Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Chungbuk 363-883, Republic of Korea.
Oncol Rep. 2012 May;27(5):1407-12. doi: 10.3892/or.2012.1644. Epub 2012 Jan 19.
Widdrol, a natural sesquiterpene present in Juniperus sp., has been shown to exert anticancer and antifungal effects. Emerging evidence has suggested that AMP-activated protein kinase (AMPK), which functions as a cellular energy sensor, is a potential therapeutic target for human cancers. In this study, we found that AMPK mediates the anticancer effects of widdrol through induction of apoptosis in HT-29 colon cancer cells. We showed that widdrol induced the phosphorylation of AMPK in a dose- and time-dependent manner. The selective AMPK inhibitor compound C abrogated the inhibitory effect of widdrol on HT-29 cell growth. In addition, we demonstrated that widdrol induced apoptosis and this was associated with the activation of caspases, including caspase‑3/7 and caspase-9, in HT-29 cells. We also demonstrated that transfection of HT-29 cells with AMPK siRNAs significantly suppressed the widdrol-mediated apoptosis and the activation of caspases. However, cell cycle arrest induced by widdrol was not affected by transfection of HT-29 cells with AMPK siRNAs. Furthermore, widdrol inhibited HT-29 tumor growth in a human tumor xenograft model. Taken together, our results suggest that the anticancer effect of widdrol may be mediated, at least in part, by induction of apoptosis via AMPK activation.
威德罗醇，一种存在于杜松属植物中的天然倍半萜烯，已被证明具有抗癌和抗真菌作用。新出现的证据表明，作为细胞能量传感器的 AMP 激活蛋白激酶 (AMPK) 可能是人类癌症的潜在治疗靶点。在这项研究中，我们发现 AMPK 通过诱导 HT-29 结肠癌细胞凋亡来介导威德罗醇的抗癌作用。我们表明威德罗醇以剂量和时间依赖的方式诱导 AMPK 的磷酸化。选择性 AMPK 抑制剂化合物 C 阻断了威德罗醇对 HT-29 细胞生长的抑制作用。此外，我们证明威德罗醇诱导了 HT-29 细胞的凋亡，这与包括 caspase-3/7 和 caspase-9 在内的半胱天冬酶的激活有关。我们还表明，用 AMPK siRNAs 转染 HT-29 细胞可显著抑制威德罗醇介导的凋亡和半胱天冬酶的激活。然而，威德罗醇诱导的细胞周期停滞不受 AMPK siRNAs 转染 HT-29 细胞的影响。此外，威德罗醇抑制了人肿瘤异种移植模型中的 HT-29 肿瘤生长。总之，我们的结果表明，威德罗醇的抗癌作用可能至少部分通过 AMPK 激活诱导细胞凋亡来介导。
