Abstract
Antcin-H, a natural triterpene, is purified from a famous anticancer medicinal mushroom, Antrodia cinnamomea, in Taiwan. This study showed that antcin-H inhibited the growth of human renal carcinoma 786-0 cells; the IC50 value (for 48 h) was 170 μM. Besides, the migration and invasion of 786-0 cells were suppressed by antcin-H under noncytotoxic concentrations (<100 μM); these events were accompanied by inhibition of FAK and Src kinase activities, decrease of paxillin phosphorylation, impairment of lamellipodium formation, and upregulation of TIMPs and downregulation of MMPs, especially MMP-7 expression. Luciferase reporter assay showed that antcin-H repressed the MMP-7 promoter activity, in parallel to inhibiting c-Fos/AP-1 and C/EBP-β transactivation abilities. Moreover, antcin-H suppressed the activity of ERK1/2 and decreased the binding ability of C/EBP-β and c-Fos on the upstream/enhancer region of MMP-7 promoter. Overall, this study demonstrated that the anti-invasive effect of antcin-H in human renal carcinoma 786-0 cells might be at least in part by abrogating focal adhesion complex and lamellipodium formation through inhibiting the Src/FAK-paxillin signaling pathways and decreasing MMP-7 expression through suppressing the ERK1/2-AP-1/c-Fos and C/EBP-β signaling axis. Our findings provide the evidence that antcin-H may be an active component existing in A. cinnamomea with anticancer effect.
Highlights
Human renal cell carcinoma (RCC), the second common but most lethal cancer of urologic origins, is relatively rare compared to the other carcinomas, but the incidence of RCC is increasing [1]
Our results firstly showed that antcin-H inhibited the Src/FAK/paxillin and Src/FAK/ERKc-Fos-C/EBP-β signaling pathways to impair lamellipodium formation and decrease matrix metalloproteinases (MMPs)-7 expression, suppressing RCC cell migration and invasion, suggesting that antcin-H might have the potential for treating metastatic RCC
The present study showed for the first time that antcinH, a steroid-like compound isolated from a famous anticancer medicinal mushroom A. cinnamomea, inhibited Src, FAK, and ERK1/2 signaling pathways and thereby decreased phosphorylated-paxillin, phosphorylated-C/EBP-β, and total c-Fos levels and downregulated vimentin and MMPs expression, leading to impaired lamellipodium formation and cellular migration/invasion at nontoxic concentrations in human RCC 786-0 cells
Summary
Human renal cell carcinoma (RCC), the second common but most lethal cancer of urologic origins, is relatively rare compared to the other carcinomas, but the incidence of RCC is increasing [1]. RCC is curable when it is diagnosed in the very early stage of the disease [2], due to its asymptomatic clinical course, by the time of diagnosis about 25% of RCC patients present with invasion of the tumor to the surrounding tissues and distant metastasis [3, 4]. New treatment modalities including immunotherapies with interferon or interleukin-2 and targeting therapies focusing on vascular endothelial growth factor and mTOR pathway have been developed recently for the patients with metastatic diseases [5, 6]. Relatively higher costs and unpredictable side effects limit the clinical uses of all these potential treatment options. An effective therapeutic strategy is a critical issue in the management of these patients
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