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Pancreas. 2007 Oct;35(3):e16-26.

Dissociation of gemcitabine sensitivity and protein kinase B signaling in pancreatic ductal adenocarcinoma models.

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1
Ontario Cancer Institute and Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.

Abstract

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.

PMID:
17895832
DOI:
10.1097/mpa.0b013e318095a747
[Indexed for MEDLINE]
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