ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2021
The doxorubicin-induced cell motility network is under the control of the ceramide-activated protein phosphatase 1 alpha.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 10 citations in OpenAlex.
- Therapeutic Potential for Sphingolipids in Inflammatory Bowel Disease and Colorectal Cancer.Cancers · 2024Review
- LASS2 enhances chemosensitivity to cisplatin by inhibiting PP2A-mediated β-catenin dephosphorylation in a subset of stem-like bladder cancer cells.BMC medicine · 2024Article
- Biological function, topology, and quantification of plasma membrane Ceramide.Advances in biological regulation · 2024Review
- Compartmentalization of Sphingolipid metabolism: Implications for signaling and therapy.Pharmacology & therapeutics · 2022Review
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
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.
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Registered trials
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