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Lipid raft modulation inhibits NSCLC cell migration through delocalization of the focal adhesion complex

 Jeong Hee Jeon  ;  Se Kyu Kim  ;  Hyung Jung Kim  ;  Joon Chang  ;  Chul Min Ahn  ;  Yoon Soo Chang 
 LUNG CANCER, Vol.69(2) : 165-171, 2010 
Journal Title
Issue Date
Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/metabolism* ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Line, Tumor ; Cell Movement/drug effects ; Cholesterol/deficiency* ; Cholesterol/metabolism ; Epidermal Growth Factor/metabolism ; Focal Adhesion Kinase 1/genetics ; Focal Adhesion Kinase 1/metabolism* ; Focal Adhesions/drug effects ; Humans ; Lovastatin/pharmacology ; Membrane Microdomains/drug effects ; Membrane Microdomains/metabolism* ; Oncogene Protein pp60(v-src)/metabolism ; Phosphorylation ; Protein Stability/drug effects ; Protein Transport ; Pseudopodia/genetics ; Receptor Aggregation/drug effects ; Receptor, Epidermal Growth Factor/metabolism* ; beta-Cyclodextrins/pharmacology
Lipid raft, a specialized membrane structure enriched with cholesterol and glycosphingolipid, contains molecules that convey environmental stimuli to the intracellular systems. Authors investigated the effects of raft cholesterol depletion on non-small cell lung cancer (NSCLC) cell migration. Incubation of NSCLC cells in media containing lovastatin resulted in inhibition of cell migration by 63.1-83.3%, whereas raft cholesterol depletion with successive treatment using methyl-beta cyclodextrin (MbetaCD) followed by lovastatin further suppressed their migration by 35.0-57.8%. Raft cholesterol depletion partially inhibited EGF-induced phosphorylation of EGFR and FAK, however, no change was observed in other molecules comprising focal adhesion complex. It resulted in disappearance of filopodia, inhibition of EGF-induced pY397 FAK aggregation, and its destabilization. Cholesterol depletion inhibited phosphorylation of Src on Y416 in the detergent-insoluble fraction followed by decreased localization of total and pY397 FAK in the detergent-insoluble fraction. Minimal changes in these molecules were observed in the detergent-soluble fraction and interactions between FAK and other molecules of the focal adhesion complex were not influenced. Immunocytochemical analysis confirmed translocation of Src from the raft into cytoplasm and disappearance of EGF-induced membrane ruffling by raft cholesterol depletion. In cholesterol-depleted cells, EGF-induced phosphorylation of Src, Akt, and p44/42 in the detergent-insoluble fraction were inhibited whereas phosphorylation of GSK-3beta was unaffected. We conclude that raft cholesterol depletion inhibited NSCLC migration through inhibition of phosphorylation of raft associated Src and dislocation of molecules comprising focal adhesion complexes from raft rather than by inhibiting their recruitment to Src and interaction.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Se Kyu(김세규)
Kim, Hyung Jung(김형중) ORCID logo https://orcid.org/0000-0003-2498-0683
Ahn, Chul Min(안철민)
Chang, Yoon Soo(장윤수) ORCID logo https://orcid.org/0000-0003-3340-4223
Chang, Joon(장준) ORCID logo https://orcid.org/0000-0003-4542-6841
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