Antioxidant dieckol downregulates the Rac1/ROS signaling pathway and inhibits Wiskott-Aldrich syndrome protein (WASP)-family verprolin-homologous protein 2 (WAVE2)-mediated invasive migration of B16 mouse melanoma cells |
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Authors: | Sun Joo Park Yong Tae Kim You Jin Jeon |
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Institution: | Department of Chemistry, Pukyong National University, Busan 608-737, Korea. parksj@pknu.ac.kr |
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Abstract: | Reactive oxygen species (ROS) generation is linked to dynamic actin cytoskeleton reorganization, which is involved in tumor
cell motility and metastasis. Thus, inhibition of ROS generation and actin polymerization in tumor cells may represent an
effective anticancer strategy. However, the molecular basis of this signaling pathway is currently unknown. Here, we show
that the Ecklonia cava-derived antioxidant dieckol downregulates the Rac1/ROS signaling pathway and inhibits Wiskott-Aldrich syndrome protein (WASP)-family
verprolin-homologous protein 2 (WAVE2)-mediated invasive migration of B16 mouse melanoma cells. Steady-state intracellular
ROS levels were higher in malignant B16F10 cells than in parental, nonmetastatic B16F0 cells. Elevation of ROS by H2O2 treatment increased migration and invasion ability of B16F0 cells to level similar to that of B16F10 cells, suggesting that
intracellular ROS signaling mediates the prometastatic properties of B16 mouse melanoma cells. ROS levels and the cell migration
and invasion ability of B16 melanoma cells correlated with Rac1 activation and WAVE2 expression. Overexpression of dominant
negative Rac1 and depletion of WAVE2 by siRNA suppressed H2O2-induced cell invasion of B16F0 and B16F10 cells. Similarly, dieckol attenuates the ROS-mediated Rac1 activation and WAVE2
expression, resulting in decreased migration and invasion of B16 melanoma cells. In addition, we found that dieckol decreases
association between WAVE2 and NADPH oxidase subunit p47phox. Therefore, this finding suggests that WAVE2 acts to couple intracellular Rac1/ROS signaling to the invasive migration of
B16 melanoma cells, which is inhibited by dieckol. |
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Keywords: | dieckol invasion migration ROS WAVE2 |
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