A549 cells showed an augmentation of ATP-induced Ca2+ transients, thapsigargin-induced Ca2+ transients, and store-operated Ca2+ entry compared with those in control cells. Basal level of the extracellular ATP concentration was significantly lower in TGFβ1-treated A549 cells than in control cells. We conclude from these results that TGFβ1 augments ATP-induced Ca2+ mobilization, which leads to the acceleration of migration, in A549 cells but, it markedly reduces endogenous ATP release. This implies that the actions of ATP would become a novel therapeutic target for inhibiting cancer cell migration.