title: C6-ceramide nanoliposome suppresses tumor metastasis by eliciting PI3K and PKCζ tumor-suppressive activities and regulating integrin affinity modulation.
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.
authors: 1] College of Pharmaceutical Sciences, Southwest University, Chongqing, China, 400715 [2] Department of Bioengineering, Pennsylvania State University, University Park, PA, US 16801.
authors: Pu
authors: P
authors: Zhang
authors: Department of Bioengineering, Pennsylvania State University, University Park, PA, US 16801.
authors: Changliang
authors: C
authors: Fu
authors: Rollins School of Public Health, Emory University, Atlanta, GA, US 30322.
authors: Yijuan
authors: Y
authors: Hu
authors: Department of Bioengineering, Pennsylvania State University, University Park, PA, US 16801.
authors: Cheng
authors: C
authors: Dong
authors: College of Pharmaceutical Sciences, Southwest University, Chongqing, China, 400715.
authors: Yang
authors: Y
authors: Song
authors: College of Pharmaceutical Sciences, Southwest University, Chongqing, China, 400715.
authors: Erqun
authors: E
authors: Song
mesh_terms: D045744:Cell Line, Tumor; D002518:Ceramides / Q000494:pharmacology*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008081:Liposomes; D049329:Nanostructures; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism*; D021381:Protein Transport; D000099221:Protein Kinase C zeta
chemical_list: D002518:Ceramides; D016023:Integrins; D008081:Liposomes; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D000099221:Protein Kinase C zeta