Human T-cell lymphotropic virus type I-transformed T-cells have a partial defect in ceramide synthesis in response to N-(4-hydroxyphenyl)retinamide.
Treatment with the synthetic retinoid HPR [N-(4-hydroxyphenyl)-retinamide] causes growth arrest and apoptosis in HTLV-I (human T-cell lymphotropic virus type-I)-positive and HTLV-I-negative malignant T-cells. It was observed that HPR-mediated growth inhibition was associated with ceramide accumulation only in HTLV-I-negative cells. The aim of the present study was to investigate the mechanism by which HPR differentially regulates ceramide metabolism in HTLV-I-negative and HTLV-I-positive malignant T-cells. Clinically achievable concentrations of HPR caused early dose-dependent increases in ceramide levels only in HTLV-I-negative cells and preceded HPR-induced growth suppression. HPR induced de novo synthesis of ceramide in HTLV-I-negative, but not in HTLV-I-positive, cells. Blocking ceramide glucosylation in HTLV-I-positive cells, which leads to accumulation of endogenous ceramide, rendered these cells more sensitive to HPR. Exogenous cell-permeant ceramides that function partially by generating endogenous ceramide induced growth suppression in all tested malignant lymphocytes, were consistently found to be less effective in HTLV-I-positive cells confirming their defect in de novo ceramide synthesis. Owing to its multipotent activities, the HTLV-I-encoded Tax protein was suspected to inhibit ceramide synthesis. Tax-transfected Molt-4 and HELA cells were less sensitive to HPR and C6-ceramide mediated growth inhibition respectively and produced lower levels of endogenous ceramide. Together, these results indicate that HTLV-I-positive cells are defective in de novo synthesis of ceramide and that therapeutic modalities that bypass this defect are more likely to be successful.
Darwiche
Nadine
N
Department of Biology, American University of Beirut, Beirut, Lebanon. darwichn@aub.edu.lb
Abou-Lteif
Ghada
G
Najdi
Tarek
T
Kozhaya
Lina
L
Tayoun
Ahmad Abou
AA
Abou Tayyoun
Ahmad
A
Bazarbachi
Ali
A
Dbaibo
Ghassan S
GS
D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D002518:Ceramides / Q000096:biosynthesis*; D017313:Fenretinide / Q000494:pharmacology*; D016356:Gene Products, tax / Q000378:metabolism; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D009025:Morpholines / Q000494:pharmacology
D002518:Ceramides; D016356:Gene Products, tax; D009025:Morpholines; D017313:Fenretinide; C033110:RV 538; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase