Selective activation of PPARgamma inhibits pancreatic cancer invasion and decreases expression of tissue plasminogen activator.
BACKGROUND
PPARgamma is a ligand-activated transcription factor with antitumor effects; its ability to inhibit pancreatic cancer invasion is unknown. The purpose of this study was to define the inhibitory effect of PPARgamma ligands on pancreatic cancer invasion and the expression of invasion-related genes.


METHODS
Western blotting was used to establish expression of PPARgamma in AsPC-1 and SUIT-2 cells. AsPC-1 cells were treated with nontoxic doses of PPARgamma ligands (15d-PGJ(2), troglitazone, or rosiglitazone) and Matrigel Invasion chambers were used to assess invasion in vitro. A microarray for genes that contribute to invasion was used to investigate the antiinvasive targets of PPARgamma. Gene array results were confirmed by use of ribonuclease protection assay or Northern blotting.


RESULTS
Rosiglitazone and 15d-PGJ(2) decreased AsPC-1 cell invasion; GW9662, which inhibits PPARgamma, reversed this effect. The expression of tissue plasminogen activator (tPA) was decreased by rosiglitazone treatment, which was confirmed by Northern blotting. Secreted levels of tPA in AsPC-1 conditioned media were also decreased.


CONCLUSIONS
We demonstrate, for the first time, that secretion of the invasive factor tPA was decreased by rosiglitazone treatment in AsPC-1 cells. PPARgamma ligands inhibit pancreatic cancer cell invasion, suggesting that these agents may represent novel strategies to treat pancreatic cancer.
Farrow
Buckminster
B
Department of Surgery, The University of Texas Medical Branch, Galveston, TX 77555, USA.
O'Connor
Kathleen L
KL
Hashimoto
Koji
K
Iwamura
Takeshi
T
Evers
B Mark
BM
D002839:Chromans / Q000494:pharmacology; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors*; D014157:Transcription Factors / Q000378:metabolism*; D000077288:Troglitazone; D014407:Tumor Cells, Cultured
C477819:15-deoxyprostaglandin J2; D002839:Chromans; D016023:Integrins; D061965:Matrix Metalloproteinase Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D010959:Tissue Plasminogen Activator; D000077288:Troglitazone; D015230:Prostaglandin D2