title: Inhibition of SAPK2/p38 enhances sensitivity to mTORC1 inhibition by blocking IRES-mediated translation initiation in glioblastoma.
abstract: A variety of mechanisms confer hypersensitivity of tumor cells to the macrolide rapamycin, the prototypic mTORC1 inhibitor. Several studies have shown that the status of the AKT kinase plays a critical role in determining hypersensitivity. Cancer cells in which AKT activity is elevated are exquisitely sensitive to mTORC1 inhibitors while cells in which the kinase is quiescent are relatively resistant. Our previous work has shown that a transcript-specific protein synthesis salvage pathway is operative in cells with quiescent AKT levels, maintaining the translation of crucial mRNAs involved in cell-cycle progression in the face of global eIF-4E-mediated translation inhibition. The activation of this salvage pathway is dependent on SAPK2/p38-mediated activation of IRES-dependent initiation of the cyclin D1 and c-MYC mRNAs, resulting in the maintenance of their protein expression levels. Here, we show that both genetic and pharmacologic inhibition of SAPK2/p38 in glioblastoma multiforme cells significantly reduces rapamycin-induced IRES-mediated translation initiation of cyclin D1 and c-MYC, resulting in increased G(1) arrest in vitro and inhibition of tumor growth in xenografts. Moreover, we observed that the AKT-dependent signaling alterations seen in vitro are also displayed in engrafted tumors cells and were able to show that combined inhibitor treatments markedly reduced the mRNA translational state of cyclin D1 and c-MYC transcripts in tumors isolated from mice. These data support the combined use of SAPK2/p38 and mTORC1 inhibitors to achieve a synergistic antitumor therapeutic response, particularly in rapamycin-resistant quiescent AKT-containing cells.
authors.affiliation: Department of Research & Development, Greater Los Angeles VA Healthcare System, 16111 Plummer Street (151), Sepulveda, CA 91343, USA.
authors.forename: Cheri
authors.initials: C
authors.lastname: Cloninger
authors.forename: Andrew
authors.initials: A
authors.lastname: Bernath
authors.forename: Tariq
authors.initials: T
authors.lastname: Bashir
authors.forename: Brent
authors.initials: B
authors.lastname: Holmes
authors.forename: Nicholas
authors.initials: N
authors.lastname: Artinian
authors.forename: Teresa
authors.initials: T
authors.lastname: Ruegg
authors.forename: Lauren
authors.initials: L
authors.lastname: Anderson
authors.forename: Janine
authors.initials: J
authors.lastname: Masri
authors.forename: Alan
authors.initials: A
authors.lastname: Lichtenstein
authors.forename: Joseph
authors.initials: J
authors.lastname: Gera
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001665:Binding Sites / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019940:Genes, bcl-1 / Q000187:drug effects; D016259:Genes, myc / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D016513:Mice, SCID; D048290:Mitogen-Activated Protein Kinase 11 / Q000037:antagonists & inhibitors; D046912:Multiprotein Complexes; D014176:Protein Biosynthesis / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011506:Proteins; D034741:RNA, Small Interfering; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D048290:Mitogen-Activated Protein Kinase 11; D048051:p38 Mitogen-Activated Protein Kinases