Antidiabetic thiazolidinediones induce ductal differentiation but not apoptosis in pancreatic cancer cells.
OBJECTIVE
Thiazolidinediones (TZD) are a new class of oral antidiabetic drugs that have been shown to inhibit growth of same epithelial cancer cells. Although TZD were found to be ligands for peroxisome proliferator-activated receptor gamma (PPARgamma), the mechanism by which TZD exert their anticancer effect is presently unclear. In this study, we analyzed the mechanism by which TZD inhibit growth of human pancreatic carcinoma cell lines in order to evaluate the potential therapeutic use of these drugs in pancreatic adenocarcinoma.


METHODS
The effects of TZD in pancreatic cancer cells were assessed in anchorage-independent growth assay. Expression of PPARgamma was measured by reverse-transcription polymerase chain reaction and confirmed by Western blot analysis. PPARgamma activity was evaluated by transient reporter gene assay. Flow cytometry and DNA fragmentation assay were used to determine the effect of TZD on cell cycle progression and apoptosis respectively. The effect of TZD on ductal differentiation markers was performed by Western blot.


RESULTS
Exposure to TZD inhibited colony formation in a PPARgamma-dependent manner. Growth inhibition was linked to G1 phase cell cycle arrest through induction of the ductal differentiation program without any increase of the apoptotic rate.


CONCLUSIONS
TZD treatment in pancreatic cancer cells has potent inhibitory effects on growth by a PPAR-dependent induction of pancreatic ductal differentiation.
Ceni
Elisabetta
E
Gastroenterology Unit, Department of Clinical Pathophysiology, University of Florence, Viale Morgani 85, 50134 Firenze, Italy.
Mello
Tommaso
T
Tarocchi
Mirko
M
Crabb
David-W
DW
Caldini
Anna
A
Invernizzi
Pietro
P
Surrenti
Calogero
C
Milani
Stefano
S
Galli
Andrea
A
D000230:Adenocarcinoma; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D047495:PPAR gamma / Q000378:metabolism; D010183:Pancreatic Ducts / Q000166:cytology; D010190:Pancreatic Neoplasms; D010641:Phenotype; D045162:Thiazolidinediones / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones