Elevated levels of cholesterol-rich lipid rafts in cancer cells are correlated with apoptosis sensitivity induced by cholesterol-depleting agents.
Lipid rafts/caveolae are membrane platforms for signaling molecules that regulate various cellular functions, including cell survival. To better understand the role of rafts in tumor progression and therapeutics, we investigated the effect of raft disruption on cell viability and compared raft levels in human cancer cell lines versus their normal counterparts. Here, we report that cholesterol depletion using methyl-beta cyclodextrin caused anoikis-like apoptosis, which in A431 cells involved decreased raft levels, Bcl-xL down-regulation, caspase-3 activation, and Akt inactivation regardless of epidermal growth factor receptor activation. Cholesterol repletion replenished rafts on the cell surface and restored Akt activation and cell viability. Moreover, the breast cancer and the prostate cancer cell lines contained more lipid rafts and were more sensitive to cholesterol depletion-induced cell death than their normal counterparts. These results indicate that cancer cells contain increased levels of rafts and suggest a potential use of raft-modulating agents as anti-cancer drugs.
Li
Ying Chun
YC
Division of Specific Organs Cancer, Pediatric Oncology Division, National Cancer Center, 809 Madu 1-dong, Ilsan-gu, Goyang-si, Gyeonggi-do 411-769, Korea.
Park
Mi Jung
MJ
Ye
Sang-Kyu
SK
Kim
Chul-Woo
CW
Kim
Yong-Nyun
YN
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001943:Breast Neoplasms; D002294:Carcinoma, Squamous Cell; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D002784:Cholesterol / Q000378:metabolism*; D015536:Down-Regulation; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008297:Male; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D011471:Prostatic Neoplasms; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D019821:Simvastatin / Q000494:pharmacology; D051020:bcl-X Protein / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000494:pharmacology*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051020:bcl-X Protein; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D002784:Cholesterol; D019821:Simvastatin; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases