Kwanhwan Wi, Sun-Young Hwang, Young-Gwon Kim, Soong-In Lee, Cheol-Jung Lee, Geul Bang, Je-Ho Lee, Mee-Hyun Lee
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引用次数: 0
摘要
背景：木犀草内酯（COS）是从木犀草根中提取的一种倍半萜内酯，对结肠癌、口腔癌和肺癌等多种癌症具有抗癌作用，但其在皮肤癌发生中的作用机制尚未探明。本研究探讨了 COS 在体外和体内对皮肤炎症和癌变的化学预防机制：方法：使用 WST-8 试验检测 COS 对正常小鼠表皮细胞系 JB6 的细胞毒性。随后，通过软琼脂试验评估了 COS 对 12-O-十四碳酰基樟脑酚-13-乙酸酯（TPA）诱导的细胞转化的影响。此外，还分别通过流式细胞仪和 Western 印迹法测定了细胞周期和凋亡分析以及相关蛋白质的表达。通过 H&E 染色和免疫组化分析，确定了 COS 对 DMBA/TPA 处理诱导的肿瘤的促进作用及其在小鼠皮肤癌发生中的分子机制：结果：COS能明显抑制TPA诱导的JB6细胞转化中的菌落生长和数量，使细胞周期停滞在G2/M期，增加p21的表达，降低细胞周期蛋白B的表达。此外，COS 还能诱导细胞凋亡，并增加相关标志物的表达，包括裂解的 caspase-3 和 - 7。COS 可抑制磷酸化 AKT 及其下游信号蛋白的表达，并有效减少磷酸化 NF-κB 从细胞膜向细胞核的转位。此外，COS 还能减少小鼠皮肤乳头状瘤的形成，抑制组织增生和磷酸化 AKT 的表达：这些结果表明，COS 可通过 AKT 信号通路在体外和体内抑制 TPA 诱导的细胞转化和皮肤癌变。我们的研究结果表明，COS 具有作为皮肤癌发生的化学预防剂的潜力，这凸显了其在癌症预防和治疗方面的进一步研究意义。
Costunolide inhibits the progression of TPA-induced cell transformation and DMBA/TPA-induced skin carcinogenesis by regulation of AKT-mediated signaling.
Background: Costunolide (COS), a sesquiterpene lactone extracted from the roots of Saussurea costus, is known to possess anticancer properties in various cancers, including colon, oral, and lung cancers, but its mechanism of action in skin carcinogenesis has not yet been explored. Present study investigates the chemopreventive mechanism of COS on skin inflammation and carcinogenesis both in vitro and in vivo.
Methods: The cytotoxicity of COS was examined on a normal murine epidermal cell line, JB6, by treating with COS using the WST-8 assay. Subsequently, the effect of COS on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cellular transformation was assessed through a soft-agar assay. Furtherly, cell cycle and apoptosis analysis and the expression of related proteins were determined via flow cytometry and Western blotting, respectively. The effects of COS on tumor promotion induced by DMBA/TPA treatment and the underlying molecular mechanisms in mouse skin carcinogenesis were identified through H&E staining and immunohistochemical analysis.
Results: COS significantly inhibited colony growth and number in TPA-induced JB6 cells transformation, arrested the cell cycle at the G2/M phase, increased p21 expression, and decreased cyclin B expression. In addition, COS induced cell apoptosis and increased the related markers expression including cleaved caspase-3 and - 7. COS suppressed the expression of phosphorylated AKT and its downstream signaling proteins and effectively reduced the translocation of phosphorylated NF-κB from the cytosol to the nucleus. Moreover, COS reduced papilloma formation in mouse skin and inhibited hyperplasia and phosphorylated AKT expression in tissues.
Conclusion: These results demonstrate that COS inhibits TPA-induced cellular transformation and skin carcinogenesis both in vitro and in vivo through the AKT signaling pathway. Our findings suggest the potential of COS as a chemopreventive agent for skin carcinogenesis, highlighting its significance for further investigation in cancer prevention and therapy.
期刊介绍：
Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques.
The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors.
Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.
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