title: Dual modulation of Ras-Mnk and PI3K-AKT-mTOR pathways: A Novel c-FLIP inhibitory mechanism of 3-AWA mediated translational attenuation through dephosphorylation of eIF4E.
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.
authors.affiliation: Academy of Scientific &Innovative Research (AcSIR), New Delhi, India.|Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, J&K - 180001, India.
authors.forename: Reyaz
authors.initials: R
authors.lastname: ur Rasool
authors.affiliation: Academy of Scientific &Innovative Research (AcSIR), New Delhi, India.|Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, J&K - 180001, India.
authors.forename: Bilal
authors.initials: B
authors.lastname: Rah
authors.affiliation: Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, J&K - 180001, India.
authors.forename: Hina
authors.initials: H
authors.lastname: Amin
authors.affiliation: Academy of Scientific &Innovative Research (AcSIR), New Delhi, India.|Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, J&K - 180001, India.
authors.forename: Debasis
authors.initials: D
authors.lastname: Nayak
authors.affiliation: Academy of Scientific &Innovative Research (AcSIR), New Delhi, India.|Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, J&K - 180001, India.
authors.forename: Souneek
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Center for Cellular and Molecular Biology, Uppal Road, Hyderabad, AP-50007, India.
authors.forename: Abdul
authors.initials: A
authors.lastname: Rawoof
authors.affiliation: Academy of Scientific &Innovative Research (AcSIR), New Delhi, India.|Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, J&K - 180001, India.
authors.forename: Mubashir Javed
authors.initials: MJ
authors.lastname: Mintoo
authors.affiliation: Natural Product Chemistry, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, J&K - 180001, India.
authors.forename: Khalid
authors.initials: K
authors.lastname: Yousuf
authors.affiliation: Natural Product Chemistry, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, J&K - 180001, India.
authors.forename: Debaraj
authors.initials: D
authors.lastname: Mukherjee
authors.affiliation: Center for Cellular and Molecular Biology, Uppal Road, Hyderabad, AP-50007, India.
authors.forename: Lekha Dinesh
authors.initials: LD
authors.lastname: Kumar
authors.affiliation: Academy of Scientific &Innovative Research (AcSIR), New Delhi, India.|Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, J&K - 180001, India.
authors.forename: Dilip Manikaro
authors.initials: DM
authors.lastname: Mondhe
authors.affiliation: Academy of Scientific &Innovative Research (AcSIR), New Delhi, India.|Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, J&K - 180001, India.
authors.forename: Anindya
authors.initials: A
authors.lastname: Goswami
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism; D002286:Carcinoma, Ehrlich Tumor / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D000073840:Copper-Transporting ATPases; D004195:Disease Models, Animal; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D039642:Eukaryotic Initiation Factors; D006801:Humans; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D054358:Withanolides / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; D053181:Caspase 8; D027682:Cation Transport Proteins; D018797:Cell Cycle Proteins; D000073840:Copper-Transporting ATPases; D039561:Eukaryotic Initiation Factor-4E; D039642:Eukaryotic Initiation Factors; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D054358:Withanolides; D019014:fas Receptor; D018631:ras Proteins; C486201:Atp7a protein, mouse; C506387:Cflar protein, mouse; C499527:Eif4ebp1 protein, mouse; C009684:withaferin A