Nrf2 Redirects Glucose and Glutamine into Anabolic Pathways in Metabolic Reprogramming

Mitsuishi, Yoichiro; Taguchi, Keiko; Kawatani, Yukie; Shibata, Tatsuhiro; Nukiwa, Toshihiro; Aburatani, Hiroyuki; Yamamoto, Masayuki; Motohashi, Hozumi

doi:10.1016/j.ccr.2012.05.016

Cited by 1,194 publications

(1,279 citation statements)

References 47 publications

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“…1A,B). Twenty-four of 25 Nrf2 mutations were located in the Nrf2 regions coding for either the LxxQDxDLG motif (spanning amino acids [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] or the DxETGE motif (amino acids 77-82) (Fig. 1C).…”

Section: Resultsmentioning

confidence: 99%

Nrf2, but not β‐catenin, mutation represents an early event in rat hepatocarcinogenesis

et al. 2015

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Hepatocellular carcinoma (HCC) develops through a multistage process, but the nature of the molecular changes associated with the different steps, the very early ones in particular, is largely unknown. Recently, dysregulation of the NRF2/KEAP1 pathway and mutations of these genes have been observed in experimental and human tumors, suggesting their possible role in cancer development. To assess whether Nrf2/Keap1 mutations are early or late events in HCC development, we investigated their frequency in the rat Resistant Hepatocyte model, consisting of the administration of diethylnitrosamine followed by a brief exposure to 2-acetylaminofluorene. This model enables the dissection of all stages of hepatocarcinogenesis. We found that Nrf2/Keap1 mutations were present in 71% of early preneoplastic lesions and in 78.6% and 59.3% of early and advanced HCCs, respectively. Mutations of Nrf2 were more frequent, missense, and located in the Nrf2-Keap1 binding region. Mutations of Keap1 occurred at a much lower frequency in both preneoplastic lesions and HCCs and were mutually exclusive with those of Nrf2. Functional in vitro and in vivo studies showed that Nrf2 silencing inhibited the ability of tumorigenic rat cells to grow in soft agar and to form tumors. Unlike Nrf2 mutations, those of Ctnnb1, which are frequent in human HCC, were a later event as they appeared only in fully advanced HCCs (18.5%). Conclusion: In the Resistant Hepatocyte model of hepatocarcinogenesis the onset of Nrf2 mutations is a very early event, likely essential for the clonal expansion of preneoplastic hepatocytes to HCC, while Ctnnb1 mutations occur only at very late stages. Moreover, functional experiments demonstrate that Nrf2 is an oncogene critical for HCC progression and development. (HEPATOLOGY 2015;62:851-862) See Editorial on Page 677 H epatocellular carcinoma (HCC) is the third most frequent cause of cancer-related deaths worldwide. 1 Unfortunately, our knowledge of the genomic alterations implicated in HCC initiation and progression is still fragmentary. Moreover, different from other solid tumors, no driving genetic alteration to which tumor cells are addicted and that can be effectively targeted has ever been identified. In this scenario, HCC is probably one of the tumor types where a more complete understanding of the underlying genetic alterations could have a major impact on the development of new treatment strategies. Also known as NFE2L2, NRF2 is of particular interest as conflicting results have been reported concerning the role of the NRF2/KEAP1 pathway in cancer development. 2 It is a master transcriptional activator of genes encoding enzymes that protect cells from oxidative stress and

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Section: Resultsmentioning

confidence: 99%

Nrf2, but not β‐catenin, mutation represents an early event in rat hepatocarcinogenesis

et al. 2015

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“…An antineoplastic compound, brusatol, is an Nrf2 inhibitor that increases the chemotherapeutic efficacy of cisplatin, a common chemotherapeutic (Ren et al 2011). PI3K inhibitors (Mitsuishi et al 2012) and Nrf2 siRNA inhibit Nrf2 in cancer cells. Cancer suicide gene therapy, which is an alternative approach, has been utilised to target the cancer cells with high Nrf2 levels.…”

Section: Role Of the Nrf2-keap1 Pathway In Cancermentioning

confidence: 99%

“…Also, other metabolic genes, including malic enzyme 1 (ME1), pyrophosphate phosphoribosyl amidotransferase (PPAT), methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) and isocitrate dehydrogenase 1 (IDH1), were also identified as transcription targets of Nrf2. These proteins are responsible for purines synthesis, which are the building blocks of DNA and RNA, which in turn, leads to the proliferation of cancer cells (Mitsuishi et al 2012). Several studies have shown that elevated levels of Nrf2 in cancer cells are less sensitive to chemotherapeutic treatments and renders more resistant to cancer cells against a variety of anti-cancer agents (Shibata et al 2008a, b;Wang et al 2008).…”

Section: Role Of the Nrf2-keap1 Pathway In Cancermentioning

confidence: 99%

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

et al. 2016

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The overproduction of reactive oxygen species (ROS) generates oxidative stress in cells. Oxidative stress results in various pathophysiological conditions, especially cancers and neurodegenerative diseases (NDD). The Keap1-Nrf2 [Kelch-like ECH-associated protein 1-nuclear factor (erythroid-derived 2)-like 2] regulatory pathway plays a central role in protecting cells against oxidative and xenobiotic stresses. The Nrf2 transcription factor activates the transcription of several cytoprotective genes that have been implicated in protection from cancer and NDD. The Keap1-Nrf2 system acts as a double-edged sword: Nrf2 activity protects cells and makes the cell resistant to oxidative and electrophilic stresses, whereas elevated Nrf2 activity helps in cancer cell survival and proliferation. Several groups in the recent past, from both academics and industry, have reported the potential role of Nrf2-mediated transcription to protect from cancer and NDD, resulting from mechanisms involving xenobiotic and oxidative stress. It suggests that the Keap1-Nrf2 system is a potential therapeutic target to combat cancer and NDD by designing and developing modulators (inhibitors/activators) for Nrf2 activation. Herein, we review and discuss the recent advancement in the regulation of the Keap1-Nrf2 system, its role under physiological and pathophysiological conditions including cancer and NDD, and modulators design strategies for Nrf2 activation.

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“…G6PD is a rate‐limiting enzyme of PPP which activates this pathway in response to the breakdown of NADPH (Ben‐Yoseph et al., 1996). In addition, G6PD is one of the biological protective factors orchestrated by Nrf2 (Mitsuishi et al., 2012), which is a transcriptional factor that ubiquitously responds to various physiological and pathological conditions.…”

Section: Resultsmentioning

confidence: 99%

Ketone body 3‐hydroxybutyrate mimics calorie restriction via the Nrf2 activator, fumarate, in the retina

et al. 2017

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SummaryCalorie restriction (CR) being the most robust dietary intervention provides various health benefits. D‐3‐hydroxybutyrate (3HB), a major physiological ketone, has been proposed as an important endogenous molecule for CR. To investigate the role of 3HB in CR, we investigated potential shared mechanisms underlying increased retinal 3HB induced by CR and exogenously applied 3HB without CR to protect against ischemic retinal degeneration. The repeated elevation of retinal 3HB, with or without CR, suppressed retinal degeneration. Metabolomic analysis showed that the antioxidant pentose phosphate pathway and its limiting enzyme, glucose‐6‐phosphate dehydrogenase (G6PD), were concomitantly preserved. Importantly, the upregulation of nuclear factor erythroid 2 p45‐related factor 2 (Nrf2), a regulator of G6PD, and elevation of the tricarboxylic acid cycle's Nrf2 activator, fumarate, were also shared. Together, our findings suggest that CR provides retinal antioxidative defense by 3HB through the antioxidant Nrf2 pathway via modification of a tricarboxylic acid cycle intermediate during 3HB metabolism.

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Nrf2 Redirects Glucose and Glutamine into Anabolic Pathways in Metabolic Reprogramming

Cited by 1,194 publications

References 47 publications

Nrf2, but not β‐catenin, mutation represents an early event in rat hepatocarcinogenesis

Nrf2, but not β‐catenin, mutation represents an early event in rat hepatocarcinogenesis

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

Ketone body 3‐hydroxybutyrate mimics calorie restriction via the Nrf2 activator, fumarate, in the retina

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