D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol alters cellular cholesterol homeostasis by modulating the endosome lipid domains.
D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) is a frequently used inhibitor of glycosphingolipid biosynthesis. However, some interesting characteristics of D-PDMP cannot be explained by the inhibition of glycolipid synthesis alone. In the present study, we showed that d-PDMP inhibits the activation of lysosomal acid lipase by late endosome/lysosome specific lipid, bis(monoacylglycero)phosphate (also called as lysobisphosphatidic acid), through alteration of membrane structure of the lipid. When added to cultured fibroblasts, D-PDMP inhibits the degradation of low-density lipoprotein (LDL) and thus accumulates both cholesterol ester and free cholesterol in late endosomes/lysosomes. This accumulation results in the inhibition of LDL-derived cholesterol esterification and the decrease of cell surface cholesterol. We showed that D-PDMP alters cellular cholesterol homeostasis in a glycosphingolipid-independent manner using L-PDMP, a stereoisomer of D-PDMP, which does not inhibit glycosphingolipid synthesis, and mutant melanoma cell which is defective in glycolipid synthesis. Altering cholesterol homeostasis by D-PDMP explains the unique characteristics of sensitizing multidrug resistant cells by this drug.
Makino
Asami
A
RIKEN Wako-shi, Saitama 351-0198, Japan, School of Pharmacy, Shujitsu University, Okayama 703-8516, Japan.
Ishii
Kumiko
K
Murate
Motohide
M
Hayakawa
Tomohiro
T
Suzuki
Yusuke
Y
Suzuki
Minoru
M
Ito
Kazuki
K
Fujisawa
Tetsuro
T
Matsuo
Hirotami
H
Ishitsuka
Reiko
R
Kobayashi
Toshihide
T
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000494:pharmacology; D009327:4-Chloro-7-nitrobenzofurazan / Q000031:analogs & derivatives / Q000378:metabolism; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D011992:Endosomes / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts; D005964:Glucosyltransferases / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D008049:Lipase / Q000378:metabolism; D008246:Lysophospholipids / Q000502:physiology; D021962:Membrane Microdomains / Q000737:chemistry / Q000187:drug effects*; D050178:Monoglycerides / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology*; D009447:Neuroblastoma / Q000378:metabolism; D017239:Paclitaxel / Q000493:pharmacokinetics; D013237:Stereoisomerism; D002787:Sterol Esterase / Q000378:metabolism
D002518:Ceramides; D008246:Lysophospholipids; D050178:Monoglycerides; D009025:Morpholines; C012786:bis(monoacylglyceryl)phosphate; D017485:1-Deoxynojirimycin; C033110:RV 538; C037974:N-(7-(4-nitrobenzo-2-oxa-1,3-diazole))-6-aminocaproyl sphingosine; D002784:Cholesterol; C059896:miglustat; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D002787:Sterol Esterase; D008049:Lipase; D009327:4-Chloro-7-nitrobenzofurazan; D017239:Paclitaxel