Abstract:Cellular homeostasis is continuously challenged by damage from reactive oxygen species (ROS) and numerous reactive electrophiles. Human cells contain various protective systems that are upregulated in response to protein damage by electrophilic or oxidative stress. In addition to the NRF2mediated antioxidant response, ROS and reactive electrophiles also activate HSF1 and HIF1 that control heat shock response and hypoxia response, respectively. Here, we review chemical and biological mechanisms of activation of… Show more
“…Indeed, NFE2L2 which encodes Nrf2, the master regulator of antioxidant response in cells was a top TF co‐regulator of HIF‐1 correlated genes in LUAD and CRC in many cancer stages. Owing to hyperoxygenation, lung tissue is endowed with high Nrf2 activity to limit oxidative damage, and can crosstalk with HIF‐1 downstream signaling to effect specificity in gene expression 27 . Among the more specific co‐regulating TFs in these cancers was CEBPB in colon cancer, NONO and XBP1 in lung cancer, and interferon regulator factor (IRF)1/3/7, BHLHE40 and STAT1 in pancreatic cancer.…”
Section: Resultsmentioning
confidence: 99%
“…Owing to hyperoxygenation, lung tissue is endowed with high Nrf2 activity to limit oxidative damage, and can crosstalk with HIF-1 downstream signaling to effect specificity in gene expression. 27 Among the more specific co-regulating TFs in these cancers was CEBPB in colon cancer, NONO and XBP1 in lung cancer, and interferon regulator factor (IRF)1/3/7, BHLHE40 and STAT1 in pancreatic cancer. CEBPB regulates bile acid receptor signaling in colon, and is typically upregulated in colon cancer.…”
Section: Cancer Cells With Hif-1 Activation Exhibit Dissimilar Gene E...mentioning
Hypoxia‐inducible factor‐1 (HIF‐1) is the master regulator of cellular response to hypoxia, and is activated in many cancers contributing to many steps in the metastatic cascade by acting as a key transcription co‐regulator for a large number of downstream genes. Presence of hypoxia within a tumor is spatially nonuniform, and can also by dynamic. Further, although HIF‐1 is primarily stabilized and activated by lack of molecular O2, its stability is also affected by other factors present in the tumor microenvironment. HIF‐1 also crosstalks with other transcription factors in co‐regulating gene expression. Consequently, it is nontrivial to predict the gene expression patterns in cells in response to hypoxia, or HIF‐1 activation. Additionally, cancers originating from tissue origins with different basal level of partial oxygen tension may activate HIF‐1 at different threshold of hypoxia. We analyzed large published single cell RNAseq data for colorectal, lung, and pancreatic cancers to investigate the phenotypic outcome of HIF‐1 activation in cancer cells. We found that cancers from tissues with different partial O2 tension levels exhibit HIF‐1 activation at different stages of metastasis, and phenotypically respond differently to HIF‐1 activation, likely by contextual co‐option of different transcription factors. We experimentally confirmed these predictions by using cell lines representative of colorectal, lung, and pancreatic cancers, finding that while hypoxia enhances growth of colorectal cancer, it induces increased invasion of lung, and pancreatic cancers. Our analysis suggest that HIF‐1 activation may act as a rheostat regulating downstream gene expression towards phenotypic outcomes differently in various cancers.
“…Indeed, NFE2L2 which encodes Nrf2, the master regulator of antioxidant response in cells was a top TF co‐regulator of HIF‐1 correlated genes in LUAD and CRC in many cancer stages. Owing to hyperoxygenation, lung tissue is endowed with high Nrf2 activity to limit oxidative damage, and can crosstalk with HIF‐1 downstream signaling to effect specificity in gene expression 27 . Among the more specific co‐regulating TFs in these cancers was CEBPB in colon cancer, NONO and XBP1 in lung cancer, and interferon regulator factor (IRF)1/3/7, BHLHE40 and STAT1 in pancreatic cancer.…”
Section: Resultsmentioning
confidence: 99%
“…Owing to hyperoxygenation, lung tissue is endowed with high Nrf2 activity to limit oxidative damage, and can crosstalk with HIF-1 downstream signaling to effect specificity in gene expression. 27 Among the more specific co-regulating TFs in these cancers was CEBPB in colon cancer, NONO and XBP1 in lung cancer, and interferon regulator factor (IRF)1/3/7, BHLHE40 and STAT1 in pancreatic cancer. CEBPB regulates bile acid receptor signaling in colon, and is typically upregulated in colon cancer.…”
Section: Cancer Cells With Hif-1 Activation Exhibit Dissimilar Gene E...mentioning
Hypoxia‐inducible factor‐1 (HIF‐1) is the master regulator of cellular response to hypoxia, and is activated in many cancers contributing to many steps in the metastatic cascade by acting as a key transcription co‐regulator for a large number of downstream genes. Presence of hypoxia within a tumor is spatially nonuniform, and can also by dynamic. Further, although HIF‐1 is primarily stabilized and activated by lack of molecular O2, its stability is also affected by other factors present in the tumor microenvironment. HIF‐1 also crosstalks with other transcription factors in co‐regulating gene expression. Consequently, it is nontrivial to predict the gene expression patterns in cells in response to hypoxia, or HIF‐1 activation. Additionally, cancers originating from tissue origins with different basal level of partial oxygen tension may activate HIF‐1 at different threshold of hypoxia. We analyzed large published single cell RNAseq data for colorectal, lung, and pancreatic cancers to investigate the phenotypic outcome of HIF‐1 activation in cancer cells. We found that cancers from tissues with different partial O2 tension levels exhibit HIF‐1 activation at different stages of metastasis, and phenotypically respond differently to HIF‐1 activation, likely by contextual co‐option of different transcription factors. We experimentally confirmed these predictions by using cell lines representative of colorectal, lung, and pancreatic cancers, finding that while hypoxia enhances growth of colorectal cancer, it induces increased invasion of lung, and pancreatic cancers. Our analysis suggest that HIF‐1 activation may act as a rheostat regulating downstream gene expression towards phenotypic outcomes differently in various cancers.
“…Thus, non-hypoxic stimuli can also activate HIF-1α through redox signaling by activating specific kinases or inactivating phosphatases. BNIP3 acts as a receptor for mitochondrial autophagy and induces autophagy through direct binding to LC3 (microtubule-associated protein one light chain 3) 31 Figure 3 depicts the mechanism of HIF-1α/BNIP3 signaling. Figure 3 HIF-1a/BNIP3 signaling mechanism.…”
Section: Biological Properties Of Hif-1α/bnip3mentioning
Recurrence of hepatocellular carcinoma (HCC) negatively affects the quality of life of patients and leads to death. Studies have shown that recurrent hepatocellular carcinoma (RHCC) is closely related to tissue hypoxia and autophagy. It has been shown that hypoxia-inducible factor-1α (HIF-1α) and its downstream factor BCL-2 19 kDa-interacting protein 3 (BNIP3) promote cellular autophagy under hypoxic conditions, resulting in metastasis and RHCC. In this article, the molecular structures of HIF-1α and BNIP3 are described, and the significance of the HIF-1α/BNIP3 signaling pathway in RHCC is explained. Moreover, the role and mechanism of traditional Chinese medicine (TCM) in treating RHCC by modulating the HIF-1α/BNIP3 signaling pathway is discussed. Studies have shown that the HIF-1α/BNIP3 signaling pathway is a potential target of TCM in the treatment of RHCC. The mechanism of the HIF-1α/BNIP3 signaling pathway in RHCC and the progress achieved in TCM research on targeting and regulating this pathway are also reviewed in this article. The objective was to provide a theoretical basis for the prevention and treatment of RHCC, as well as further drug development.
“…Not every molecule and biological reaction involved in the fascinating process of cellular response to hypoxia have been cited here (there are indeed many other participants including peroxiredoxin reductase/oxygenases and catalase, to name just a few), both for the sake of simplicity and because out of the focus of our review which is not to provide a full biological molecular description (thoroughly described elsewhere [38,47,48]) but to summarize new experimental evidence of practical application of the normobaric oxygen paradox and illustrate the perspective of its desirable future clinical applications.…”
Hypoxia, even at non-lethal levels, is one of the most stressful events for all aerobic organisms as it significantly affects a wide spectrum of physiological functions and energy production. Aerobic organisms activate countless molecular responses directed to respond at cellular, tissue, organ, and whole-body levels to cope with oxygen shortage allowing survival, including enhanced neo-angiogenesis and systemic oxygen delivery. The benefits of hypoxia may be evoked without its detrimental consequences by exploiting the so-called normobaric oxygen paradox. The intermittent shift between hyperoxic-normoxic exposure, in addition to being safe and feasible, has been shown to enhance erythropoietin production and raise hemoglobin levels with numerous different potential applications in many fields of therapy as a new strategy for surgical preconditioning aimed at frail patients and prevention of postoperative anemia. This narrative review summarizes the physiological processes behind the proposed normobaric oxygen paradox, focusing on the latest scientific evidence and the potential applications for this strategy. Future possibilities for hyperoxic-normoxic exposure therapy include implementation as a synergistic strategy to improve a patient’s pre-surgical condition, a stimulating treatment in critically ill patients, preconditioning of athletes during physical preparation, and, in combination with surgery and conventional chemotherapy, to improve patients’ outcomes and quality of life.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
