Abstract
The human T-cell leukemia virus type-1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATL) is incurable by currently known therapies. ATL samples and cell lines derived from ATL patients show restricted sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD95 ligand (CD95L). We have recently shown that HTLV-1-infected cells express elevated levels of cellular caspase-8 FLICE-inhibitory protein (c-FLIP) conferring resistance to receptor-mediated apoptosis. This finding underscores the demand to develop new strategies for treatment of ATL. In this study, we show that the naturally occurring herbal compound Rocaglamide (Roc) sensitizes CD95L- and TRAIL-induced apoptosis in HTLV-1-infected cells by downregulation of c-FLIP expression. Investigation of the molecular mechanism of Roc-mediated downregulation of c-FLIP revealed that it inhibits phosphorylation of the translation initiation factor 4E (eIF4E), a key factor that controls the rate-limiting step of translation, through inhibition of the MEK-ERK-MNK1 signaling pathway. This event prevents de novo synthesis of short-lived proteins such as c-FLIP in HTLV-1-infected cells. Our data suggest that Roc may serve as an adjuvant for TRAIL-based anticancer therapy.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Antineoplastic Agents / pharmacology*
-
Apoptosis
-
Benzofurans / pharmacology*
-
CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
-
CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
-
Carrier Proteins / metabolism
-
Cell Line, Tumor
-
Down-Regulation
-
Eukaryotic Initiation Factor-4E / metabolism
-
Extracellular Signal-Regulated MAP Kinases / metabolism
-
Fas Ligand Protein / metabolism
-
Human T-lymphotropic virus 1*
-
Humans
-
Intracellular Signaling Peptides and Proteins / metabolism
-
Leukemia-Lymphoma, Adult T-Cell / genetics
-
Leukemia-Lymphoma, Adult T-Cell / metabolism*
-
Leukemia-Lymphoma, Adult T-Cell / virology
-
MAP Kinase Kinase Kinases / metabolism
-
Phosphorylation
-
Protein Biosynthesis
-
Protein Serine-Threonine Kinases / metabolism
-
Signal Transduction
-
TNF-Related Apoptosis-Inducing Ligand / pharmacology*
Substances
-
Antineoplastic Agents
-
Benzofurans
-
CASP8 and FADD-Like Apoptosis Regulating Protein
-
CFLAR protein, human
-
Carrier Proteins
-
Eukaryotic Initiation Factor-4E
-
Fas Ligand Protein
-
Intracellular Signaling Peptides and Proteins
-
RBX1 protein, human
-
TNF-Related Apoptosis-Inducing Ligand
-
rocaglamide
-
MKNK1 protein, human
-
Protein Serine-Threonine Kinases
-
Extracellular Signal-Regulated MAP Kinases
-
MAP Kinase Kinase Kinases