| Summary: | 碩士 === 中國醫藥大學 === 中國藥學暨中藥資源學系碩士班 === 102 === Lung cancer is the leading cause of cancer mortality, and metastasis is a primary cause of cancer death. Inoscavin A is a new compound isolated from a medicinal mushroom Inonotus sanghuang. In this study, we first observed that inoscavin A exerted a dose-dependent inhibitory effect on adhesion, migration, and invasion of the highly metastatic A549 and LLC lung cancer cell lines in the absence of cytotoxicity. These effects were associated with a decreased protein expression of MMP-2 and MMP-9 together with an increased expression of TIMP-1 and PAI-1. Inoscavin A also inhibited the enzymatic activity level of uPA and MMP-9. Moreover, we demonstrated that treatment with inoscavin A reduced phosphorylation of FAK. Further studies showed that inoscavin A repressed the activation of MAPK and PI3K/Akt/mTOR signaling pathway, as evidenced by inhibited the phosphorylation of ERK1/2, JNK1/2, p38, PI3K, AKT, mTOR, p70S6K and 4EBP1. In addition, the treatment of A549 cells with inhibitor specific for PI3K /AKT (LY294002), ERK1/2 (PD98059), JNK1/2 (SP600125), p38(SB203580) and mTOR (rapamycin) decreased the expression of MMP-2 and MMP-9. Taken together, these results suggested that inoscavin A inhibits cell adhesion, migration and invasion by reducing uPA, MMP-2 and MMP-9 activation through the suppression of the FAK, mainly mediated by inhibition of MAPK and PI3K/Akt/mTOR signaling pathways. Additionally, induction of TIMP-1 and PAI-1 expression is at least partially involved in the inhibition of MMP-9 and uPA activation by inoscavin A. These findings identify inoscavin A as a promising novel therapeutic agent for lung cancer.
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