Thiazolidinedione drugs down-regulate CXCR4 expression on human colorectal cancer cells in a peroxisome proliferator activated receptor γ-dependent manner

  • Authors:
    • Cynthia Lee Richard
    • Jonathan Blay
  • View Affiliations

  • Published online on: May 1, 2007     https://doi.org/10.3892/ijo.30.5.1215
  • Pages: 1215-1222
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Abstract

Peroxisome proliferator activated receptor (PPAR) γ is a nuclear receptor involved primarily in lipid and glucose metabolism. PPARγ is also expressed in several cancer types, and has been suggested to play a role in tumor progression. PPARγ agonists have been shown to reduce the growth of colorectal carcinoma cells in culture and in xenograft models. Furthermore, the PPARγ 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 PPARγ agonists might act in part by reducing CXCR4 expression. We found that rosiglitazone, a thiazolidinedione PPARγ 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 PPARγ in thiazolidinedione-induced CXCR4 down-regulation, we used PPARγ antagonists GW9662 and T0070907, both of which completely blocked the effect of rosiglitazone on CXCR4 expression. Furthermore, HT-29 cells in which PPARγ 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 PPARγ-dependent manner.

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May 2007
Volume 30 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Richard CL and Richard CL: Thiazolidinedione drugs down-regulate CXCR4 expression on human colorectal cancer cells in a peroxisome proliferator activated receptor γ-dependent manner. Int J Oncol 30: 1215-1222, 2007
APA
Richard, C.L., & Richard, C.L. (2007). Thiazolidinedione drugs down-regulate CXCR4 expression on human colorectal cancer cells in a peroxisome proliferator activated receptor γ-dependent manner. International Journal of Oncology, 30, 1215-1222. https://doi.org/10.3892/ijo.30.5.1215
MLA
Richard, C. L., Blay, J."Thiazolidinedione drugs down-regulate CXCR4 expression on human colorectal cancer cells in a peroxisome proliferator activated receptor γ-dependent manner". International Journal of Oncology 30.5 (2007): 1215-1222.
Chicago
Richard, C. L., Blay, J."Thiazolidinedione drugs down-regulate CXCR4 expression on human colorectal cancer cells in a peroxisome proliferator activated receptor γ-dependent manner". International Journal of Oncology 30, no. 5 (2007): 1215-1222. https://doi.org/10.3892/ijo.30.5.1215