Thiazolidinediones inhibit growth and invasiveness of the human adrenocortical cancer cell line H295R.
Thiazolidinediones (TZDs) are a new class of antidiabetic drugs that have also been shown to possess antitumoral properties in different human cancers. TZDs bind and activate the peroxisome proliferator-activated receptor (PPAR)-gamma, which is a nuclear receptor acting as a transcription factor in several tissues. In the present study, we evaluated PPARgamma mRNA and protein expression in tissue samples of human adrenocortical carcinomas (ACCs), normal adrenal glands, and the human ACC cell line H295R. PPARgamma mRNA was expressed in six of eight ACC, two of three normal adrenal glands and the H295R cells. These results were confirmed by immunohistochemistry. PPARgamma transcriptional activity in H295R cells, monitored by a reporter gene assay, was induced 2- to 3-fold by TZDs, such as rosiglitazone (RGZ) and pioglitazone, whereas in PPARgamma-transfected cells RGZ alone or RGZ plus 9-cis retinoic acid further increased reporter activity. TZDs inhibited both the proliferation and invasiveness of H295R cells in a dose-dependent manner. Thymidine incorporation was reduced by about 60% by 20 mum of both TZDs. Cotreatment with the retinoic X receptor ligand 9-cis retinoic acid had an additive effect. TZDs increased the number of cells in the G(0)/G(1) phase and decreased them in the S phase. Western blot analysis showed that TZDs increased the expression of the cell cycle inhibitors p21 and p27 and reduced the expression of cyclin D1. Twenty micromoles of RGZ and pioglitazone reduced H295R invasiveness through Matrigel by about 85%. Zymography and ELISA tests showed that TZD inhibited metalloproteinase-2 secretion by H295R cells in a dose-dependent manner. These data suggest that TZDs reduce the malignant potential of the H295R ACC cell line and, therefore, might potentially constitute a novel tool in the medical treatment of human ACCs.
Ferruzzi
Pietro
P
Department of Clinical Pathophysiology, Endocrine Unit, Viale Pieraccini, 6, 50139 Florence, Italy.
Ceni
Elisabetta
E
Tarocchi
Mirko
M
Grappone
Cecilia
C
Milani
Stefano
S
Galli
Andrea
A
Fiorelli
Gianna
G
Serio
Mario
M
Mannelli
Massimo
M
D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000311:Adrenal Glands / Q000166:cytology / Q000473:pathology; D000328:Adult; D000368:Aged; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000032:analysis; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D020778:Matrix Metalloproteinase 2; D000077205:Pioglitazone