C-6-ceramide nanoliposome suppresses tumor metastasis by eliciting PI3K and PKC zeta tumor-suppressive activities and regulating integrin affinity modulation

• Type of Material: Article
• Authors: Pu Zhang, Southwest University; Changliang Fu, Pennsylvania State University; Yijuan Hu, Emory University; Cheng Dong, Pennsylvania State University; Yang Song, Southwest University; Erqun Song, Southwest University
• Language: English
• Date: 2015-03-20
• Publisher: Nature Publishing Group: Open Access Journals - Option C
• Publication Version: Final Published Version
• Copyright Statement: © 2015, NPG. All rights reserved.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/srep09275
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 5
• Start Page: 9275
• End Page: 9275
• Grant/Funding Information: .Research was supported in part by U.S. National Institutes of Health grant (CA-125707 to C.D.) and National Science Foundation grants (CBET-0729091 to C.D.).; This study was funded by Fundamental Research Funds for the Central Universities (XDJK2014C176 to P.Z.), The Start-up Foundation of Southwest University (SWU114017 to P.Z.) and the National Natural Science Foundation of China (NSFC-81402393 to P.Z.).
• Keywords: Science & Technology - Other Topics; Science & Technology; MIGRATION; Multidisciplinary Sciences; ENDOTHELIAL-CELLS; MELANOMA ADHESION; HYDRODYNAMIC SHEAR; NF-KAPPA-B; STRUCTURAL BASIS; FLOW CONDITIONS; PROTEIN-KINASE-C; CERAMIDE INHIBITION; BREAST-CANCER CELLS
• Research Categories: Engineering, Biomedical; Chemistry, Pharmaceutical

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.