Inhibition of c-Met Activation Sensitizes Osteosarcoma Cells to Cisplatin via Suppression of the PI3K-Akt Signaling

Arch Biochem Biophys. 2012 Oct 1;526(1):38-43. doi: 10.1016/j.abb.2012.07.003. Epub 2012 Jul 20.

Abstract

Osteosarcoma is a common malignant bone tumor. Cisplatin (CDDP) achieves a high response rate in osteosarcoma. However, osteosarcoma usually exhibits cisplatin resistance. Many members of receptor tyrosine kinases (RTKs)(1) have been demonstrated to be overexpressed and constitutively activated in various tumors including osteosarcoma, resulting in malignant progression and insensitivity to chemotherapy. Hepatocyte growth factor receptor (HGFR/c-Met) also appears overexpressed and activated in osteosarcoma cells. Nevertheless, which role of c-Met activation in cisplatin efficacy against osteosarcoma cells remains still elusive. This study found that inhibition of c-Met activity by PHA-665752 or blockade of the interaction of autocrined HGF with c-Met with neutralizing anti-HGF antibody promoted cisplatin efficacy in osteosarcoma cells, while addition of recombinant human HGF (rh-HGF) counteracts cisplatin cytotoxicity. Specifically, we demonstrated that inhibition of c-Met activity led to suppression of the PI3K-Akt pathway, thus enhancing cisplatin chemosensitivity. Our study clearly suggests that inhibition of c-Met activity can effectively sensitize osteosarcoma cells to cisplatin via suppression of the PI3K-Akt signaling.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Bone Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chromones / pharmacology
  • Cisplatin / pharmacology*
  • Enzyme Activation / drug effects
  • Hepatocyte Growth Factor / pharmacology
  • Humans
  • Morpholines / pharmacology
  • Osteosarcoma / pathology*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins c-met / metabolism*
  • Signal Transduction / drug effects*

Substances

  • Antineoplastic Agents
  • Chromones
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met
  • Proto-Oncogene Proteins c-akt
  • Cisplatin