Genomes and Genes
Affiliation: Johns Hopkins University
- Semenza G. Cancer-stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis. Oncogene. 2013;32:4057-63 pubmed publisher..In addition, lysyl oxidase (LOX) and LOX-like proteins, which are secreted by hypoxic breast cancer cells, remodel extracellular matrix in the lungs, which leads to BMDC recruitment and metastatic niche formation. ..
- Hubbi M, Semenza G. Regulation of cell proliferation by hypoxia-inducible factors. Am J Physiol Cell Physiol. 2015;309:C775-82 pubmed publisher..This review will discuss major molecular mechanisms by which hypoxia regulates cell proliferation in different cell populations, with a particular focus on the role of hypoxia-inducible factors. ..
- Li J, Yang Q, Bai Z, Zhou W, Semenza G, Ge R. Chronic cold exposure results in subcutaneous adipose tissue browning and altered global metabolism in Qinghai-Tibetan plateau pika (Ochotona curzoniae). Biochem Biophys Res Commun. 2018;500:117-123 pubmed publisher..Understanding the regulatory mechanisms underlying this adaptation may lead to novel therapeutic strategies for treating obesity and metabolic disorders. ..
- Semenza G, Prabhakar N. Neural regulation of hypoxia-inducible factors and redox state drives the pathogenesis of hypertension in a rodent model of sleep apnea. J Appl Physiol (1985). 2015;119:1152-6 pubmed publisher..Thus sympathetic nervous system homeostasis is dependent on a balance between HIF-1Î± and HIF-2Î±, disruption of which results in hypertension in OSA patients. ..
- Lu H, Samanta D, Xiang L, Zhang H, Hu H, Chen I, et al. Chemotherapy triggers HIF-1-dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype. Proc Natl Acad Sci U S A. 2015;112:E4600-9 pubmed publisher..These results suggest that, in combination with chemotherapy, targeting BCSCs by inhibiting HIF-1-regulated glutathione synthesis may improve outcome in TNBC. ..
- Semenza G. Hypoxia-inducible factor 1 (HIF-1) pathway. Sci STKE. 2007;2007:cm8 pubmed..A growing number of proteins and small molecules have been identified that regulate HIF-1 activity by modulating the physical or functional interaction of PHD2, VHL, FIH-1, RACK1, or HSP90 with HIF-1alpha. ..
- Semenza G. Dynamic regulation of stem cell specification and maintenance by hypoxia-inducible factors. Mol Aspects Med. 2016;47-48:15-23 pubmed publisher..HIF inhibitors target cancer stem cells and improve the responses to angiogenesis inhibitors and cytotoxic chemotherapy in mouse models of breast cancer. ..
- Semenza G. Regulation of physiological responses to continuous and intermittent hypoxia by hypoxia-inducible factor 1. Exp Physiol. 2006;91:803-6 pubmed
- Semenza G, Prabhakar N. The role of hypoxia-inducible factors in oxygen sensing by the carotid body. Adv Exp Med Biol. 2012;758:1-5 pubmed publisher..Thus, IH disrupts the balance between HIF-1-dependent pro-oxidant and HIF-2-dependent anti-oxidant activities, and this loss of redox homeostasis underlies the pathogenesis of autonomic morbidities associated with IH. ..
- Prabhakar N, Semenza G. Regulation of carotid body oxygen sensing by hypoxia-inducible factors. Pflugers Arch. 2016;468:71-5 pubmed publisher..Thus, mutual antagonism between HIF-Î± isoforms determines the redox state and thereby establishes the set point for hypoxic sensing by the carotid body. ..
- Semenza G. Regulation of the breast cancer stem cell phenotype by hypoxia-inducible factors. Clin Sci (Lond). 2015;129:1037-45 pubmed publisher..HIF inhibitors block chemotherapy-induced enrichment of BCSCs, suggesting that their use may improve the response to chemotherapy and increase the survival of breast cancer patients. ..
- Semenza G. Expression of hypoxia-inducible factor 1: mechanisms and consequences. Biochem Pharmacol. 2000;59:47-53 pubmed..Pharmacologic manipulation of HIF-1 levels may provide a novel therapeutic approach to diseases that represent the most common causes of mortality in Western society, including cancer, chronic lung disease, and myocardial ischemia. ..
- Zhang H, Lu H, Xiang L, Bullen J, Zhang C, Samanta D, et al. HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells. Proc Natl Acad Sci U S A. 2015;112:E6215-23 pubmed publisher..Thus, CD47 expression contributes to the lethal breast cancer phenotype that is mediated by HIF-1. ..
- Zhang C, Samanta D, Lu H, Bullen J, Zhang H, Chen I, et al. Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m?A-demethylation of NANOG mRNA. Proc Natl Acad Sci U S A. 2016;113:E2047-56 pubmed publisher..Thus, HIF-dependent ALKBH5 expression mediates enrichment of BCSCs in the hypoxic tumor microenvironment. ..
- Samanta D, Gilkes D, Chaturvedi P, Xiang L, Semenza G. Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells. Proc Natl Acad Sci U S A. 2014;111:E5429-38 pubmed publisher..Based on these results, clinical trials are warranted to test whether treatment of patients with TNBC with a combination of cytotoxic chemotherapy and HIF inhibitors will improve patient survival. ..
- Semenza G. HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell. 2001;107:1-3 pubmed..A molecular basis for O(2)-regulated expression of the HIF-1 alpha subunit has now been determined, providing a mechanism for changes in gene expression in response to changes in cellular oxygenation. ..
- Semenza G. Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol. 2002;64:993-8 pubmed
- Semenza G. Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin Cancer Biol. 2009;19:12-6 pubmed publisher..Targeting HIF-1 or metabolic enzymes encoded by HIF-1 target genes may represent a novel therapeutic approach to cancer. ..
- Semenza G. Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology (Bethesda). 2009;24:97-106 pubmed publisher..HIF-1 also mediates maladaptive responses to chronic continuous and intermittent hypoxia, which underlie the development of pulmonary and systemic hypertension, respectively. ..
- Semenza G. HIF-1 inhibitors for cancer therapy: from gene expression to drug discovery. Curr Pharm Des. 2009;15:3839-43 pubmed
- Semenza G. HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev. 2010;20:51-6 pubmed publisher..Many metabolic abnormalities in cancer cells increase HIF-1 activity. As a result, a feed-forward mechanism can be activated that drives HIF-1 activation and may promote tumor progression. ..
- Bullen J, Tchernyshyov I, Holewinski R, Devine L, Wu F, Venkatraman V, et al. Protein kinase A-dependent phosphorylation stimulates the transcriptional activity of hypoxia-inducible factor 1. Sci Signal. 2016;9:ra56 pubmed publisher..These data link stimuli that promote cAMP signaling, HIF-1Î±-dependent changes in gene expression, and increased adenosine, all of which contribute to the pathophysiology of cancer and heart disease. ..
- Semenza G. Hypoxia-inducible factors: coupling glucose metabolism and redox regulation with induction ofÂ the breast cancer stem cell phenotype. EMBO J. 2017;36:252-259 pubmed publisher..I discuss how these findings have important implications for understanding the logic of the tumor microenvironment and for improving therapeutic responses in women with breast cancer. ..
- Semenza G. Tumor metabolism: cancer cells give and take lactate. J Clin Invest. 2008;118:3835-7 pubmed publisher..MCT1 expression was detected exclusively in nonhypoxic regions of human cancer biopsy samples, and in combination, these data suggest that MCT1 inhibition holds potential as a novel cancer therapy. ..
- Schito L, Semenza G. Hypoxia-Inducible Factors: Master Regulators of Cancer Progression. Trends Cancer. 2016;2:758-770 pubmed publisher..In this review, our current understanding of the consequences of HIF activity and the translational potential of targeting HIFs for cancer therapy are discussed. ..
- Semenza G. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol (1985). 2000;88:1474-80 pubmed..Genetic or pharmacological modulation of HIF-1 activity in vivo may represent a novel therapeutic approach to these disorders...
- Wang T, Gilkes D, Takano N, Xiang L, Luo W, Bishop C, et al. Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis. Proc Natl Acad Sci U S A. 2014;111:E3234-42 pubmed publisher..In breast cancer patients, RAB22A mRNA overexpression in the primary tumor is associated with decreased overall and metastasis-free survival and, in an orthotopic mouse model, RAB22A knockdown impairs breast cancer metastasis. ..
- Semenza G. Hypoxia-inducible factor 1 and cancer pathogenesis. IUBMB Life. 2008;60:591-7 pubmed publisher..Proof of principle studies in mouse models suggests that inhibition of HIF-1 activity may have therapeutic effects, especially in combination with other anticancer drugs. ..
- Samanta D, Semenza G. In Vitro Assays of Breast Cancer Stem Cells. Methods Mol Biol. 2018;1742:237-246 pubmed publisher..Using this method, a significant enrichment of CSCs compared to bulk populations is observed when breast cancer cells are exposed to 1% O2 for 72 h. ..
- Semenza G. A compendium of proteins that interact with HIF-1?. Exp Cell Res. 2017;356:128-135 pubmed publisher..This review provides a compendium of proteins that interact with the HIF-1? subunit, many of which regulate HIF-1 activity in either an O2-dependent or O2-independent manner. ..
- Lu H, Chen I, Shimoda L, Park Y, Zhang C, Tran L, et al. Chemotherapy-Induced Ca2+ Release Stimulates Breast Cancer Stem Cell Enrichment. Cell Rep. 2017;18:1946-1957 pubmed publisher..HIF inhibition blocks chemotherapy-induced GSTO1 expression and BCSC enrichment. Combining HIF inhibitors with chemotherapy may improve clinical outcome in breast cancer. ..
- Samanta D, Semenza G. Serine Synthesis Helps Hypoxic Cancer Stem Cells Regulate Redox. Cancer Res. 2016;76:6458-6462 pubmed publisher..Cancer Res; 76(22); 6458-62. Â©2016 AACR. ..
- Samanta D, Park Y, Andrabi S, Shelton L, Gilkes D, Semenza G. PHGDH Expression Is Required for Mitochondrial Redox Homeostasis, Breast Cancer Stem Cell Maintenance, and Lung Metastasis. Cancer Res. 2016;76:4430-42 pubmed publisher..Our findings highlight a role for PHGDH in the formation of secondary (recurrent or metastatic) tumors, with potential implications for therapeutic targeting of advanced cancers. Cancer Res; 76(15); 4430-42. ©2016 AACR. ..
- Semenza G. Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis. Blood. 2009;114:2015-9 pubmed publisher..Intense efforts are under way to identify small molecule hydroxylase inhibitors that can be administered chronically to selectively induce erythropoiesis without undesirable side effects. ..