The IGF-1R/AKT pathway has opposing effects on Nutlin-3a-induced apoptosis

Cancer Biol Ther. 2017 Nov 2;18(11):895-903. doi: 10.1080/15384047.2017.1345397. Epub 2017 Jul 11.


Nutlin-3a is a small molecule MDM2 antagonist and potent activator of wild-type p53. Nutlin-3a disrupts MDM2 binding to p53, thus increasing p53 levels and allowing p53 to inhibit proliferation or induce cell death. Factors that control sensitivity to Nutlin-3a-induced apoptosis are incompletely understood. In this study we isolated cisplatin-resistant clones from MHM cells, an MDM2-amplified and p53 wild-type osteosarcoma cell line. Cisplatin resistance in these clones resulted in part from heightened activation of the IGF-1R/AKT pathway. Interestingly, these cisplatin resistant clones showed hyper-sensitivity to Nutlin-3a induced apoptosis. Increased Nutlin-3a sensitivity was associated with reduced authophagy flux and a greater increase in p53 levels in response to Nutlin-3a treatment. IGF-1R and AKT inhibitors further increased apoptosis by Nutlin-3a in parental MHM cells and the cisplatin-resistant clones, confirming IGF-1R/AKT signaling promotes apoptosis resistance. However, IGF-1R and AKT inhibitors also reduced p53 accumulation in Nutlin-3a treated cells and increased autophagy flux, which we showed can promote apoptosis resistance. We conclude the IGF-1R/AKT pathway has opposing effects on Nutlin-3a-induced apoptosis. First, it can inhibit apoptosis, consistent with its well-established role as a survival-signaling pathway. Second, it can enhance Nutlin-3a induced apoptosis through a combination of maintaining p53 levels and inhibiting pro-survival autophagy.

Keywords: Apoptosis; IGF-1/AKT pathway; Nutlin-3a; osteosarcoma; p53.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / metabolism*
  • Bone Neoplasms / pathology
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • Imidazoles / pharmacology*
  • Osteosarcoma / drug therapy*
  • Osteosarcoma / metabolism*
  • Osteosarcoma / pathology
  • Piperazines / pharmacology*
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Pyrazines / pharmacology
  • Receptor, IGF Type 1
  • Receptors, Somatomedin / antagonists & inhibitors
  • Receptors, Somatomedin / metabolism*


  • 3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
  • Antineoplastic Agents
  • Heterocyclic Compounds, 3-Ring
  • IGF1R protein, human
  • Imidazoles
  • MK 2206
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrazines
  • Receptors, Somatomedin
  • nutlin 3
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins c-akt
  • Cisplatin