Nrf2-dependent and Nrf2-independent induction of phase 2 detoxifying and antioxidant enzymes during keratinocyte differentiation

Piao, Mei Shan; Park, Jae-Jeong; Choi, Jee‐Young Jasmine; Lee, Dong‐Hoon; Yun, Sook Jung; Lee, Jee-Bum; Lee, Seung−Chul

doi:10.1007/s00403-012-1215-7

Cited by 35 publications

(21 citation statements)

References 31 publications

(38 reference statements)

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“…23, 24 We further demonstrate that transcriptional regulation of HO-1 expression occurs via an NRF2-independent manner similar to human keratinocytes. 25 Although HO-1 overexpression in BeWo choriocarcinoma cells increased tumor cell adhesion and expression of PXDN, 26 we did not observe marked changes in PXDN or adhesion function with HO-1 overexpression in T80 cells.…”

Section: Discussionmentioning

confidence: 56%

Iron modulates cell survival in a Ras- and MAPK-dependent manner in ovarian cells

et al. 2013

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Ovarian cancer is a leading cause of cancer death in women in the United States. While the majority of ovarian cancers are serous, some rarer subtypes (i.e. clear cell) are often associated with endometriosis, a benign gynecological disease. Iron is rich in the cyst fluid of endometriosis-associated ovarian cancers and induces persistent oxidative stress. The role of iron, an essential nutrient involved in multiple cellular functions, in normal ovarian cell survival and ovarian cancer remains unclear. Iron, presented as ferric ammonium citrate (FAC), dramatically inhibits cell survival in ovarian cancer cell types associated with Ras mutations, while it is without effect in immortalized normal ovarian surface epithelial (T80) and endometriotic epithelial cells (lacking Ras mutations). Interestingly, FAC induced changes in cytoplasmic vacuolation concurrently with increases in LC3-II levels (an autophagy marker); these changes occurred in an ATG5/ATG7-dependent, beclin-1/hVps34-independent, and Ras-independent manner. Knockdown of autophagy mediators in HEY ovarian cancer cells reversed FAC-induced LC3-II levels, but there was little effect on reversing the cell death response. Intriguingly, transmission electron microscopy of FAC-treated T80 cells demonstrated abundant lysosomes (confirmed using Lysotracker) rich in iron particles, which occurred in a Ras-independent manner. Although the mitogen-activated protein kinase (MAPK) inhibitor, U0126, reversed FAC-induced LC3-II/autophagic punctae and lysosomes in a Ras-independent manner, it was remarkable that U0126 reversed cell death in malignant ovarian cells associated with Ras mutations. Moreover, FAC increased heme oxygenase-1 expression in H-Ras-overexpressing T80 cells, which was associated with increased cell death when overexpressed in T80 cells. Disruption of intracellular iron levels, via chelation of intracellular iron (deferoxamine), was also detrimental to malignant ovarian cell survival; thus, homeostatic intracellular iron levels are essential for cell survival. Collectively, our results implicate iron in modulating cell death in a Ras- and MAPK-dependent manner in ovarian cancer cells.

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Section: Discussionmentioning

confidence: 56%

Iron modulates cell survival in a Ras- and MAPK-dependent manner in ovarian cells

et al. 2013

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“…Unlike HO-1, in our results, expression of NQO1 upregulated by oleanolic acid was more prominent on day 7 than on day 3. There appears to be some differences in the expression of phase 2 enzymes according to the experimental model: the regulatory mechanisms of phase 2 enzymes in relation to the Nrf2 pathway may be tissue- or cell-specific [28]. Our results suggest that HO-1, rather than NQO1, plays a major role in the attenuation of renal inflammation and fibrosis in this UUO model.…”

Section: Discussionmentioning

confidence: 79%

Oleanolic acid attenuates renal fibrosis in mice with unilateral ureteral obstruction via facilitating nuclear translocation of Nrf2

et al. 2014

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BackgroundRenal interstitial fibrosis is a common final pathological process in the progression of kidney disease. This is primarily due to oxidative stress, which contributes to renal inflammation and fibrosis. Nuclear factor-erythroid-2-related factor 2 (Nrf2) is known to coordinate induction of genes that encode antioxidant enzymes. We investigated the effects of oleanolic acid, a known Nrf2 activator, on oxidative stress-induced renal inflammation and fibrosis.MethodsOne day before unilateral ureteral obstruction (UUO) performed in C57BL/6 mice, oleanolic acid treatment was initiated and was continued until 3 and 7 days after UUO. Renal inflammation and fibrosis, markers of oxidative stress, and changes in Nrf2 expression were subsequently evaluated.ResultsIn the obstructed kidneys of UUO mice, oleanolic acid significantly attenuated UUO-induced collagen deposition and fibrosis on day 7. Additionally, significantly less inflammatory cell infiltration, a lower ratio of Bax to Bcl-2 expression, and fewer apoptotic cells on TUNEL staining were observed in the obstructed kidneys of oleanolic acid-treated mice. Oleanolic acid increased the expression of nuclear Nrf2, heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1 and heat shock protein 70, and decreased lipid peroxidation in the obstructed kidney of UUO mice. There were no changes in the expression of total Nrf2 and Kelch-like ECH-associated protein 1, indicating that oleanolic acid enhanced nuclear translocation of Nrf2.ConclusionsThese results suggest that oleanolic acid may exert beneficial effects on renal fibrosis by increasing nuclear translocation of Nrf2 and subsequently reducing renal oxidative stress.

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“…Similar modulation of these phase II enzymes was observed during keratinocyte differentiation as well. 34 These results suggested that other mechanisms besides Nrf2 pathway might be involved in the induction of the antioxidant genes in this ALS mouse model. Indeed, previous study showing the induction of HO-1 in Nrf2-deficient MEF and HEK-293 cells provided evidence that HO-1 can be regulated by Nrf2-independent mechanisms.…”

Section: Effect Of Nrf2 Knockout On Als Mice Y Guo Et Almentioning

confidence: 73%

The modest impact of transcription factor Nrf2 on the course of disease in an ALS animal model

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Zhang

Wen

et al. 2013

Laboratory Investigation

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Nrf2-dependent and Nrf2-independent induction of phase 2 detoxifying and antioxidant enzymes during keratinocyte differentiation

Cited by 35 publications

References 31 publications

Iron modulates cell survival in a Ras- and MAPK-dependent manner in ovarian cells

Iron modulates cell survival in a Ras- and MAPK-dependent manner in ovarian cells

Oleanolic acid attenuates renal fibrosis in mice with unilateral ureteral obstruction via facilitating nuclear translocation of Nrf2

The modest impact of transcription factor Nrf2 on the course of disease in an ALS animal model

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