Clofibrate induces heme oxygenase 1 expression through a PPARα-independent mechanism in human cancer cells.

Abstract

BACKGROUND AND AIMS:

Clofibrate, an established PPARα ligand, has recently been shown to have anticancer activity yet its mechanisms of action remain to be characterized. This study examined the effect of clofibrate on heme oxygenase-1 (HO-1) gene expression in A2780 (human ovarian cancer) and DU145 (human prostate cancer) cells.

METHODS AND RESULTS:

We demonstrate that clofibrate induces HO-1 expression in a concentration- and time-dependent manner. The induction of HO-1 by clofibrate was detected at both mRNA and protein levels and the HO-1 gene promoter activity was also dramatically induced by clofibrate, indicating that clofibrate up-regulates HO-1 gene transcription. Surprisingly, the induction of HO-1 by clofibrate was mediated by the Nrf2 signaling pathway, not by the PPARα pathway. This was primarily demonstrated by siRNA knockdown of Nrf2 expression that significantly attenuated clofibrate-induced HO-1 gene transcription, and siRNA knockdown of PPARα that had no effect on clofibrate-induced HO-1 promoter activity. Furthermore, deletion of the antioxidant response elements (AREs) in the HO-1 gene promoter diminished clofibrate-induced HO-1 transcription and deletion of the PPAR response elements (PPREs) had no such effect. Likewise, application of PPARα antagonists had no effect on clofibrate-induced HO-1 expression.

CONCLUSION:

Clofibrate induces HO-1 gene expression in cancer cells through a PPARα-independent mechanism and the Nrf2 signaling pathway is indispensible for this induction.

• Authors: Shuai Wang, Bethany N Hannafon, Jundong Zhou, Wei-Qun Ding
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 32 Issue 5 Pg. 1255-64 ( 2013) ISSN: 1421-9778 [Electronic] Germany
• PMID: 24247298 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 S. Karger AG, Basel.

Chemical References

• NF-E2-Related Factor 2
• NFE2L2 protein, human
• PPAR alpha
• HMOX1 protein, human
• Heme Oxygenase-1
• Clofibrate

Topics

• Cell Line, Tumor (drug effects)
• Clofibrate (pharmacology)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Heme Oxygenase-1 (genetics)
• Humans
• Male
• NF-E2-Related Factor 2 (genetics, metabolism)
• Ovarian Neoplasms (drug therapy, genetics, metabolism)
• PPAR alpha (genetics, metabolism)
• Promoter Regions, Genetic
• Prostatic Neoplasms (drug therapy, genetics, metabolism)
• Response Elements (drug effects)
• Signal Transduction (drug effects)