Inhibition of AKT abrogates chemotherapy-induced NF-kappaB survival mechanisms: implications for therapy in pancreatic cancer.
J Am Coll Surg
; 198(4): 591-9, 2004 Apr.
Article
en En
| MEDLINE
| ID: mdl-15051014
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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias Pancreáticas
/
FN-kappa B
/
Proteínas Proto-Oncogénicas
/
Proteínas Serina-Treonina Quinasas
/
Apoptosis
/
Desoxicitidina
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
J Am Coll Surg
Asunto de la revista:
GINECOLOGIA
/
OBSTETRICIA
Año:
2004
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos