Induction of heme oxygenase-1 and inhibition of TPA-induced matrix metalloproteinase-9 expression by andrographolide in MCF-7 human breast cancer cells

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Title:	Induction of heme oxygenase-1 and inhibition of TPA-induced matrix metalloproteinase-9 expression by andrographolide in MCF-7 human breast cancer cells
Authors:	趙哲毅;Chao, Che-Yi;李宗貴;Lii, Chong-Kuei;Hsu, YT;Hsu, YT;Lu, CY;Lu, CY;Liu, KL;Liu, KL;Li, CC;Li, CC;Chen, HW;Chen, HW
Contributors:	保健營養生技學系
Keywords:	穿心蓮內酯;基質金屬蛋白酶-9;血基質氧化酶-1;侵襲;乳癌;NF-KAPPA-B;PI3K/AKT SIGNALING PATHWAY;PMA-INDUCED INVASION;GENE-EXPRESSION;MMP-9 EXPRESSION;DOWN-REGULATION;MIGRATION;INFLAMMATION;ACTIVATOR;ACID
Date:	201308
Issue Date:	2013-10-29 09:37:44 (UTC+0)
Abstract:	基質金屬蛋白酶(matrix metalloproteinase, MMPs)是一群可降解細胞外基質(extracellular matrix, ECM)的胜肽酶總稱，其中MMP-9的表現在癌細胞轉移過程中扮演重要角色。研究指出穿心蓮內酯(andrographolide, AP)具有抗癌生理活性，但其相關機制尚未明確，因此本研究以人類乳癌細胞株MCF-7為實驗模式，探討穿心蓮內酯對12-O-tetradecanoylphorbol-13-acetate (TPA)誘發細胞侵襲能力之影響及其相關分子機制。結果發現，穿心蓮內酯對TPA誘發MMP-9 mRNA、蛋白質表現、酵素活性、細胞遷移和侵襲能力有抑制效果，同時穿心蓮內酯也可誘發HO-1 mRNA和蛋白質表現。利用siRNA將HO-1基因knockdown後，原本受穿心蓮內酯抑制的MMP-9蛋白質表現和酵素活性被部分回復。除此之外，HO-1路徑代謝產物之類似物RuCO、FeCl3和bilirubin也可抑制TPA誘發MMP-9蛋白質表現、酵素活性、細胞遷移和侵襲能力。訊息傳遞路徑結果顯示，穿心蓮內酯可抑制TPA誘發ERK1/2和Akt磷酸化，也可降低轉錄因子AP-1、NF-κB與DNA的結合能力。利用tube formation assay 和雞胚胎chorioallantoic membrane assay證實穿心蓮內酯可抑制血管新生作用。綜合上述結果，穿心蓮內酯透過上調HO-1表現，可減少MMP-9表現和酵素活性，抑制乳癌細胞遷移和侵襲能力。另外，穿心蓮內酯也可抑制TPA誘發的ERK和PI3K/Akt訊號傳遞路徑，降低轉錄因子AP-1、NF-κB與DNA結合活性。這些作用都可能具有參與穿心蓮內酯降低乳癌惡化之潛力。 Matrix metalloproteinase-9 (MMP-9) plays a critical role in cancer metastasis. Andrographolide (AP) is a diterpene lactone in the leaves and stem of Andrographis paniculata (Burm. f) Ness that has been reported to possess anticancer activity. In this study, we investigated the effect of AP on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MMP-9 expression and invasion in MCF-7 breast cancer cells and the possible mechanisms involved. The results showed that AP dose-dependently inhibited TPA-induced MMP-9 protein expression, enzyme activity, migration and invasion. In addition, AP significantly induced heme oxygenase-1 (HO-1) messenger RNA (mRNA) and protein expression. Transfection with HO-1 small interfering RNA knocked down the HO-1 expression and reversed the inhibition of MMP-9 expression by AP. HO-1 end products, such as carbon monoxide, free iron and bilirubin, suppressed the TPA-induced MMP-9 mRNA and protein expression, enzyme activity, migration and invasion in MCF-7 cells. Furthermore, TPA-induced extracellular signal-regulated kinase (ERK) 1/2 and Akt phosphorylation and the DNA binding activity of activator protein-1 (AP-1) and nuclear factor-kappa B (NF-κB) were attenuated by pretreatment with AP and HO-1 end products. In conclusion, these results suggest that AP inhibits TPA-induced cell migration and invasion by reducing MMP-9 activation, which is mediated mainly by inhibition of the ERK1/2 and phosphatidylinositol 3-kinase/Akt signaling pathways and subsequent AP-1 and NF-κB transactivation. Additionally, induction of HO-1 expression is at least partially involved in the inhibition of TPA-induced MMP-9 activation and cell migration in MCF-7 cells by AP.
Relation:	CARCINOGENESIS, 34(8):1843-51.
Appears in Collections:	[食品營養與保健生技學系] 期刊論文

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