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

• Published in: Journal of the American College of Surgeons Vol. 198; no. 4; pp. 591 - 599
• Main Authors: Fahy, Bridget N, Schlieman, Michael G, Virudachalam, Subbulakshmi, Bold, Richard J
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.04.2004; Elsevier Science
• Subjects: Biological and medical sciences; General aspects; Medical sciences; Antineoplastic agent; Prognosis; Protein kinase B; Survival; Mechanism; Medicine; Chemotherapy; Treatment; Surgery; Pancreas cancer; Inhibitor; Transcription factor NFκB; Inhibition
• ISSN: 1072-7515; 1879-1190
• DOI: 10.1016/j.jamcollsurg.2003.12.005

When activated, the nuclear factor (NF)-κB 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-κB pathway in response to chemotherapy and whether inhibition of this response altered the apoptotic efficacy of chemotherapy. We determined NF-κB 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-κB, was determined. We examined the effect of inhibition of Akt, an upstream activator of NF-κB, on the molecular (NF-κB function and BCL-2 transcription) and cellular (apoptosis) effect of chemotherapy. Both the chemotherapeutic agents gemcitabine and paclitaxel activated NF-κB and stimulated BCL-2 gene promoter activity. The stimulation of BCL-2 promoter function was directly regulated by NF-κB. These cellular responses were blocked by inhibition of Akt. The apoptotic effect of gemcitabine and paclitaxel also was enhanced after Akt inhibition. Part of the apoptotic resistance of pancreatic cancer may be mediated by activation of the NF-κB survival pathway in response to chemotherapy. Inhibition of this response may be an important adjunct to increase the efficacy of chemotherapy.