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Biochem J ; 392(Pt 1): 231-9, 2005 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-16086670

RESUMO

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.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Ceramidas/biossíntese , Fenretinida/farmacologia , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Transformada , Produtos do Gene tax/metabolismo , Glucosiltransferases/antagonistas & inibidores , Humanos , Morfolinas/farmacologia
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