The marine natural product manzamine A targets vacuolar ATPases and inhibits autophagy in pancreatic cancer cells.
The marine natural product manzamine A targets vacuolar ATPases and inhibits autophagy in pancreatic cancer cells.
复制标题
海洋天然产物Manzamine A靶向液泡ATPases，并抑制胰腺癌细胞中的自噬。
DOI：
10.3390/md11093500
复制
发表时间：
2013-09-17
期刊：
影响因子：
5.4
通讯作者：
Wright AE
中科院分区：
文献类型：
--
作者：
Kallifatidis G;Hoepfner D;Jaeg T;Guzmán EA;Wright AE
Manzamine A是Manzamine生物碱的一个成员，最初是从海绵属海绵中分离出来的。它最近被证明对胰腺癌细胞有活性，但确切的作用机制尚不清楚。为了进一步了解manzamine A的作用机制，我们对酿酒酵母进行了化学基因组分析，表明manzamine A是液泡atp酶的解偶联剂。荧光显微镜证实了这种对酵母液泡的影响，其中manzamine A产生的表型与已建立的v- atp酶抑制剂巴菲霉素A1非常相似。western blot结果显示，在胰腺癌细胞中，10µM manzamine A影响液泡atp酶活性，显著提高自噬体标志物LC3-II和p62/SQSTM1的水平。manzamine A联合bailomycin A1（自噬体-溶酶体融合抑制剂）治疗与单独使用bailomycin A1治疗相比，没有改变LC3-II的水平，这表明manzamine A通过阻止自噬体的转换是一种潜在的自噬抑制剂。由于自噬是胰腺肿瘤生长所必需的，用曼扎明A阻断这一途径为治疗胰腺癌提供了一个有希望的策略。
Manzamine A, a member of the manzamine alkaloids, was originally isolated from marine sponges of the genus Haliclona. It was recently shown to have activity against pancreatic cancer cells, but the precise mechanism of action remained unclear. To further our understanding of the mechanism of action of manzamine A, chemogenomic profiling in the yeast S. cerevisiae was performed, suggesting that manzamine A is an uncoupler of vacuolar ATPases. Fluorescence microscopy confirmed this effect on yeast vacuoles, where manzamine A produced a phenotype very similar to that of the established v-ATPase inhibitor bafilomycin A1. In pancreatic cancer cells, 10 µM manzamine A affected vacuolar ATPase activity and significantly increased the level of autophagosome marker LC3-II and p62/SQSTM1 as observed by western blot analysis. Treatment with manzamine A in combination with bafilomycin A1 (inhibitor of autophagosome-lysosome fusion) did not change the levels of LC3-II when compared to cells treated with bafilomycin A1 alone, suggesting that manzamine A is a potential inhibitor of autophagy by preventing autophagosome turnover. As autophagy is essential for pancreatic tumor growth, blocking this pathway with manzamine A suggests a promising strategy for the treatment of pancreatic cancer.
登录
查看更多内容
影响因子：
5.1
作者：
Edrada, RA;Proksch, P;VanSoest, RWM
通讯作者：
VanSoest, RWM
DOI：
10.1038/labinvest.2011.8
发表时间：
2011-05
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
通讯作者：
--
影响因子：
2.3
作者：
Guzman, Esther A.;Johnson, Jacob D.;Wright, Amy E.
通讯作者：
Wright, Amy E.
影响因子：
2.7
作者：
Nakashima, S;Hiraku, Y;Kawanishi, S
通讯作者：
Kawanishi, S
影响因子：
3.4
作者：
Guzman, Esther A.;Johnson, Jacob D.;Linley, Patricia A.;Gunasekera, Sarath E.;Wright, Amy E.
通讯作者：
Wright, Amy E.