ERK1/2 deactivation enhances cytoplasmic Nur77 expression level and improves the apoptotic effect of fenretinide in human liver cancer cells

Abstract

Fenretinide, a synthetic retinoid, is a promising anticancer agent based on many in vitro, animal, and chemoprevention clinical trial studies. However, cells such as HepG2 human liver cancer cells are resistant to the apoptotic effect of fenretinide. Previously, we have shown that fenretinideinduced apoptosis is Nur77 dependent, and the sensitivity of the cancer cells to fenretinideinduced apoptosis is positively associated with cytoplasmic enrichment of Nur77. The goal of current study was to identify means to modulate nuclear export of Nur77 in order to improve the efficacy of fenretinide. Fenretinide treatment deactivated ERK1/2 in Huh7 cells, but activated ERK1/2 in HepG2 cells, which was positively associated with the sensitivity of cells to the apoptotic effect of fenretinide. Neither fenretinide nor ERK1/2 inhibitor PD98059 alone could affect the survival of HepG2 cells, but the combination of both induced cell death and increased caspase 3/7 activity. In fenretinide sensitive Huh7 cells, activation of ERK1/2 by epidermal growth factor (EGF) prevented fenretinide-induced cell death and caspase 3/7 induction. In addition, modulation of ERK1/2 changed the intracellular localization of Nur77. Fenretinide/ PD98059-induced cell death of HepG2 cell was positively associated with induction and cytoplasmic location as well as mitochondria enrichment of Nur77. The effect was specific for ERK1/2 because other mitogen activated protein kinases such as P38, Akt, and JNK did not have correlated changes in their phosphorylation levels. Taken together, the current study demonstrates that ERK1/2-modulated Nur77 intracellular location dictates the efficacy of fenretinide-induced apoptosis.

Comprehensive transcriptome profiling of squamous cell carcinoma of horn in Bos indicus

“…TR3 suppresses Wnt signalling activity thereby suppressing intestinal tumourigenesis . Many groups of scientist reported it as a potential therapeutic target due to its tumour suppressive effect on various types of cancer …”

Bile Acids Regulate Nuclear Receptor (Nur77) Expression and Intracellular Location to Control Proliferation and Apoptosis

“…Nur77 post-translational modification studies have shown that ERK1/2 phosphorylation promoted nuclear localization of Nur77, whereas Chk2 phosphorylation led to nuclear export (16, 32). RXRα as well as RARβ also regulate Nur77-dependent apoptotic pathways by forming a complex with Nur77 (15, 25).…”

“…Epidermal growth factor (EGF) and other mitogens rapidly and potently induce the expression of nuclear Nur77, which serves as a transcription factor to enhance cell survival (14). The apoptotic effect of cytosolic Nur77 has also been studied using apoptosis inducers (15, 16). In the cytosol, Nur77 unmasks the BH-3 domain of Bcl-2, converting Bcl-2 into a pro-apoptotic molecule (12).…”

High expression of orphan nuclear receptor NR4A1 in a subset of ovarian tumors with worse outcome

“…Many pro-apoptotic agents and stimuli have been reported to be associated with nuclear export and translocation of NR4A1 [17, 33]. Apoptosis induced in hepatocellular carcinoma cells by retinoids have been demonstrated to be NR4A1 dependent and to be associated with localization of NR4A1 in the mitochondria [34]. In androgen sensitive LNCaP adenocarcinoma cells several apoptosis inducers consistently caused mitochondrial localization of NR4A1, and mutants that lacked mitochondrial localization failed to induce apoptosis [33].…”