期刊
FASEB JOURNAL
卷 35, 期 3, 页码 -出版社
WILEY
DOI: 10.1096/fj.202002427R
关键词
ceramide; doxorubicin; migration; phosphatase; sphingomyelinase
资金
- National Cancer Institute (NCI) [CA218678]
The study revealed that low doses of the chemotherapeutic compound doxorubicin result in dysregulation of cytoskeletal proteins, enhancing cancer cell migration, which could explain the reported effects of doxorubicin worsening cancer metastasis in animal models.
We have recently reported that a specific pool of ceramide, located in the plasma membrane, mediated the effects of sublethal doses of the chemotherapeutic compound doxorubicin on enhancing cancer cell migration. We identified neutral sphingomyelinase 2 (nSMase2) as the enzyme responsible to generate this bioactive pool of ceramide. In this work, we explored the role of members of the protein phosphatases 1 family (PP1), and we identified protein phosphatase 1 alpha isoform (PP1 alpha) as the specific PP1 isoform to mediate this phenotype. Using a bioinformatics approach, we build a functional interaction network based on phosphoproteomics data on plasma membrane ceramide. This led to the identification of several ceramide-PP1 alpha downstream substrates. Studies on phospho mutants of ezrin (T567) and Scrib (S1378/S1508) demonstrated that their dephosphorylation is sufficient to enhance cell migration. In summary, we identified a mechanism where reduced doses of doxorubicin result in the dysregulation of cytoskeletal proteins and enhanced cell migration. This mechanism could explain the reported effects of doxorubicin worsening cancer metastasis in animal models.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据