Growth inhibition and differentiation of pancreatic cancer cell lines by PPAR gamma ligand troglitazone.
BACKGROUND
Ligand activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) results in growth inhibition and differentiation of various cancer cells.


OBJECTIVE
We determined whether the PPAR gamma ligand, troglitazone, inhibits the growth of pancreatic cancer cells and clarified the underlying mechanisms with a special focus on restriction point control of the late G1 phase of the cell cycle.


METHODS
Nine pancreatic cancer cell lines were used to study a variety of troglitazone effects on cell growth by MTT assay, on cell cycle by flow cytometry, on cell cycle regulating factors of late G1 phase by Western and Northern blotting and CDK2 kinase assay, and on morphology by collagen gel culture and electron-microscopy.


RESULTS
Troglitazone showed a potent dose-response effect on the growth inhibition of six pancreatic cancer cell lines, which were suppressed to less than 50% of control at the concentration of 10 microM. The growth inhibition was linked to the G1 phase cell cycle arrest through the upregulation of p21 mRNA and protein expression simultaneously with the inhibition of CDK2 kinase activity and the hypophosphorylation of Rb protein. The upregulation of expression of p21 mRNA was mainly due to stabilization of mRNA. Troglitazone induced significant morphologic changes of duct structure with apoptotic cells in the lumen.


CONCLUSIONS
Troglitazone had growth inhibitory and differentiation induction effects on the pancreatic cancer cell lines through the upregulation of p21 expression, suggesting that ligand activation of PPAR gamma is a new molecular target for effective therapy against pancreatic cancer.
Kawa
Shigeyuki
S
The Second Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan. skawapc@hsp.md.shinshu-u.ac.jp
Nikaido
Toshio
T
Unno
Hiroshi
H
Usuda
Nobuteru
N
Nakayama
Kohzo
K
Kiyosawa
Kendo
K
D000230:Adenocarcinoma / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D008024:Ligands; D010190:Pancreatic Neoplasms / Q000473:pathology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000096:biosynthesis; D000077288:Troglitazone; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D002839:Chromans; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077288:Troglitazone