Enrichment of Nur77 mediated by retinoic acid receptor β leads to apoptosis of human hepatocellular carcinoma cells induced by fenretinide and histone deacetylase inhibitors
Open Access
- 7 December 2010
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 53 (3), 865-874
- https://doi.org/10.1002/hep.24101
Abstract
The synthetic retinoid fenretinide is one of the most promising clinically tested retinoids. Previously, we have shown that fenretinide induces apoptosis of Huh7 cells, but HepG2 cells are relatively resistant to fenretinide‐induced apoptosis. This study examines the interactive role of fenretinide and histone deacetylase inhibitors (HDACi) in inducing apoptosis of human hepatocellular carcinoma (HCC) cells and the underlying mechanism. Trichostatin A and scriptaid can either enhance fenretinide‐induced apoptosis in the fenretinide sensitive HCC cells (Huh7 and Hep3B) or sensitize the fenretinide resistant cells (HepG2) to become sensitive to the apoptotic effect of fenretinide in a cancer cell–specific manner. The sensitivity of cells to fenretinide‐induced apoptosis was not associated with reactive oxygen species production nor with antioxidant gene expression. However, the level of retinoic acid receptor β (RARβ) and Nur77 (NR4A1) was important for inducing apoptosis. Upon fenretinide and HDACi treatment, the expression of RARβ and Nur77 were induced and colocalized in the cytosol. The induction of Nur77 protein level, but not the messenger RNA level, was RARβ‐dependent. In addition, RARβ interacted with Nur77. Nur77 was essential for fenretinide‐induced and HDACi‐induced apoptosis of Huh7 cells. Induction of the expression, the interaction, and the nuclear export of RARβ and Nur77 mediate fenretinide‐induced and HDACi‐induced apoptosis. Conclusion: Our findings suggest that targeting Nur77 and RARβ simultaneously provides an effective way to induce HCC cell death. (HEPATOLOGY 2011)Keywords
This publication has 39 references indexed in Scilit:
- Retinoid pathway and cancer therapeuticsAdvanced Drug Delivery Reviews, 2010
- Induction and intracellular localization of Nur77 dictate fenretinide-induced apoptosis of human liver cancer cellsBiochemical Pharmacology, 2010
- Long-term Fenretinide treatment prevents high-fat diet-induced obesity, insulin resistance, and hepatic steatosisAmerican Journal of Physiology-Endocrinology and Metabolism, 2009
- Rational Combinations Using HDAC InhibitorsClinical Cancer Research, 2009
- NRF2 as a determinant of cellular resistance in retinoic acid cytotoxicityFree Radical Biology & Medicine, 2008
- Histone deacetylase inhibitors: Mechanisms of cell death and promise in combination cancer therapyCancer Letters, 2008
- Fenretinide-induced apoptosis of Huh-7 hepatocellular carcinoma is retinoic acid receptor β dependentBMC Cancer, 2007
- The Epigenomics of CancerCell, 2007
- Mechanisms of fenretinide-induced apoptosisApoptosis, 2006
- Epigenetic therapy of cancer: past, present and futureNature Reviews Drug Discovery, 2006