Widdrol induces apoptosis via activation of AMP-activated protein kinase in colon cancer cells
Widdrol induces apoptosis via activation of AMP-activated protein kinase in colon cancer cells
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DOI：
10.3892/or.2012.1644
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发表时间：
2012-05-01
期刊：
影响因子：
4.2
通讯作者：
Kim, Hwan Mook
中科院分区：
文献类型：
--
作者：
Kang, Moo Rim;Park, Song-Kyu;Kim, Hwan Mook
Widdrol，一种存在于杜松属物种中的天然倍半萜，已经显示出发挥抗癌和抗真菌作用。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）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结肠癌细胞凋亡介导了维德醇的抗癌作用。我们发现，维德醇诱导AMPK磷酸化的剂量和时间依赖性的方式。选择性AMPK抑制剂化合物C可消除Widdrol对HT-29细胞生长的抑制作用。此外，我们证明，维德醇诱导细胞凋亡，这是与半胱天冬酶，包括半胱天冬酶-3/7和半胱天冬酶-9，在HT-29细胞的激活。我们还证明了用AMPK siRNA转染HT-29细胞显著抑制了Widdrol介导的凋亡和caspase的激活。然而，用AMPK siRNA转染HT-29细胞不影响Widdrol诱导的细胞周期停滞。此外，在人肿瘤异种移植模型中，维德醇抑制HT-29肿瘤生长。总而言之，我们的结果表明，维德醇的抗癌作用可能至少部分是通过AMPK激活诱导细胞凋亡来介导的。
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 si RNAs 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.