Compound K Induces Apoptosis via CAMK-IV/AMPK Pathways in HT-29 Colon Cancer Cells
Compound K Induces Apoptosis via CAMK-IV/AMPK Pathways in HT-29 Colon Cancer Cells
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DOI：
10.1021/jf902700h
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发表时间：
2009-11-25
影响因子：
6.1
通讯作者：
Chung, Sung Hyun
中科院分区：
文献类型：
--
作者：
Kim, Do Yeon;Park, Min Woo;Chung, Sung Hyun
虽然已知化合物K （CK）是人参原人参二醇皂苷的肠道代谢物，可诱导多种癌细胞凋亡，但amp活化蛋白激酶（AMPK）与HT-29结肠癌细胞凋亡的关系尚不清楚。我们假设CK可能通过调节HT-29细胞中的AMPK通路发挥抗癌活性。ck诱导的细胞凋亡与线粒体膜电位的破坏、线粒体中凋亡因子（细胞色素c和凋亡诱导因子）的释放以及caspase-9、caspase-3、caspase-8、Bid和PARP蛋白的裂解有关。我们发现CK对结肠癌细胞的这种凋亡作用是由AMPK激活引发的，AMPK是通过Ca2+/calmodulin-activated protein kinase-IV （CAMK-IV）的磷酸化激活的。用化合物C （AMPK抑制剂）或用于AMPK的siRNA处理HT-29细胞可完全消除ck诱导的细胞凋亡。CAMKs抑制剂STO-609也能减弱ck诱导的AMPK活化和细胞凋亡。综上所述，本研究表明CK介导的HT-29结肠癌细胞死亡受CAMK-IV/AMPK通路调控，这些发现为CK的抗癌作用提供了分子基础。
Although compound K (CK), an intestinal metabolite of ginseng protopanaxadiol saponins, has been known to induce apoptosis in various cancer cells, association of AMP-activated protein kinase (AMPK) with apoptosis in HT-29 colon cancer cells remains unclear. We hypothesized that CK may exert an anticancer activity through modulating the AMPK pathway in HT-29 cells. CK-induced apoptosis was associated with the disruption of the mitochondrial membrane potential, release of apoptogenic factors (cytochrome c and apoptosis-inducing factor) from mitochondria, and cleavage of caspase-9, caspase-3, caspase-8, Bid, and PARP proteins. This apoptotic effect of CK on colon cancer cells was found to be initiated by AMPK activation, and AMPK was activated through phosphorylation by Ca2+/calmodulin-activated protein kinase-IV (CAMK-IV). Treatment of HT-29 cells with compound C (AMPK inhibitor) or siRNA for AMPK completely abolished the CK-induced apoptosis. STO-609, CAMKs inhibitor, also attenuated CK-induced AMPK activation and apoptosis. In conclusion, the present study demonstrates that CK-mediated cell death of HT-29 colon cancer cells is regulated by CAMK-IV/AMPK pathways, and these findings provide a molecular basis for the anticancer effect of CK.