Aberrant expression and activation of insulin-like growth factor-1 receptor (IGF-1R) are mediated by an induction of IGF-1R promoter activity and stabilization of IGF-1R mRNA and contributes to growth factor independence and increased survival of the pancreatic cancer cell line MIA PaCa-2

Oncogene. 2001 Dec 13;20(57):8203-14. doi: 10.1038/sj.onc.1205044.

Abstract

In the present study we investigated the mechanisms responsible for and the biological consequences of the constitutive activation of the insulin-like growth factor-1 receptor (IGF-1R) in the MIA PaCa-2 cells. An aberrant increase in the expression and activation of the IGF-1R was observed during the transition of growth states from exponential to quiescent. The increase in IGF-1R expression is preceded by an increase in IGF-1R mRNA transcript and is associated with an increase in the IGF-1R promoter activity. Inhibition of de novo transcription by actinomycin D increased the stability of IGF-1R mRNA in exponentially growing cells, thereby increasing the expression of IGF-1R to a level similar to that seen in quiescent cells. Increased IGF-1R signaling mediated the growth factor independence of quiescent MIA PaCa-2 cells through the constitutive activation of mitogen-activated protein kinase (MAPK). Exogenous IGF-1 increased cell proliferation and activated MAPK and AKT signaling pathways. The resistance of cells to apoptosis by IGF-1R signaling was mediated through MAPK and phosphatidylinositol 3-kinase (PI3K) pathways and a yet unidentified pathway(s). Thus, aberrant regulation of IGF-1R signaling is required for resistance to apoptosis and growth factor independence of MIA PaCa-2 cells. This likely protects cells from unfavorable conditions and allows cells to rapidly re-enter the cell cycle when conditions are favorable.

MeSH terms

  • Apoptosis
  • Cell Division
  • Cell Survival
  • Culture Media, Serum-Free
  • Gene Expression Regulation, Neoplastic
  • Growth Substances / physiology
  • Humans
  • Insulin-Like Growth Factor I / pharmacology
  • Mitogen-Activated Protein Kinases / metabolism
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Promoter Regions, Genetic
  • RNA Stability*
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / metabolism
  • Receptor, IGF Type 1 / genetics*
  • Receptor, IGF Type 1 / metabolism*
  • Receptor, IGF Type 1 / physiology
  • Signal Transduction
  • Transcriptional Activation*
  • Tumor Cells, Cultured

Substances

  • Culture Media, Serum-Free
  • Growth Substances
  • RNA, Messenger
  • RNA, Neoplasm
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • Receptor, IGF Type 1
  • Mitogen-Activated Protein Kinases