C6-ceramide nanoliposome suppresses tumor metastasis by eliciting PI3K and PKCζ tumor-suppressive activities and regulating integrin affinity modulation

Scientific Reports
Pu ZhangErqun Song

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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Citations

Dec 21, 2018·Current Medicinal Chemistry·Sarah VisentinKrešimir Pavelić
Aug 30, 2020·Cells·Lorry CarriéNathalie Andrieu-Abadie
Oct 31, 2020·Cancers·Laurence PellerinNathalie Andrieu-Abadie
Jul 22, 2021·Molecular Oncology·Antonia PiazzesiGerhild van Echten-Deckert

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Methods Mentioned

BETA
transfection
flow cytometry
dynamic light scattering
Fluorescence

Software Mentioned

ImageJ
NIH ImageJ

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