Transforming growth factor alpha promotes osteosarcoma metastasis by ICAM-1 and PI3K/Akt signaling pathway

Biochem Pharmacol. 2014 Jun 15;89(4):453-63. doi: 10.1016/j.bcp.2014.03.010. Epub 2014 Mar 28.

Abstract

Osteosarcoma is the most common primary malignancy of bone and is characterized by a high malignant and metastatic potential. Transforming growth factor alpha (TGF-α) is classified as the EGF (epidermal growth factor)-like family, which is involved in cancer cellular activities such as proliferation, motility, migration, adhesion and invasion abilities. However, the effect of TGF-α on human osteosarcoma is largely unknown. We found that TGF-α increased the cell migration and expression of intercellular adhesion molecule-1 (ICAM-1) in human osteosarcoma cells. Transfection of cells with ICAM-1 siRNA reduced TGF-α-mediated cell migration. We also found that the phosphatidylinositol 3'-kinase (PI3K)/Akt/NF-κB pathway was activated after TGF-α treatment, and TGF-α-induced expression of ICAM-1 and cell migration was inhibited by the specific inhibitors and siRNAs of PI3K, Akt, and NF-κB cascades. In addition, knockdown of TGF-α expression markedly decreased cell metastasis in vitro and in vivo. Our results indicate that TGF-α/EGFR interaction elicits PI3K and Akt activation, which in turn activates NF-κB, resulting in the expression of ICAM-1 and contributing the migration of human osteosarcoma cells.

Keywords: Migration; Osteosarcoma; TGF-α.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Bone Neoplasms / drug therapy
  • Bone Neoplasms / metabolism*
  • Bone Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • ErbB Receptors / agonists*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Humans
  • Intercellular Adhesion Molecule-1 / chemistry
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Lung Neoplasms / prevention & control
  • Lung Neoplasms / secondary
  • Male
  • Mice
  • Mice, SCID
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Osteosarcoma / drug therapy
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology
  • Osteosarcoma / secondary*
  • Phosphatidylinositol 3-Kinase / chemistry
  • Phosphatidylinositol 3-Kinase / genetics
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt / agonists
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Second Messenger Systems* / drug effects
  • Transforming Growth Factor alpha / antagonists & inhibitors
  • Transforming Growth Factor alpha / genetics
  • Transforming Growth Factor alpha / metabolism*
  • Tumor Burden / drug effects
  • Up-Regulation / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • ICAM1 protein, human
  • NF-kappa B
  • Phosphoinositide-3 Kinase Inhibitors
  • Recombinant Proteins
  • TGFA protein, human
  • Transforming Growth Factor alpha
  • Intercellular Adhesion Molecule-1
  • Phosphatidylinositol 3-Kinase
  • EGFR protein, human
  • ErbB Receptors
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt