title: Inhibition of AKT abrogates chemotherapy-induced NF-kappaB survival mechanisms: implications for therapy in pancreatic cancer.
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.
  
  
  METHODS
  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.
authors.affiliation: Department of Surgery, University of California-Davis Medical Center, 4501 X Street, Sacramento, CA 95817, USA.
authors.forename: Bridget N
authors.initials: BN
authors.lastname: Fahy
authors.forename: Michael G
authors.initials: MG
authors.lastname: Schlieman
authors.forename: Subbulakshmi
authors.initials: S
authors.lastname: Virudachalam
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bold
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019254:Genes, bcl-2 / Q000187:drug effects; D006801:Humans; D016328:NF-kappa B / Q000502:physiology*; D017239:Paclitaxel / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010742:Phospholipid Ethers / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D010742:Phospholipid Ethers; D011518:Proto-Oncogene Proteins; D003841:Deoxycytidine; D011505:Protein-Tyrosine Kinases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017239:Paclitaxel; D000093542:Gemcitabine