Differential effects of PPARgamma activation by the oral antidiabetic agent pioglitazone in Barrett's carcinoma in vitro and in vivo.
OBJECTIVE
The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a key transcription factor regulating genes involved in adipogenesis, glucose homeostasis and cell differentiation. Moreover, PPARgamma has been demonstrated to control proliferation and apoptosis in various cancer cells. We investigated the biological effects of PPARgamma activation by the oral antidiabetic agent pioglitazone in Barrett's adenocarcinoma cells in vitro and in vivo.


RESULTS
PPARgamma mRNA and protein were overexpressed in endoscopic biopsies of Barrett's epithelium and the human Barrett's adenocarcinoma cancer cell line OE33 as compared to normal esophagus and stomach and the esophageal squamous epithelium cancer cell line Kyse-180. PPARgamma activation by pioglitazone in OE33 cells in vitro led to reduced cell growth by induction of apoptosis. Effects of systemic PPARgamma activation by the thiazolidinedione pioglitazone on tumor cell proliferation and apoptosis were then assessed in vivo in nude mice bearing transplantable Barrett's adenocarcinomas derived from OE33 cells. Unexpectedly, enhanced growth of OE33 derived transplantable adenocarcinomas was observed in Balb/c nu/nu mice upon systemic pioglitazone treatment due to increased cell proliferation.


CONCLUSIONS
These results indicate that PPARgamma is involved in the molecular pathogenesis of Barrett's adenocarcinoma formation and growth. However, activation of PPARgamma exerts differential effects on growth of Barrett's adenocarcinoma cells in vitro and in vivo emphasizing the importance of additional cell context specific factors and systemic metabolic status for the modulation of PPARgamma action in vivo.
Al-Taie
Oliver H
OH
Medizinische Klinik II, Klinikum Aschaffenburg, Am Hasenkopf 1, 63739, Aschaffenburg, Germany. oliver.altaie@klinikum-aschaffenburg.de
Graf
Tilmann
T
Illert
Bertram
B
Katzenberger
Tiemo
T
Mörk
Hubert
H
Kraus
Michael R
MR
Barthelmes
Hans U
HU
Scheurlen
Michael
M
Seufert
Jochen
J
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001471:Barrett Esophagus / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D047495:PPAR gamma / Q000187:drug effects* / Q000378:metabolism; D000077205:Pioglitazone; D012333:RNA, Messenger; D045162:Thiazolidinediones / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077205:Pioglitazone