title: microRNA-21-induced dissociation of PDCD4 from rictor contributes to Akt-IKKβ-mTORC1 axis to regulate renal cancer cell invasion.
abstract: Renal cancer metastasis may result from oncogenic forces that contribute to the primary tumor. We have recently identified microRNA-21 as an oncogenic driver of renal cancer cells. The mechanism by which miR-21 controls renal cancer cell invasion is poorly understood. We show that miR-21 directly downregulates the proapoptotic protein PDCD4 to increase migration and invasion of ACHN and 786-O renal cancer cells as a result of phosphorylation/activation of Akt and IKKβ, which activate NFκB-dependent transcription. Constitutively active (CA) Akt or CA IKKβ blocks PDCD4-mediated inhibition and restores renal cancer cell migration and invasion. PDCD4 inhibits mTORC1 activity, which was reversed by CA IKKβ. Moreover, CA mTORC1 restores cell migration and invasion inhibited by PDCD4 and dominant negative IKKβ. Moreover, PDCD4 negatively regulates mTORC2-dependent Akt phosphorylation upstream of this cascade. We show that PDCD4 forms a complex with rictor, an exclusive component of mTORC2, and that this complex formation is reduced in renal cancer cells due to increased miR-21 expression resulting in enhanced phosphorylation of Akt. Thus our results identify a previously unrecognized signaling node where high miR-21 levels reduce rictor-PDCD4 interaction to increase phosphorylation of Akt and contribute to metastatic fitness of renal cancer cells.
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, TX, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Bera
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, TX, USA.
authors.forename: Falguni
authors.initials: F
authors.lastname: Das
authors.affiliation: Veterans Administration Research Service, South Texas Veterans Health Care System, San Antonio, TX, USA; Department of Pathology, University of Texas Health Science Center at San Antonio, TX, USA.
authors.forename: Nandini
authors.initials: N
authors.lastname: Ghosh-Choudhury
authors.affiliation: Veterans Administration Research Service, South Texas Veterans Health Care System, San Antonio, TX, USA; Department of Medicine, University of Texas Health Science Center at San Antonio, TX, USA.
authors.forename: Balakuntalam S
authors.initials: BS
authors.lastname: Kasinath
authors.affiliation: Veterans Administration Research Service, South Texas Veterans Health Care System, San Antonio, TX, USA; Department of Medicine, University of Texas Health Science Center at San Antonio, TX, USA.
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Abboud
authors.affiliation: Veterans Administration Research Service, South Texas Veterans Health Care System, San Antonio, TX, USA; Department of Medicine, University of Texas Health Science Center at San Antonio, TX, USA; Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA. Electronic address: choudhuryg@uthscsa.edu.
authors.forename: Goutam Ghosh
authors.initials: GG
authors.lastname: Choudhury
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D047468:Immunoprecipitation; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D035683:MicroRNAs / Q000235:genetics*; D046912:Multiprotein Complexes / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D046912:Multiprotein Complexes; C114487:PDCD4 protein, human; C492571:RICTOR protein, human; D016601:RNA-Binding Proteins; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051550:I-kappa B Kinase; C496560:IKBKB protein, human
keywords: Akt kinase; Renal carcinoma; mTOR; miR-21