Nuclear Factor Erythroid 2–Related Factor 2 Depletion Sensitizes Pancreatic Cancer Cells to Gemcitabine via Aldehyde Dehydrogenase 3a1 Repression

Matsumoto, Ryotaro; Hamada, Shin; Tanaka, Yu; Taguchi, Keiko; Yamamoto, Masayuki; Masamune, Atsushi

doi:10.1124/jpet.121.000744

Cited by 13 publications

(6 citation statements)

References 23 publications

(34 reference statements)

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“…Being NRF2-activated cancers in a status of NRF2 addiction, NRF2 inhibition is a straightforward therapeutic strategy [89,90]. However, NRF2 in the cancerbearing host, especially in myeloid cells and regulatory T cells, plays beneficial roles in the invigoration of antitumour immunity [91][92][93][94][95], suggesting that therapeutic targets other than NRF2 would be more appropriate and have less adverse effects.…”

Section: Discussionmentioning

confidence: 99%

Genetic, metabolic and immunological features of cancers with NRF2 addiction

2022

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Nuclear factor erythroid‐derived 2‐like 2 (NRF2) is a master transcription factor that coordinately regulates the expression of many cytoprotective genes and plays a central role in defense mechanisms against oxidative and electrophilic insults. Although increased NRF2 activity is principally beneficial for our health, NRF2 activation in cancer cells is detrimental. Many human cancers exhibit persistent NRF2 activation and such cancer cells rely on NRF2 for most of their malignant characteristics, such as therapeutic resistance and aggressive tumourigenesis, and thus fall into NRF2 addiction. The persistent activation of NRF2 confers great advantages on cancer cells, whereas it is not tolerated by normal cells, suggesting that certain requirements are necessary for a cell to exploit NRF2 and evolve into malignant cancer cells. In this review, recent reports and data on the genetic, metabolic and immunological features of NRF2‐activated cancer cells are summarized, and prerequisites for NRF2 addiction in cancer cells and their therapeutic applications are discussed.

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Section: Discussionmentioning

confidence: 99%

Genetic, metabolic and immunological features of cancers with NRF2 addiction

2022

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“…However, other aspects of the relationship between ALDH3A1 and fibrosis are not clear. ALDH3A1 can be upregulated by nuclear factor erythroid 2-related factor 2 (Nrf2) ( 74 ). In SSc, the lack of Nrf2, a key fighter against oxidative stress, aggravates the fibrosis ( 75 ).…”

Section: Discussionmentioning

confidence: 99%

Intimate intertwining of the pathogenesis of hypoxia and systemic sclerosis: A transcriptome integration analysis

Shi²,

Zeng³

et al. 2022

Front. Immunol.

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ObjectivesSystemic sclerosis (SSc) is an autoimmune disease caused by various pathogenic factors, including hypoxia. Hypoxia stimulates the production of the extracellular matrix to promote fibrosis. However, the integrated function and the underlying mechanism of hypoxia in SSc are unclear.MethodsIn the present study, we used Agilent SurePrint G3 Human Gene Expression v3 for the transcriptional sequencing of fibroblasts with and without hypoxia to detect differentially expressed genes (DEGs) in hypoxia. We analyzed the results with the transcriptome data of SSc lesions (GSE95065) to select the co-DEGs. Then, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed on the basis of the co-DEGs using the R package ClusterProfiler, which showed that hypoxia and cross talk of hypoxia with other pathogenic factors are involved in the pathogenesis of SSc. Furthermore, we constructed a protein–protein interaction (PPI) network of co-DEGs and screened two significant functional expression modules.ResultsWe identified nine hub genes (ALDH1A1, EGF, NOX4, LYN, DNTT, PTGS2, TKT, ACAA2, and ALDH3A1). These genes affect the pentose phosphate pathway, oxidative stress, and lipolysis.ConclusionOur study provides insights into the mechanisms underlying the effects of hypoxia on SSc pathogenesis, which will help to better understand SSc pathogenesis and develop new therapeutic strategies for SSc.

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“…This agent also attenuated the growth of NRF2-activated cancer cells, both in vitro and in vivo. In a study that tested the combined administration of halofuginone and gemcitabine in pancreatic cancer, halofuginone administration sensitized KPC mouse-derived pancreatic cancer cell lines to gemcitabine in vitro and in vivo, along with reduction of aldehyde dehydrogenase 3a1 (Aldh3a1) [ 99 ]. This effect was observed in halofuginone-treated KPC mouse pancreas, and the subcutaneous tumors of immunodeficient mice received KPC cell line implantation.…”

Section: Application To Therapeutic Strategymentioning

confidence: 99%

HIF-1 and NRF2; Key Molecules for Malignant Phenotypes of Pancreatic Cancer

Hamada

Matsumoto

Masamune

2022

Cancers

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Pancreatic cancer is intractable due to early progression and resistance to conventional therapy. Dense fibrotic stroma, known as desmoplasia, is a characteristic feature of pancreatic cancer, and develops through the interactions between pancreatic cancer cells and stromal cells, including pancreatic stellate cells. Dense stroma forms harsh tumor microenvironments characterized by hypoxia, few nutrients, and oxidative stress. Pancreatic cancer cells as well as pancreatic stellate cells survive in the harsh microenvironments through the altered expression of signaling molecules, transporters, and metabolic enzymes governed by various stress response mechanisms. Hypoxia inducible factor-1 and KEAP1-NRF2, stress response mechanisms for hypoxia and oxidative stress, respectively, contribute to the aggressive behaviors of pancreatic cancer. These key molecules for stress response mechanisms are activated, both in pancreatic cancer cells and in pancreatic stellate cells. Both factors are involved in the mutual activation of cancer cells and stellate cells, by inducing cancer-promoting signals and their mediators. Therapeutic interventions targeting these pathways are promising approaches for novel therapies. In this review, we summarize the roles of stress response mechanisms, focusing on hypoxia inducible factor-1 and KEAP1-NRF2, in pancreatic cancer. In addition, we discuss the potential of targeting these molecules for the treatment of pancreatic cancer.

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Nuclear Factor Erythroid 2–Related Factor 2 Depletion Sensitizes Pancreatic Cancer Cells to Gemcitabine via Aldehyde Dehydrogenase 3a1 Repression

Cited by 13 publications

References 23 publications

Genetic, metabolic and immunological features of cancers with NRF2 addiction

Genetic, metabolic and immunological features of cancers with NRF2 addiction

Intimate intertwining of the pathogenesis of hypoxia and systemic sclerosis: A transcriptome integration analysis

HIF-1 and NRF2; Key Molecules for Malignant Phenotypes of Pancreatic Cancer

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