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alpha-tocopheryl phosphate suppresses tumor invasion concurrently with dynamic morphological changes and delocalization of cortactin from invadopodia.

alpha-tocopheryl phosphate (TocP) has been elucidated for diverse effectiveness through unequivocal mechanisms independent of its conversion to alpha-tocopherol (Toc). The present study showed that TocP, in a dose-dependent manner, repressed invasion of human fibrosarcoma HT-1080 cells through the basement membrane, more markedly than Toc and several other Toc derivatives, although no cytotoxic effect was shown in either HT-1080 cells or human skin dermal fibroblastic cells DUMS-16. TocP diminished intracellular reactive oxygen species such as peroxides, lipid hydroperoxides and superoxide anion radicals in HT-1080 cells, but the effects were nearly equal or less than those of Toc. TocP suppressed either the cell motility or adhesion to extracellular matrix (ECM), and induced diagnostic morphological changes such as appearance of numerous spike-shaped processes and vesicles. Localization of cortactin in the membrane of invadopodia, which dispatches signal transduction for tumor invasion, was lost by TocP as shown by immunostaining. Similar result was obtained also by Western blots showing that cortactin in the membrane fraction was markedly diminished by TocP in contrast to unchanged cortactin amounts in other subcellular fractions including nuclei, cytoplasms and cytoskeletons. In contrast, TocP scarcely affected the invasiveness-related gelatinases MMP-2/9 and cell membrane fluidity. Thus, TocP markedly exerted anti-invasive activities through decrease in cell motility, repression of adhesion to the ECM, cell morphological changes and, especially, alteration of cortactin distribution. Moreover, TocP also preferentially inhibited tumor invasion without cytotoxicity to normal cells derived from the corresponding tissue type. Consequently, TocP is suggested as a potent tumor-invasion suppressor.