2. Academic Validation
  3. Mechanistic Target of Rapamycin (mTOR) Inhibition Synergizes with Reduced Internal Ribosome Entry Site (IRES)-mediated Translation of Cyclin D1 and c-MYC mRNAs to Treat Glioblastoma

Mechanistic Target of Rapamycin (mTOR) Inhibition Synergizes with Reduced Internal Ribosome Entry Site (IRES)-mediated Translation of Cyclin D1 and c-MYC mRNAs to Treat Glioblastoma

  • J Biol Chem. 2016 Jul 1;291(27):14146-14159. doi: 10.1074/jbc.M116.726927.
Brent Holmes 1,  Jihye Lee 2,  Kenna A Landon 3,  Angelica Benavides-Serrato 3,  Tariq Bashir 3,  Michael E Jung 4,  Alan Lichtenstein 5,  Joseph Gera 6
Affiliations

Affiliations

  • 1 Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90048; Department of Research and Development, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 91343.
  • 2 Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90048.
  • 3 Department of Research and Development, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 91343.
  • 4 Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90048; Jonnson Comprehensive Cancer Center, University of California, Los Angeles, California 90048; Molecular Biology Institute, University of California, Los Angeles, California 90048.
  • 5 Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90048; Department of Research and Development, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 91343; Jonnson Comprehensive Cancer Center, University of California, Los Angeles, California 90048.
  • 6 Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90048; Department of Research and Development, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 91343; Jonnson Comprehensive Cancer Center, University of California, Los Angeles, California 90048; Molecular Biology Institute, University of California, Los Angeles, California 90048. Electronic address: jgera@mednet.ucla.edu.
PMID: 27226604 DOI: 10.1074/jbc.M116.726927
Abstract

Our previous work has demonstrated an intrinsic mRNA-specific protein synthesis salvage pathway operative in glioblastoma (GBM) tumor cells that is resistant to mechanistic target of rapamycin (mTOR) inhibitors. The activation of this internal ribosome entry site (IRES)-dependent mRNA translation initiation pathway results in continued translation of critical transcripts involved in cell cycle progression in the face of global eIF-4E-mediated translation inhibition. Recently we identified compound 11 (C11), a small molecule capable of inhibiting c-Myc IRES translation as a consequence of blocking the interaction of a requisite c-Myc IRES trans-acting factor, heterogeneous nuclear ribonucleoprotein A1, with its IRES. Here we demonstrate that C11 also blocks cyclin D1 IRES-dependent initiation and demonstrates synergistic anti-GBM properties when combined with the mechanistic target of rapamycin kinase inhibitor PP242. The structure-activity relationship of C11 was investigated and resulted in the identification of IRES-J007, which displayed improved IRES-dependent initiation blockade and synergistic anti-GBM effects with PP242. Mechanistic studies with C11 and IRES-J007 revealed binding of the inhibitors within the UP1 fragment of heterogeneous nuclear ribonucleoprotein A1, and docking analysis suggested a small pocket within close proximity to RRM2 as the potential binding site. We further demonstrate that co-therapy with IRES-J007 and PP242 significantly reduces tumor growth of GBM xenografts in mice and that combined inhibitor treatments markedly reduce the mRNA translational state of cyclin D1 and c-Myc transcripts in these tumors. These data support the combined use of IRES-J007 and PP242 to achieve synergistic antitumor responses in GBM.

Keywords

IRES; ITAF; Myc (c-Myc); cyclin D1; glioblastoma; heterogeneous nuclear ribonucleoprotein (hnRNP); mRNA translation; mechanistic target of rapamycin (mTOR); translation.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-124811
    99.03%, c-MYC IRES inhibitor