Low Cholesterol Triggers Membrane Microdomain-dependent CD44 Shedding and Suppresses Tumor Cell Migration

Toshiyuki Murai,Yuusuke Maruyama,Kazuhiro Mio,Hidetoshi Nishiyama,Mitsuo Suga,Chikara Sato

doi:10.1074/jbc.m110.184010

Abstract

CD44 is a cell surface adhesion molecule for hyaluronan and is implicated in tumor invasion and metastasis. Proteolytic cleavage of CD44 plays a critical role in the migration of tumor cells and is regulated by factors present in the tumor microenvironment, such as hyaluronan oligosaccharides and epidermal growth factor. However, molecular mechanisms underlying the proteolytic cleavage on membranes remain poorly understood. In this study, we demonstrated that cholesterol depletion with methyl-β-cyclodextrin, which disintegrates membrane lipid rafts, enhances CD44 shedding mediated by a disintegrin and metalloproteinase 10 (ADAM10) and that cholesterol depletion disorders CD44 localization to the lipid raft. We also evaluated the effect of long term cholesterol reduction using a statin agent and demonstrated that statin enhances CD44 shedding and suppresses tumor cell migration on a hyaluronan-coated substrate. Our results indicate that membrane lipid organization regulates CD44 shedding and propose a possible molecular mechanism by which cholesterol reduction might be effective for preventing and treating the progression of malignant tumors.

Highlights

Physiological inducers of CD44 shedding have been identified; hyaluronan small fragments, frequently detected in association with pathological conditions including cancer [7], induce CD44 shedding from tumor cells [8]
Cholesterol Depletion with M␤CD Induces CD44 Shedding from Tumor Cells—To study the influence of the cellular cholesterol level on CD44 shedding, we treated a human glioblastoma cell line, U-251 MG, which is known to release CD44 upon certain kinds of stimulation [9, 11, 27], with M␤CD
The results of this study clearly demonstrate that depleting cellular cholesterol with M␤CD induces CD44 shedding

Summary

Introduction

Physiological inducers of CD44 shedding have been identified; hyaluronan small fragments, frequently detected in association with pathological conditions including cancer [7], induce CD44 shedding from tumor cells [8]. We demonstrated that M␤CD-induced cholesterol depletion enhances the ADAM10-mediated shedding of CD44. Cholesterol Depletion with M␤CD Induces CD44 Shedding from Tumor Cells—To study the influence of the cellular cholesterol level on CD44 shedding, we treated a human glioblastoma cell line, U-251 MG, which is known to release CD44 upon certain kinds of stimulation [9, 11, 27], with M␤CD.

Results

Conclusion