Dissociation of gemcitabine sensitivity and protein kinase B signaling in pancreatic ductal adenocarcinoma models.
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.
Pham
Nhu-An
NA
Ontario Cancer Institute and Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
Tsao
Ming-Sound
MS
Cao
Pinjiang
P
Hedley
David William
DW
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor / Q000201:enzymology / Q000637:transplantation; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology*; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D000077191:Wortmannin; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D000730:Androstadienes; D000964:Antimetabolites, Antineoplastic; D009363:Neoplasm Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D003841:Deoxycytidine; C494918:AKT1 protein, human; C494921:AKT2 protein, human; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; D000093542:Gemcitabine