Thiazolidinedione drugs down-regulate CXCR4 expression on human colorectal cancer cells in a peroxisome proliferator activated receptor gamma-dependent manner.
Peroxisome proliferator activated receptor (PPAR) gamma is a nuclear receptor involved primarily in lipid and glucose metabolism. PPARgamma is also expressed in several cancer types, and has been suggested to play a role in tumor progression. PPARgamma agonists have been shown to reduce the growth of colorectal carcinoma cells in culture and in xenograft models. Furthermore, the PPARgamma agonist thiazolidinedione has been shown to reduce metastasis in a murine model of rectal cancer. Since the chemokine receptor CXCR4 has emerged as an important player in tumorigenesis, particularly in the process of metastasis, we sought to determine if PPARgamma agonists might act in part by reducing CXCR4 expression. We found that rosiglitazone, a thiazolidinedione PPARgamma agonist used primarily in the treatment of type 2 diabetes, significantly reduced cell-surface expression of CXCR4 protein on HT-29 human colorectal carcinoma cells. This effect occurred at concentrations as low as 1 nM, and was first evident after 8 h of drug exposure. CXCR4 mRNA was also down-regulated after treatment with rosiglitazone, indicating that the effect occurs at the level of transcription. Four other thiazolidinedione compounds (ciglitazone, pioglitazone, troglitazone, and MCC555) also significantly reduced CXCR4 expression. To confirm the involvement of PPARgamma in thiazolidinedione-induced CXCR4 down-regulation, we used PPARgamma antagonists GW9662 and T0070907, both of which completely blocked the effect of rosiglitazone on CXCR4 expression. Furthermore, HT-29 cells in which PPARgamma expression was reduced using shRNA were less responsive to rosiglitazone. In conclusion, we have shown that thiazolidinedione compounds reduce CXCR4 mRNA and cell-surface protein expression in a PPARgamma-dependent manner.
Richard
Cynthia Lee
CL
Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
Blay
Jonathan
J
D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047495:PPAR gamma / Q000378:metabolism*; D000077205:Pioglitazone; D019718:Receptors, CXCR4 / Q000235:genetics*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
D000970:Antineoplastic Agents; D047495:PPAR gamma; D019718:Receptors, CXCR4; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C115174:netoglitazone; C039671:ciglitazone; D000077205:Pioglitazone