Dissociation of gemcitabine sensitivity and protein kinase B signaling in pancreatic ductal adenocarcinoma models.
Pancreas
; 35(3): e16-26, 2007 Oct.
Article
in En
| MEDLINE
| ID: mdl-17895832
OBJECTIVE: To understand the impact of protein kinase B (PKB; Akt) signaling on growth and protection from apoptosis in pancreatic ductal adenocarcinoma models demonstrating differences in PKB activity. METHODS: Gemcitabine sensitivity was investigated in a panel of cell lines, characterized by differences in levels of activated PKB. Suppression of PKB activity was achieved with an inhibitor of phosphatidylinositol 3-kinase (wortmannin) and silencing RNA. RESULTS: Enhanced gemcitabine (2',2'-difluoro-2'-deoxycytidine)-induced cytotoxicity in vitro was achieved with suppression of high PKB activity with wortmannin in BxPC-3, PK-1, and PK-8 cells and silencing RNA targeted to total PKB, rather than PKBbeta, in PANC-1 cells. Opposite to gemcitabine sensitivity levels in vitro, the growth of PANC-1 xenografts was inhibited with gemcitabine treatment, whereas BxPC-3 became drug resistant. Monolayer cell cultures reestablished from solid tumors behaved similarly to original cultures, suggesting that the tumor microenvironment has a critical role in determining drug sensitivity. A comparison of transcript profiles of the models indicated that PKB signaling might be modulated by a number of pathways responsive to the tumor hypoxia microenvironment. CONCLUSIONS: These results suggested that gemcitabine efficacy involving the PKB pathway depends on PKB activity, its mechanisms of enhanced activity, as well as its function in a signaling network.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pancreatic Neoplasms
/
Signal Transduction
/
Drug Resistance, Neoplasm
/
Carcinoma, Pancreatic Ductal
/
Deoxycytidine
/
Proto-Oncogene Proteins c-akt
/
Neoplasm Proteins
/
Antimetabolites, Antineoplastic
Type of study:
Diagnostic_studies
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Pancreas
Journal subject:
GASTROENTEROLOGIA
Year:
2007
Document type:
Article
Affiliation country:
Canada
Country of publication:
United States