Inhibition of AKT abrogates chemotherapy-induced NF-kappaB survival mechanisms: implications for therapy in pancreatic cancer

J Am Coll Surg. 2004 Apr;198(4):591-9. doi: 10.1016/j.jamcollsurg.2003.12.005.

Abstract

Background: When activated, the nuclear factor (NF)-kappaB pathway is a potent cellular signal that inhibits apoptotic cell death. Pancreatic cancer is resistant to the apoptotic effect of chemotherapy, though it is unclear whether this is an inherent feature or a survival signal engaged in response to chemotherapy. We investigated whether pancreatic cancer cells activate the NF-kappaB pathway in response to chemotherapy and whether inhibition of this response altered the apoptotic efficacy of chemotherapy.

Study design: We determined NF-kappaB activity after chemotherapy treatment of the MIA-PaCa-2 human pancreatic cancer cell line using both physical (electrophoretic mobility shift assay) and functional (luciferase) techniques. The effect of chemotherapy on transcription of the antiapoptotic gene BCL-2, a target of NF-kappaB, was determined. We examined the effect of inhibition of Akt, an upstream activator of NF-kappaB, on the molecular (NF-kappaB function and BCL-2 transcription) and cellular (apoptosis) effect of chemotherapy.

Results: Both the chemotherapeutic agents gemcitabine and paclitaxel activated NF-kappaB and stimulated BCL-2 gene promoter activity. The stimulation of BCL-2 promoter function was directly regulated by NF-kappaB. These cellular responses were blocked by inhibition of Akt. The apoptotic effect of gemcitabine and paclitaxel also was enhanced after Akt inhibition.

Conclusions: Part of the apoptotic resistance of pancreatic cancer may be mediated by activation of the NF-kappaB survival pathway in response to chemotherapy. Inhibition of this response may be an important adjunct to increase the efficacy of chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Genes, bcl-2 / drug effects
  • Humans
  • NF-kappa B / physiology*
  • Paclitaxel / pharmacology
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Phospholipid Ethers / pharmacology
  • Protein-Serine-Threonine Kinases*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / physiology
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction

Substances

  • Antineoplastic Agents
  • NF-kappa B
  • Phospholipid Ethers
  • Proto-Oncogene Proteins
  • Deoxycytidine
  • gemcitabine
  • Protein-Tyrosine Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Paclitaxel