Aqueous extract of Magnolia officinalis mediates proliferative capacity, p21WAF1 expression and TNF-α-induced NF-κB activity in human urinary bladder cancer 5637 cells; involvement of p38 MAP kinase

Abstract

Abstract. Magnolia officinalis is a commonly used herb in East Asian countries and has multiple pharmacological effects. Although Magnolia officinalis has a variety of pharmacological effects on certain cancer cell types, the molecular mechanisms on urinary bladder cancer are unclear. An aqueous extract of M. officinalis inhibited cell proliferation in cultured human urinary bladder cancer 5637 cells. Inhibition of proliferation was associated with G1 cell cycle arrest. Treatment with M. officinalis extract blocked the cell cycle in the G1 phase, down-regulated the expression of cyclins and CDKs and up-regulated the expressions of p21WAF1 and p27 Kip1, which are CDK inhibitors. In addition, M. officinalis extract induced a marked activation of p38 MAP kinase and JNK. SB203580, a p38 MAP kinase specific inhibitor, blocked the expression of M. officinalis extract-dependent p38 MAP kinase and p21WAF1. Blockage of the p38 MAPK kinase function reversed M. officinalis extract-induced cell proliferation. These data demonstrate that M. officinalis extractinduced cell growth inhibition appears to be linked to the activation of p38 MAP kinase through p21WAF1 expression. Moreover, treatment of 5637 cells with M. officinalis extract suppressed constitutive and TNF-α-induced-nuclear factor-κ B (NF-κB) activation. Furthermore, the transactivation of TNF-α-stimulated NF-κB was inhibited by SB203580 treatment. Collectively, these results suggest that the p38 MAP kinase pathway contributes, at least partially, to the anti-cancer activity of M. officinalis extract in human urinary bladder tumor 5637 cells. IntroductionThe p38 MAP kinase is one of at least three mammalian MAPKs [the other two being extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase/stress activated protein kinase (JNK/SAPK)] that are activated by three homologous but distinct signaling pathways (1,2). The activation is effected by dual Ser/Thr and tyrosine phosphorylation that is catalyzed by a specific upstream MAPK kinase. Proliferative potential can be regulated by various signals, blocking growth or inducing apoptosis (3). JNK and p38 MAP kinase are known examples of such stress-activated protein kinases, because they are strongly activated in response to stressful stimuli. The p38 MAP kinase has been linked to apoptosis, proliferation and differentiation (2-5).The molecular and genetic alterations that precede morphologic changes and are responsible for tumorigenesis and progression of bladder cancer also include alterations in cell cycle regulators causing uncontrolled cancer growth. Cell proliferation depends on an ordered and tightly regulated process known as the cell cycle, involving multiple checkpoints assessing extracellular growth signals, cell size and DNA integrity (6). In general, the progression of the cell cycle in eukaryotes is a complex process including resting G0 phase and cell growth involving G1, S and G2/M phases ONCOLOGY REPORTS 18: 729-736, 2007 Abbreviations: p38 MAP kinase, p38 mitogen activated protein kinase...

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