Hydrangenol inhibits the proliferation, migration, and invasion of EJ bladder cancer cells via p21WAF1-mediated G1-phase cell cycle arrest, p38 MAPK activation, and reduction in Sp-1-induced MMP-9 expression
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Date
2018-06-06
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Abstract
Hydrangenol is a dihydroisocoumarin that is mainly obtained from Hydrangea macrophylla. Recently, hydrangenol
has garnered attention since several studies have reported that it has anti-inflammatory, anti-allergic,
anti-diabetic, and anti-malarial activities. However, there have been few studies on the effect of hydrangenol on
oncogenesis. In this study, we evaluated the anti-cancer activity of hydrangenol against the EJ bladder cancer
cell line. Hydrangenol significantly inhibited the proliferation of EJ cells in a dose-dependent manner with an
IC50 of 100 μM. Flow cytometry and immunoblotting experiments indicated that EJ cells were arrested in the
G1-phase of the cell cycle and showed reduced expression of CDK2, CDK4, cyclin D1, and cyclin E mediated
via the upregulation of p21WAF1. Hydrangenol increased the phosphorylation of p38 MAPK without affecting the
phosphorylation of ERK and JNK. In addition, hydrangenol significantly inhibited the migratory and invasive
activities of EJ cells by suppressing the enzymatic activity of MMP-9. Electrophoretic mobility shift assays suggested
that the inhibition of MMP-9 activity by hydrangenol was attributable to its suppression of the Sp-1 transcription
factor binding activity. This study is the first report on the mode of action of hydrangenol as an inhibitor
of bladder cancer. We believe that these results provide novel insights that could aid the development of hydrangenol-
based chemotherapeutic agents.
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Keywords
Hydrangenol, Proliferation, Invasion, Migration, MMP-9