Lysosomal Degradation of CD44 Mediates Ceramide Nanoliposome-induced Anoikis and Diminished Extravasation in Metastatic Carcinoma Cells*

Background: Even though ceramide selectively induces apoptosis in multiple cancer models, the mechanisms by which ceramide limits cancer metastasis are unknown. Results: The ceramide nanoliposome (CNL) inhibits cancer cell metastasis by inducing anoikis and inhibiting extravasation via lysosomal degradation of CD44. Conclusion: Ceramide reduces the metastatic potential of multiple cancer cell models. Significance: CNL may have therapeutic utility in preventing and treating metastatic cancers. The ceramide nanoliposome (CNL) has shown promise in being able to treat a variety of primary tumors. However, its potential for treating metastatic cancer remains unknown. In this study, we demonstrate that CNL increases anoikis while preventing cancer cell extravasation under both static and physiological fluid flow conditions. Mechanistically, CNL limits metastases by decreasing CD44 protein levels in human breast and pancreatic cancer cells via lysosomal degradation of CD44, independent of palmitoylation or proteasome targeting. siRNA down-regulation of CD44 mimics CNL-induced anoikis and diminished extravasation of cancer cells. Taken together, our data indicate that ceramide limits CD44-dependent cancer cell migration, suggesting that CNL could be used to prevent and treat solid tumor metastasis.