Cholesterol-rich lipid rafts mediate akt-regulated survival in prostate cancer cells.
Although cholesterol accumulation in tumors was first reported in the early20th century, the mechanistic implications of this observation are still obscure. Here we report that caveolin-negative human prostate cancer (LNCaP) cells contain cholesterol-rich lipid rafts that mediate epidermal growth factor (EGF)-induced and constitutive signaling through the Akt1 serine-threonine kinase. EGF receptor and Akt1 phosphorylation were inhibited and autonomous cell survival was reduced when the rafts were disrupted. Reconstitution of the rafts with cholesterol restored EGF receptor-->Akt1 axis signaling and cytoprotection from a phosphoinositide 3-kinase-dependent apoptotic signal. These results suggest that cholesterol present in membrane microdomains is a prominent mediator of survival in prostate cancer cells.
Zhuang
Liyan
L
The Urologic Laboratory, Department of Urology, Harvard Medical School, Boston, MA 02115, USA.
Lin
Jianqing
J
Lu
Michael L
ML
Solomon
Keith R
KR
Freeman
Michael R
MR
D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000502:physiology; D006801:Humans; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology
D002784:Cholesterol; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D008563:Membrane Lipids; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; C494918:AKT1 protein, human