Abstract
The eukaryotic translation initiation factor 4E (eIF4E) is considered as a key survival protein involved in cell cycle progression, transformation and apoptosis resistance. Herein, we demonstrate that medicinal plant derivative 3-AWA (from Withaferin A) suppressed the proliferation and metastasis of CaP cells through abrogation of eIF4E activation and expression via c-FLIP dependent mechanism. This translational attenuation prevents the de novo synthesis of major players of metastatic cascades viz. c-FLIP, c-Myc and cyclin D1. Moreover, the suppression of c-FLIP due to inhibition of translation initiation complex by 3-AWA enhanced FAS trafficking, BID and caspase 8 cleavage. Further ectopically restored c-Myc and GFP-HRas mediated activation of eIF4E was reduced by 3-AWA in transformed NIH3T3 cells. Detailed underlying mechanisms revealed that 3-AWA inhibited Ras-Mnk and PI3-AKT-mTOR, two major pathways through which eIF4E converges upon eIF4F hub. In addition to in vitro studies, we confirmed that 3-AWA efficiently suppressed tumor growth and metastasis in different mouse models. Given that 3-AWA inhibits c-FLIP through abrogation of translation initiation by co-targeting mTOR and Mnk-eIF4E, it (3-AWA) can be exploited as a lead pharmacophore for promising anti-cancer therapeutic development.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Adenosine Triphosphatases / metabolism*
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Animals
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CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
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CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
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Carcinoma, Ehrlich Tumor / genetics
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Carcinoma, Ehrlich Tumor / metabolism
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Carcinoma, Ehrlich Tumor / pathology
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Carrier Proteins / metabolism
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Caspase 8 / metabolism
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Cation Transport Proteins / metabolism*
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Cell Cycle Proteins
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Cell Line, Tumor
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Cell Movement / genetics
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Copper-Transporting ATPases
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Disease Models, Animal
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Eukaryotic Initiation Factor-4E / metabolism
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Eukaryotic Initiation Factors
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Humans
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Male
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Mice
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Neoplasm Metastasis
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoproteins / metabolism
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Phosphorylation
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Protein Biosynthesis / drug effects
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Protein Transport
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Proto-Oncogene Proteins c-akt / metabolism*
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Signal Transduction*
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TOR Serine-Threonine Kinases / metabolism*
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Withanolides / pharmacology
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fas Receptor / metabolism
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ras Proteins / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Atp7a protein, mouse
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Carrier Proteins
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Cation Transport Proteins
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Cell Cycle Proteins
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Cflar protein, mouse
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Eif4ebp1 protein, mouse
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Eukaryotic Initiation Factor-4E
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Eukaryotic Initiation Factors
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Phosphoproteins
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Withanolides
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fas Receptor
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Caspase 8
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Adenosine Triphosphatases
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ras Proteins
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Copper-Transporting ATPases
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withaferin A