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

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Abstract

Esophageal squamous cell carcinoma (ESCC) is a deadly disease that requires extensive research. Here, we review the current understanding of the functions of the NRF2 signaling pathway in the esophagus. Genomic data suggest that gene mutations and several other mechanisms result in NRF2 hyperactivation in human ESCC. As a consequence, NRF2 high ESCC is more resistant to chemoradiotherapy and has poorer survival than NRF2 low ESCC. Mechanistically, we believe NRF2, functioning as a transcription factor, causes an esophageal phenotype through regulation of gene transcriptional. We discuss metabolism, mitochondria, proteasomes, and several other signaling pathways as downstream players that may contribute to esophageal phenotype due to NRF2 hyperactivation. Finally, strategies are proposed to target the NRF2 signaling pathway for future therapy of NRF2 high ESCC. Genomic data suggest that gene mutations and several other mechanisms result in NRF2 hyperactivation in human esophageal squamous cell carcinoma (ESCC). As a consequence, NRF2 high ESCC is more resistant to chemoradiotherapy and has poorer survival than NRF2 low ESCC. We discuss metabolism, mitochondria, proteasomes, and other signaling pathways as downstream players that may contribute to phenotypes due to NRF2 hyperactivation

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Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1.

N. Agrawal, M Frederick, C. R. Pickering … (2011)

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA, and HRAS, we identified mutations in FBXW7 and NOTCH1. Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.

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Decades ago, Otto Warburg observed that cancers ferment glucose in the presence of oxygen, suggesting that defects in mitochondrial respiration may be the underlying cause of cancer. We now know that the genetic events that drive aberrant cancer cell proliferation also alter biochemical metabolism, including promoting aerobic glycolysis, but do not typically impair mitochondrial function. Mitochondria supply energy; provide building blocks for new cells; and control redox homeostasis, oncogenic signaling, innate immunity, and apoptosis. Indeed, mitochondrial biogenesis and quality control are often upregulated in cancers. While some cancers have mutations in nuclear-encoded mitochondrial tricarboxylic acid (TCA) cycle enzymes that produce oncogenic metabolites, there is negative selection for pathogenic mitochondrial genome mutations. Eliminating mtDNA limits tumorigenesis, and rare human tumors with mutant mitochondrial genomes are relatively benign. Thus, mitochondria play a central and multifunctional role in malignant tumor progression, and targeting mitochondria provides therapeutic opportunities.

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NRF2 and cancer: the good, the bad and the importance of context.

Michael B. Sporn, Karen Liby (2012)

Many studies of chemopreventive drugs have suggested that their beneficial effects on suppression of carcinogenesis and many other chronic diseases are mediated through activation of the transcription factor NFE2-related factor 2 (NRF2). More recently, genetic analyses of human tumours have indicated that NRF2 may conversely be oncogenic and cause resistance to chemotherapy. It is therefore controversial whether the activation, or alternatively the inhibition, of NRF2 is a useful strategy for the prevention or treatment of cancer. This Opinion article aims to rationalize these conflicting perspectives by critiquing the context dependence of NRF2 functions and the experimental methods behind these conflicting data.

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Author and article information

Journal

Title: Annals of the New York Academy of Sciences

Abbreviated Title: Ann. N.Y. Acad. Sci.

Publisher: Wiley

ISSN (Print): 0077-8923

ISSN (Electronic): 1749-6632

Publication date Created: July 05 2018

Publication date Created: December 2018

Publication date (Electronic): May 11 2018

Publication date (Print): December 2018

Volume: 1434

Issue: 1

Pages: 164-172

Affiliations

[1 ]Department of Thoracic SurgeryPeking University Third Hospital Beijing China

[2 ]Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research InstituteNorth Carolina Central University Durham North Carolina

[3 ]Department of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technology EnterpriseNorth Carolina Central University Durham North Carolina

[4 ]Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill Chapel Hill North Carolina

[5 ]Center for Esophageal Disease and Swallowing, Division of Gastroenterology and Hepatology, Department of MedicineUniversity of North Carolina at Chapel Hill Chapel Hill North Carolina