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Tanshinone IIA inhibits matrix metalloproteinase-9 expression in C6 glioma cells.
Matrix metalloproteinases (MMPs) have been implicated as important factors in the control of the invasive capability of glioma cells. Tanshinone IIA, an active ingredient purified from the Chinese herb Danshen (Radix Salvia miltiorhiza Bunge), is known to exhibit potent effects on tumor progression and invasion. In the present study, we investigated whether tanshinone IIA inhibits LPS (lipopolysaccharide) and PMA (phorbol 12-myristate 13-acetate)-induced MMP-9 gene expression in C6 glioma cells. Treatment of C6 glioma cells with LPS and PMA increased the MMP-9 expression and the expression was inhibited by pretreatment of cells with tanshinone IIA at a concentration that is not toxic to C6 glioma cells. Incubation of C6 glioma cells with tanshinone IIA increased heme oxygenase-1 (HO-1) expression, which was inhibited by pretreatment of cells with l-N-acetylcysteine (l-NAC) prior to addition of tanshinone IIA, suggesting reactive oxygen species (ROS) are involved. Inhibition of PI 3-K/Akt pathway by LY294002 or wortmannin reduced the HO-1 protein expression by tanshinone IIA. In agreement, treatment of cells with tanshinone IIA increased phosphorylation of Akt/PKB, which was attenuated by l-Nac suggesting activation of PI3-kinase–Akt is secondary to ROS production. The inhibition of MMP-9 expression by tanshinone IIA was reversed by tin protoporphyrin (SnPP) suggesting tanshinone IIA may exert this inhibitory effect through HO-1. Increase of HO-1 expression catalyzes carbon monoxide (CO) production. Addition of CO donor mimicked the tanshinone IIA effect on suppressing inducible nitrite oxygen synthease (iNOS) and MMP-9 expression. Scavenge of CO by hemoglobin (Hb) reversed the inhibition due to tanshinone IIA. Inhibition of nitric oxide (NO) production by l-NAME inhibited MMP-9 expression due to tanshinone IIA. Taken together, these results suggest that tanshinone IIA exerts its inhibitory effect through induction of HO-1 expression. HO-1 catalyzes the formation of CO, which in turn inhibit iNOS induction. Inhibition of iNOS expression subsequently reduces the MMP-9 protein level and activity.