Nuclear Nrf2 expression is related to a poor survival in pancreatic adenocarcinoma

Soini, Ylermi; Eskelinen, Matti; Juvonen, Petri; Kärjä, Vesa; Haapasaari, Kirsi‐Maria; Saarela, Arto; Karihtala, Peeter

doi:10.1016/j.prp.2013.10.001

Cited by 58 publications

(49 citation statements)

References 33 publications

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“…Our findings provide the combination strategy to modulate cellular redox status and overcome resistance to gemcitabine, resulting in a synergistic and selective cytotoxic effect in vivo. Although recent reports showed that NF-kB and Nrf2 were important for pancreatic cancer development and chemoresistance (30,34,35), we showed that gemcitabine activates NOXinduced ROS via NF-kB activation and increased ROS results in activation of Nrf2 and the increase of cellular GSH, contributing to the intrinsic resistance of PDAC. A combination of gemcitabine, which stimulates endogenous ROS generation, and PEITC, which inhibits ROS elimination, would be a logical strategy to induce pancreatic cell death, in that it would compose severe oxidative stress (Fig.…”

Section: Discussionmentioning

confidence: 58%

“…Nrf2 induces expression of many cytoprotective proteins responsible for maintaining cellular redox stability. Recent study also showed that nuclear Nrf2 expression play an important role in ROS detoxification during pancreatic carcinogenesis (29), and is related to a poor survival in patients with pancreatic adenocarcinoma (30). Western blot analysis showed that the expression of Nrf2-targeting antioxidants such as SOD1, GPX, GST-Pi, GCLC, and GCLM, was increased following gemcitabine treatment.…”

Section: Discussionmentioning

confidence: 97%

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Mechanisms of Overcoming Intrinsic Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation

Gocho

Aguilar

et al. 2015

Molecular Cancer Therapeutics

116

111

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Pancreatic ductal adenocarcinoma (PDAC) frequently develops therapeutic resistances, which can be divided into extrinsic and intrinsic resistance. The extrinsic resistance that arises from the surrounding dense tumor stroma is much better understood. However, the mechanisms of intrinsic resistance are not well understood. Here, we report that reactive oxygen species (ROS) induced by gemcitabine treatment, a newly discovered cytotoxic activity, served as a probe in our study to reveal the mechanisms of the intrinsic therapeutic resistance. Our results showed that gemcitabine-induced ROS is generated by NOX and through the increase of p22 -phox expression via NF-kB activation. As a feedback mechanism, nuclear translocation of Nrf2 stimulated the transcription of cytoprotective antioxidant genes, especially genes encoding enzymes that catalyze glutathione (GSH) production to reduce elevated ROS as an intrinsic resistance countermeasure. RNAi-mediated depletion of Nrf2 or addition of b-phenylethyl isothiocyanate inhibited the ROS detoxification process by reducing GSH levels, which, in turn, increased the efficacy of gemcitabine in vitro and in vivo. Thus, our study suggests that a redoxmediated pathway contributes to the intrinsic resistance of PDAC to gemcitabine and provides a basis for developing strategies to preferentially kill PDAC cells through ROS-mediated mechanism. The combination of gemcitabine and PEITC has a selective cytotoxic effect against pancreatic cancer cells in vivo and could thus prove valuable as a cancer treatment. Mol Cancer Ther; 14(3); 788-98.Ó2014 AACR.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 97%

Mechanisms of Overcoming Intrinsic Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation

Gocho

Aguilar

et al. 2015

Molecular Cancer Therapeutics

116

111

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“…According to the results of 1 of our previous studies, nuclear Nrf2 protein expression in PDAC cells is linked to worse survival, possibly because of the protection of malignant cells from xenobiotic and oxidative stress [20]. On the other hand, Keap1 protein expression has been associated with prolonged RFS and disease-specific survival in surgically treated pancreatic cancers [21].…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported that Keap1 and Nrf2 protein levels may play a prognostic role in pancreatic cancers [20, 21]. Now we aimed to clarify if their mRNA levels or the miRNAs known to regulate them are associated with traditional prognostic factors or survival in PDAC patients, all treated by means of pancreaticoduodenectomy.…”

Section: Introductionmentioning

confidence: 99%

Expression Levels of microRNAs miR-93 and miR-200a in Pancreatic Adenocarcinoma with Special Reference to Differentiation and Relapse-Free Survival

et al. 2018

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Objectives: Protein levels of the transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2) and its inhibitor Kelch-like ECH-associated protein 1 (Keap1) have been proposed as prognostic factors in pancreatic ductal adenocarcinomas (PDACs). These cellular redox-state-regulating enzymes are targeted by several microRNAs, including miR-93 and miR-200a. Methods: We assessed mRNA levels of Nrf2 and Keap1 and tissue expression of miR-93 and miR-200a in 51 patients with surgically treated PDAC. Expression levels were separately measured in malignant cells and adjacent benign cells. Results: Keap1 and Nrf2 mRNA expression levels in cancer cells were lower than in adjacent benign tissue (Wilcoxon’s test; p = 0.0015 and p = 0.000032, respectively). Conversely, miR-93 expression was higher in cancer cells than in adjacent benign tissue (p = 0.00082). Low levels of miR-93 and miR-200a in cancer cells were associated with poorer differentiation (p = 0.004 and p = 0.002, respectively). In univariate survival analysis, benign-tissue levels of miR-200a above the median predicted better relapse-free survival (RFS) (p = 0.045). Conclusions: High miR-93 and miR-200a levels in cancer cells of PDAC were associated with better differentiation, and miR-200a expression in benign tissue with excellent RFS. Keap1 and Nrf2 mRNA levels showed prominent down-regulation in cancerous versus benign tissue, but they were not associated with disease aggressiveness or outcome.

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“…Hong et al similarly found frequent strong cytoplasmic Nrf2 staining in pancreatic cancer specimens, but in contrast to Lister et al, a higher proportion of nuclear staining was detected in PDAC compared to normal tissue. Importantly, following pancreatic resection, an increase in nuclear Nrf2 expression was found to correlate with a significant reduction in overall survival (Soini et al, 2014). Levels of cytoplasmic Keap1 are higher in human PDAC tissue than in benign ductal epithelium, but still only detectable in ∼30%, suggesting that Keap1 transcription remains relatively low compared to the much higher Nrf2 levels (Lister et al, 2011).…”

Section: Nrf2 Expression Is Higher Than Keap1 and Correlates With Poomentioning

confidence: 97%

Keap1–Nrf2 signalling in pancreatic cancer

Hayes

Skouras

Haugk

et al. 2015

The International Journal of Biochemistry & Cell Biology

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a b s t r a c tTranscription factor NF-E2 p45-related factor 2 (Nrf2, also called Nfe2l2), a master regulator of redox homeostasis, and its dominant negative regulator, Kelch-like ECH-associated protein 1 (Keap1), together tightly control the expression of numerous detoxifying and antioxidant genes. Nrf2 and the 'antioxidant response element' (ARE)-driven genes it controls are frequently upregulated in pancreatic cancer and correlate with poor survival. Upregulation of Nrf2 is, at least in part, K-Ras oncogene-driven and contributes to pancreatic cancer proliferation and chemoresistance. In this review, we aim to provide an overview of Keap1-Nrf2 signalling as it relates to pancreatic cancer, discussing the effects of inhibiting Nrf2 or Nrf2/ARE effector proteins to increase chemosensitivity.

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Nuclear Nrf2 expression is related to a poor survival in pancreatic adenocarcinoma

Cited by 58 publications

References 33 publications

Mechanisms of Overcoming Intrinsic Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation

Mechanisms of Overcoming Intrinsic Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation

Expression Levels of microRNAs miR-93 and miR-200a in Pancreatic Adenocarcinoma with Special Reference to Differentiation and Relapse-Free Survival

Keap1–Nrf2 signalling in pancreatic cancer

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