Rocaglamide breaks TRAIL resistance in HTLV-1-associated adult T-cell leukemia/lymphoma by translational suppression of c-FLIP expression.
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.
Bleumink
M
M
Tumor Immunology Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.
Köhler
R
R
Giaisi
M
M
Proksch
P
P
Krammer
P H
PH
Li-Weber
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001572:Benzofurans / Q000494:pharmacology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism; D015368:Human T-lymphotropic virus 1; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001572:Benzofurans; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D039561:Eukaryotic Initiation Factor-4E; D053222:Fas Ligand Protein; D047908:Intracellular Signaling Peptides and Proteins; C479529:RBX1 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C107772:rocaglamide; C491395:MKNK1 protein, human; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases