Targeted therapy of esophageal squamous cell carcinoma: the NRF2 signaling pathway as target

Ma, Shaohua; Paiboonrungruan, Chorlada; Yan, Tao; Williams, Kevin P.; Major, Michael B.; Chen, Xiaoxin Luke

doi:10.1111/nyas.13681

Cited by 38 publications

(27 citation statements)

References 119 publications

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Section: Summary Hyperactive Nrf2 Causes Metabolic Reprogramming In mentioning

confidence: 99%

“…NRF2 mutations are mostly located in the DLG and ETGE motifs (KEAP1-binding domain) and the DNA-binding domain, whereas KEAP1 mutations tend to be scattered across the whole gene. NRF2 mutations and KEAP1 mutations tend to be mutually exclusive (3,4).As a major cellular defense mechanism, the NRF2 signaling pathway is known to regulate expression of enzymes involved in detoxification and anti-oxidative stress response. NRF2 forms heterodimers with small MAF proteins and binds to the antioxidant-response elements of target genes when cells are…”

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confidence: 99%

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Hyperactivity of the transcription factor Nrf2 causes metabolic reprogramming in mouse esophagus

Xiong

Huang

et al. 2019

Journal of Biological Chemistry

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Edited by Xiao-Fan WangMutations in the genes encoding nuclear factor (erythroidderived 2)-like 2 (NRF2), Kelch-like ECH-associated protein 1 (KEAP1), and cullin 3 (CUL3) are commonly observed in human esophageal squamous cell carcinoma (ESCC) and result in activation of the NRF2 signaling pathway. Moreover, hyperactivity of the transcription factor Nrf2 has been found to cause esophageal hyperproliferation and hyperkeratosis in mice. However, the underlying mechanism is unclear. In this study, we aimed to understand the molecular mechanisms of esophageal hyperproliferation in mice due to hyperactive Nrf2. Esophageal tissues were obtained from genetically modified mice that differed in the status of the Nrf2 gene and genes in the same pathway (Nrf2 ؊/؊ , Keap1 ؊/؊ , K5Cre;Pkm2 fl/fl ;Keap1 ؊/؊ , and WT) and analyzed for metabolomic profiles, Nrf2 ChIP-seq, and gene expression. We found that hyperactive Nrf2 causes metabolic reprogramming and up-regulation of metabolic genes in the mouse esophagus. One of the glycolysis genes encoding pyruvate kinase M2 (Pkm2) was not only differentially up-regulated, but also glycosylated and oligomerized, resulting in increased ATP biosynthesis. However, constitutive knockout of Pkm2 failed to inhibit this esophageal phenotype in vivo, and this failure may have been due to compensation by Pkm1 up-regulation. Transient inhibition of NRF2 or glycolysis inhibited the growth of human ESCC cells in which NRF2 is hyperactive in vitro. In summary, hyperactive Nrf2 causes metabolic reprogramming in the mouse esophagus through its transcriptional regulation of metabolic genes. Blocking glycolysis transiently inhibits cell proliferation and may therefore have therapeutically beneficial effects on NRF2 high ESCC in humans.Esophageal cancer affects 16,940 adults in the United States, and the 5-year survival rate is 18% (1). There are mainly two histological types of esophageal cancer, squamous cell carcinoma (ESCC) 4 and adenocarcinoma, each having a distinct etiology. Low income, moderate/heavy alcohol intake, tobacco use, and infrequent consumption of raw fruits and vegetables account for almost all cases of ESCC (2). With the recent technological advances in NextGen sequencing, human ESCC samples from North and South America, China, Japan, Vietnam, and Malawi have been sequenced. Among many gene mutations, nuclear factor (erythroid-derived 2)-like 2 (NRF2 or NFE2L2) mutations are commonly seen with a frequency over 5%, even up to ϳ20% in certain reports. Mutations in other genes of the NRF2 signaling pathway, Kelch-like ECH associated protein 1 (KEAP1) and cullin 3 (CUL3), are relatively less common. NRF2 mutations are mostly located in the DLG and ETGE motifs (KEAP1-binding domain) and the DNA-binding domain, whereas KEAP1 mutations tend to be scattered across the whole gene. NRF2 mutations and KEAP1 mutations tend to be mutually exclusive (3,4).As a major cellular defense mechanism, the NRF2 signaling pathway is known to regulate expression of enzymes involved in detoxification and ant...

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Section: Summary Hyperactive Nrf2 Causes Metabolic Reprogramming In mentioning

confidence: 99%

mentioning

confidence: 99%

Hyperactivity of the transcription factor Nrf2 causes metabolic reprogramming in mouse esophagus

Xiong

Huang

et al. 2019

Journal of Biological Chemistry

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“…Kawasaki et al reported the possibility of the conversion of non-responder patients to responders by Nrf2 knockdown before subjecting patients with ESCC with high-Nrf2 expression to CRT, which may lead to a more favorable prognosis [29]. In contrast, targeting the transcription factor Nrf2 was considered signi cantly challenging in clinical settings [43]. To include curative resection as a viable treatment option for ESCC, surgical resection without NAC or NACRT might be a potential treatment strategy for patients with ESCC who exhibit high Nrf2, TXNRD1, and HO-1 expression, considering the highly aggressive malignant tendencies of tumors and the probable ineffectiveness of neoadjuvant therapy [17,18,24,25,44].…”

Section: Discussionmentioning

confidence: 99%

Correlation between TXNRD1/HO-1 Expression and the Histological Response to Neoadjuvant Chemoradiation Therapy in patients with Esophageal Squamous Cell Carcinoma

Akaishi¹,

Fujishima²,

Ishida³

et al. 2020

Preprint

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BackgroundNrf2 signaling plays a pivotal role in antioxidant response, and its expression has been reported to increase in various human malignancies, including esophageal squamous cell carcinoma (ESCC). This also leads to resistance against chemotherapy and radiotherapy in patients. Thioredoxin reductase 1 (TXNRD1) and heme oxygenase-1 (HO-1) are proteins involved in this pathway that play key roles in antioxidant responses. However, the correlation between the expression of these two proteins and the therapeutic response to neoadjuvant chemoradiation therapy (NACRT), and the changes before and after chemoradiation therapy in patients with ESCC, remain unknown. MethodsThe proteins involved in the Nrf2 signaling pathway were immunolocalized in carcinoma cells in patients with ESCC undergoing NACRT with 5-fluorouracil and cisplatin followed by esophagectomy. The 8-OHdG levels were used to determine ROS levels in individual carcinoma cells. Fifty-two pre-operative endoscopic biopsy and fifty post-operative resected specimens were available for this study. Among these, 39 specimens were available for comparison of the results before and after NACRT. The changes in immunoreactivity before and after NACRT (Δ) were assessed. ResultsSignificant histological resistance to NACRT was observed in patients with high levels of Nrf2, TXNRD1, and HO-1 expression. Among pre-therapeutic biopsy specimens, the tumor reduction effect was significantly attenuated in those with high levels of Nrf2, TXNRD1, and HO-1 expression. TXNRD1Δ and HO-1Δ were both significantly higher, while 8-OHdGΔ was significantly lower in the ineffective (poor response) groups. In resected specimens, the overall survival was significantly lower in groups with high Nrf2, TXNRD1, HO-1, and HO-1Δ values. Disease-free survival was significantly lower in the groups with high expression of Nrf2, TXNRD1, HO-1, and Ki-67 and large values of HO-1Δ, and Ki-67Δ. ConclusionsThe results of this study indicate that high Nrf2, TXNRD1, and HO-1 expression in pre-therapeutic biopsy specimens could predict the histological response to NACRT, and their status in surgically resected specimens could predict clinical outcomes in patients with ESCC.

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“…Conversely, inhibition of Nrf2 signaling enhances apoptosis in response to oxidative insults [15]. There are many studies showing elevated expression of Nrf2 in various types of tumors such as head and neck [16], gastric [17], non-small cell lung [18], esophageal squamous cell carcinoma [19], breast [20], gallbladder [21] and ovarian [22] cancer. Upon oxidative stress, Nrf2 signaling is activated and protects tumor cells from cell death by upregulating ROS scavenging enzymes that counterbalance 0production [23].…”

Section: Introductionmentioning

confidence: 99%

Nrf2 overexpression increases risk of high tumor mutation burden in acute myeloid leukemia through inhibiting MSH2

Liu

Wang

et al. 2020

Preprint

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Background: Nuclear factor erythroid 2-related factor 2 (Nrf2, also called NFE2L2) has been shown to play a pivotal role in preventing cancer cells from being affected by chemotherapy. Gene mutation is a crucial reason of chemotherapy-resistance in acute myeloid leukemia (AML). However, the relationship between Nrf2 and tumor mutation burden and its mechanism in regulating chemotherapy-resistance remains unclear. Methods: The whole-exome sequencing analysis were used to measure tumor mutation. RNA sequencing, Oncomine, qRT-PCR, Western blotting and immunocytochemistry were employed to detect differences in genes and proteins. The KEGG pathway enrichment analysis and GeneMANIN were performed pathway analysis. Functional assays, such as annexin V/PI, Hoechst33342 staining and DCFH were performed to examine the apoptosis and reactive oxygen species (ROS) of AML cells in vitro. Subcutaneous xenograft model was established to investigate in vivo growth. Results: Nrf2 expression was associated with tumor mutation burden in AML. Patients with Nrf2 overexpression had higher frequency of gene mutation and drug resistance. Nrf2 overexpression protected the AML cells from apoptosis induced by cytarabine in vitro and increased the risk of gene mutant drug resistance in vivo. Furthermore, Nrf2 overexpression inhibited MSH2 protein expression, which caused DNA mismatch repair (MMR) deficiency. Mechanistically, the inhibition of MSH2 by Nrf2 was in a ROS-independent manner. Further studies showed that an increased activation of JNK/c-Jun signaling in Nrf2 overexpression cells, which inhibited the expression of MSH2 protein. Conclusions: Our findings provided evidence that high Nrf2 expression inhibited MSH2 expression, caused MMR deficiency and increased the tumor mutation burden, which can induce gene instability-dependent drug resistance in AML. This study demonstrates the reason why the high Nrf2 expression leads to the increase of gene mutation frequency in AML, and provides a new strategy for clinical practice.

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Targeted therapy of esophageal squamous cell carcinoma: the NRF2 signaling pathway as target

Cited by 38 publications

References 119 publications

Hyperactivity of the transcription factor Nrf2 causes metabolic reprogramming in mouse esophagus

Hyperactivity of the transcription factor Nrf2 causes metabolic reprogramming in mouse esophagus

Correlation between TXNRD1/HO-1 Expression and the Histological Response to Neoadjuvant Chemoradiation Therapy in patients with Esophageal Squamous Cell Carcinoma

Nrf2 overexpression increases risk of high tumor mutation burden in acute myeloid leukemia through inhibiting MSH2

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