Lysosomal Degradation of CD44 Mediates Ceramide Nanoliposome-induced Anoikis and Diminished Extravasation in Metastatic Carcinoma Cells |
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| Authors: | Jeremy K. Haakenson Andrei V. Khokhlatchev Younhee J. Choi Samuel S. Linton Pu Zhang Peter M. Zaki Changliang Fu Timothy K. Cooper Andrea Manni Junjia Zhu Todd E. Fox Cheng Dong Mark Kester |
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| Affiliation: | From the Departments of ‡Pharmacology.;‖Comparative Medicine.;**Medicine, and ;‡‡Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.;the §Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, and ;the ¶Department of Bioengineering, Pennsylvania State University, State College, Pennsylvania 16801 |
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| Abstract: | 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. |
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| Keywords: | Anoikis Breast Cancer CD44 Ceramide Metastasis Carcinoma Extravasation |
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