Abstract
Environment exposure to arsenic had been linked to increased incidents of human cancers. In cellular and animal experimental systems, arsenic has been shown to be highly capable of activating several signaling pathways that play critical roles in cell growth regulation, malignant transformation and the stemness of cancer stem-like cells. Emerging evidence indicates certain oncogenic properties of the Nrf2 transcription factor that can be activated by arsenic and many other environmental hazards. In human bronchial epithelial cells, our most recent data suggested that arsenic-activated Nrf2 signaling fosters metabolic reprogramming of the cells through shifting mitochondrial TCA cycle to cytosolic glycolysis, and some of the metabolites in glycolysis shunt the hexosamine biosynthesis and serine-glycine pathways important for the energy metabolism of the cancer cells. In the current report, we further demonstrated direct regulation of oncogenic signals by arsenic-activated Nrf2 and connection of Nrf2 with ATF3 stress transcription factor. Meanwhile, we also highlighted some unanswered questions on the molecular characteristics of the Nrf2 protein, which warrants further collaborative efforts among scientists for understanding the important role of Nrf2 in human cancers either associated or not to environmental arsenic exposure.
Highlights
Introduction published maps and institutional affilGlobally, there are about 94 million to 220 million people in more than 70 countries facing environmental exposure to arsenic [1]
In our most recent study, we showed that arsenic activates nuclear factor erythroid 2-related factor 2 (Nrf2) in bronchial epithelial cell line
We provided evidence showing the importance of Nrf2 and its downstream target HIF1α in arsenic-induced metabolic shift from mitochondrial TCA cycle to glycolysis and the generation of the cancer stem-like cells, which supports the oncogenic role of Nrf2 in cancer development [10]
Summary
Since the first discovery of Nrf and its regulation on genes mainly in the antioxidant pathways that prevent excessive cellular damages caused by oxidative stress, xenobiotics and some metabolic products, Nrf was viewed as a tumor suppressive transcription factor. In addition to HIF1α that is a known oncogenic factor regulating angiogenesis of the tumor tissue and the hypoxic growth of the cancer cells, a number of other well-documented oncogenes and stemness genes for cancer stem cells, including MYC, SOX2, KLF4, TCF19, NAMPT, BACH1, ZEB1, CD44, EGFR, etc., showed an enhanced enrichment of Nrf binding to the Nrf binding elements either in upstream, downstream or promoter region of these genes in response to arsenic treatment. The insulin signaling was not top-ranked in the pathway analyses of the Nrf2-regulated genes in the cells treated with arsenic, majority of the genes in this pathway showed a strong arsenic-induced enrichment of Nrf binding in ChIP-seq experiment, including insulin receptor (INSR), Antioxidants 2022, 11, x FOR PEER REVIEW or antiapoptotic potentials for the cancer cells.
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