C6-ceramide nanoliposome suppresses tumor metastasis by eliciting PI3K and PKC? tumor-suppressive activities and regulating integrin affinity modulation.
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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 PKC? and dephosphorylation of PKC?. Concomitantly, activated PKC? translocated into cell membrane. siRNA knockdown or pharmacological inhibition of PKC? or PI3K rescued NaL-C6-mediated suppression of tumor migration. By inducing dephosphorylation of paxillin, PKC? was responsible for NaL-C6-mediated stress fiber depolymerization and focal adhesion disassembly in the metastatic tumor cells. PKC? and PI3K regulated cell shear-resistant adhesion in a way that required integrin ?v?3 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 PKC? tumor-suppressive activities.
SUBMITTER: Zhang P
PROVIDER: S-EPMC4366857 | biostudies-literature | 2015 Mar
REPOSITORIES: biostudies-literature
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