Abstract |
Nanoliposomal formulation of C6-ceramide, a proapoptotic sphingolipid metabolite, presents an effective way to treat malignant tumor. Here, we provide evidence that acute treatment (30 min) of melanoma and breast cancer cells with nanoliposomal C6-ceramide (NaL-C6) may suppress cell migration without inducing cell death. By employing a novel flow migration assay, we demonstrated that NaL-C6 decreased tumor extravasation under shear conditions. Compared with ghost nanoliposome, NaL-C6 triggered phosphorylation of PI3K and PKCζ and dephosphorylation of PKCα. Concomitantly, activated PKCζ translocated into cell membrane. siRNA knockdown or pharmacological inhibition of PKCζ or PI3K rescued NaL-C6-mediated suppression of tumor migration. By inducing dephosphorylation of paxillin, PKCζ was responsible for NaL-C6-mediated stress fiber depolymerization and focal adhesion disassembly in the metastatic tumor cells. PKCζ and PI3K regulated cell shear-resistant adhesion in a way that required integrin αvβ3 affinity modulation. In conclusion, we identified a novel role of acute nanoliposomal ceramide treatment in reducing integrin affinity and inhibiting melanoma metastasis by conferring PI3K and PKCζ tumor-suppressive activities.
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Authors | Pu Zhang, Changliang Fu, Yijuan Hu, Cheng Dong, Yang Song, Erqun Song |
Journal | Scientific reports
(Sci Rep)
Vol. 5
Pg. 9275
(Mar 20 2015)
ISSN: 2045-2322 [Electronic] England |
PMID | 25792190
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Ceramides
- Integrins
- Liposomes
- Phosphatidylinositol 3-Kinases
- protein kinase C zeta
- Protein Kinase C
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Topics |
- Cell Line, Tumor
- Ceramides
(pharmacology)
- Humans
- Integrins
(metabolism)
- Liposomes
- Nanostructures
- Neoplasm Metastasis
(prevention & control)
- Phosphatidylinositol 3-Kinases
(metabolism)
- Phosphorylation
- Protein Binding
- Protein Kinase C
(metabolism)
- Protein Transport
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