Anoxic induction of ATF-4 through HIF-1-independent pathways of protein stabilization in human cancer cells (original) (raw)
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Enhanced Overexpression of an HIF-1/Hypoxia-Related Protein in Cancer Cells
Environmental Health Perspectives, 2002
Cap43 is a protein whose RNA is induced under conditions of severe hypoxia or prolonged elevations of intracellular calcium. Additionally, Ni and Co also induce Cap43 because they produce a state of hypoxia in cells. Cap43 protein is expressed at low levels in normal tissues; however, in a variety of cancers, including lung, brain, melanoma, liver, prostate, breast, and renal cancers, Cap43 protein is overexpressed in cancer cells. The low level of expression of Cap43 in some normal tissues compared with their cancerous counterparts, combined with the high stability of Cap43 protein and mRNA, makes the Cap43 gene a new, important cancer marker. We hypothesize that the mechanism of Cap43 overexpression in cancer cells involves a state of hypoxia characteristic of cancer cells where the Cap43 protein becomes a signature for this hypoxic state. Key words: antibody detection, Ca 2+ , cancer-specific, HIF-1α, hypoxia signature. Environ Health Perspect 110(suppl 5):783-788 (2002). http://ehpnet1.niehs.nih.gov/docs/2002/suppl-5/783-788cangul/abstract.html
Oncogene, 2007
Solid tumors often have an inadequate blood supply, which results in large regions that are subjected to hypoxic or anoxic stress. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates much of the transcriptional response of cells to hypoxia. Activating transcription factor 3 (ATF3) is another transcription factor that responds to a variety of stresses and is often upregulated in cancer. We investigated the regulation of ATF3 by oxygen deprivation. ATF3 induction occurred most robustly under anoxia, is common, and it is not dependent on presence of HIF-1 or p53, but is sensitive to the inhibition of c-Jun NH2-terminal kinase activation and the antioxidant N-acetylcystein. ATF3 could also be induced by desferrioxamine but not by the mitochondrial poison cyanide or the nonspecific 2-oxoglutarate dioxygenase inhibitor dimethyloxalylglycine. We also show that anoxic ATF3 mRNA is more stable than normoxic mRNA providing a mechanism for this induction. Thus, this study demonstrates that the regulation of ATF3 under anoxia is independent of 2-oxoglutarate dioxygenase, HIF-1 and p53, presumably involving multiple regulatory pathways.
Frontiers in Oncology
Regions of hypoxia are common in solid tumors and drive changes in gene expression that increase risk of cancer metastasis. Tumor cells must respond to the stress of hypoxia by activating genes to modify cell metabolism and antioxidant response to improve survival. The goal of the current study was to determine the effect of hypoxia on cell metabolism and markers of oxidative stress in metastatic (metM-Wntlung) compared with nonmetastatic (M-Wnt) murine mammary cancer cell lines. We show that hypoxia induced a greater suppression of glutamine to glutamate conversion in metastatic cells (13% in metastatic cells compared to 7% in nonmetastatic cells). We also show that hypoxia increased expression of genes involved in antioxidant response in metastatic compared to nonmetastatic cells, including glutamate cysteine ligase catalytic and modifier subunits and malic enzyme 1. Interestingly, hypoxia increased the mRNA level of the transaminase glutamic pyruvic transaminase 2 (Gpt2, 7.7-fold...
The American Journal of Pathology, 2008
Hypoxia and the acquisition of a glycolytic phenotype are intrinsic features of the tumor microenvironment. The hypoxia inducible factor-1␣ (HIF-1␣) pathway is activated under hypoxic conditions and orchestrates a complex transcriptional program that enhances cell survival. Although the consequences of HIF-1␣ inactivation in cancer cells have been widely investigated, only a few studies have addressed the role of HIF-1␣ in the survival of cancer cells endowed with different glycolytic capacities. In this study, we investigated this aspect in ovarian cancer cells. Hypoxia-induced toxicity was increased in highly glycolytic cells compared with poorly glycolytic cells; it was also associated with a sharp decrease in intracellular ATP levels and was prevented by glucose supplementation. Stable HIF-1␣ silencing enhanced hypoxia-induced cell death in vitro due to a lack of cell cycle arrest. Tumors bearing attenuated HIF-1␣ levels had similar growth rates and vascularization as did controls, but tumors showed higher proliferation levels and increased necrosis. Moreover, tumors formed by HIF-1␣ deficient cells had higher levels of lactate and lower ATP concentrations than controls as shown by metabolic imaging. The findings that such metabolic properties can affect the survival of cancer cells under hypoxic conditions and that these properties con-
Roles of hypoxia in tumor progression and novel strategies for cancer treatment
Biomedical Research and Therapy
The metabolic process of normal cells in general and of cancer cells in particular requires an important molecule-oxygen. In tumors, the oxygen level tends to decrease gradually from the outer layers to the central core, leading to a condition termed``hypoxia. '' Changes in the oxygen level modify the signaling pathways and metabolic activities of cancer cells. Basically, tumor development is divided into three stages: initiation, promotion, and progression. Among them, the effects of hypoxia are most evident during tumor progression. In this review, we summarize previous findings on the mechanisms underlying hypoxia-induced alterations in the expression of genes and proteins associated with hypoxia-inducible factors (HIFs), which play a central role in the development of malignancy in many types of cancer. We also present the latest evidence on HIF-targeted cancer treatment that yields positive outcomes in vitro and in vivo.
Molecular aspects of tumour hypoxia
Molecular Oncology, 2008
Hypoxia is an important feature of the microenvironment of a wide range of solid tumours. Its critical role in radio-and chemoresistance and its significance as an adverse prognostic factor have been well established over the last decades. On a cellular level, hypoxia evokes a complex molecular response with a central role for the HIF-1 pathway. The cellular processes under control of HIF-1 contain important prognostic information and comprise potential candidates for directing hypoxia-modifying therapies. This review will provide an overview of the current knowledge on the molecular aspects of tumour hypoxia and the link to clinical practice.
Molecular and Cellular Biology, 2003
The hypoxia-inducible factors 1␣ (HIF-1␣) and 2␣ (HIF-2␣) have extensive structural homology and have been identified as key transcription factors responsible for gene expression in response to hypoxia. They play critical roles not only in normal development, but also in tumor progression. Here we report on the differential regulation of protein expression and transcriptional activity of HIF-1␣ and -2␣ by hypoxia in immortalized mouse embryo fibroblasts (MEFs). We show that oxygen-dependent protein degradation is restricted to HIF-1␣, as HIF-2␣ protein is detected in MEFs regardless of oxygenation and is localized primarily to the cytoplasm. Endogenous HIF-2␣ remained transcriptionally inactive under hypoxic conditions; however, ectopically overexpressed HIF-2␣ translocated into the nucleus and could stimulate expression of hypoxia-inducible genes. We show that the factor inhibiting HIF-1 can selectively inhibit the transcriptional activity of HIF-1␣ but has no effect on HIF-2␣-mediated transcription in MEFs. We propose that HIF-2␣ is not a redundant transcription factor of HIF-1␣ for hypoxia-induced gene expression and show evidence that there is a cell type-specific modulator(s) that enables selective activation of HIF-1␣ but not HIF-2␣ in response to low-oxygen stress.
Hypoxia signalling in cancer and approaches to enforce tumour regression
Nature, 2006
We have learned, over the past two decades, how mammalian cells perceive signals to induce cell-cycle progression, proliferation and survival. Two major pathways that are frequently mutated in human cancer, the Ras-extracellular signal-regulated kinase (ERK) 1-3 and the phosphatidylinositol-3-OH kinase (PI(3)K)-AKT 4 (see the review in this issue by Shaw and Cantley, page 424) signalling cascades, are activated by a vast array of growth factor polypeptides, hormones and extracellular matrix proteins 5. Activation of these two pathways is sufficient to trigger multiple cycles of division and survival of normal cells under the 'rich' conditions of tissue culture. In vivo, however, growing cells must constantly instruct the microenvironment to maintain a supply of essential nutrients. It is remarkable that the Ras-ERK and PI(3)K-AKT pathways also control the expression of the ubiquitous vascular endothelial growth factor-A (VEGF-A), which is a key factor in vascularization/angiogenesis 6,7. During embryonic development or in the context of tumour expansion, growing cells rapidly outstrip the supply of nutrients. Although cells sense and respond to variations in concentrations of all nutrients, oxygen sensing has emerged as a central control mechanism of vasculogenesis 8,9. At the heart of this regulatory system is HIF 10,11 , which controls, among other gene products, the expression of two key angiogenic factors: VEGF-A 12 and angiopoietin-2 (Ang-2) 13. This finding has placed the hypoxia-signalling pathway at the forefront of nutritional control-a notion reinforced by the fact that growth factors enhance HIF expression and converge with hypoxia in inducing maximal expression of VEGF-A. HIF can induce a vast array of gene products controlling energy metabolism, neovascularization, survival, pH i and cell migration, and has become recognized as a strong promoter of tumour growth 14. This pro-oncogenic feature is only one facet of the dual action of HIF. Besides being a 'guardian' of oxygen homeostasis, HIF is capable of inducing pro-apoptotic genes 14 leading to autophagy and cell death, which can be features of hypoxic tissues. In this regard, HIF can be likened to p53, which has dual roles as a guardian of genome integrity and a promoter of apoptosis. In this review we highlight the most recently revealed features of hypoxia signalling, and the role of hif as a master gene controlling nutritional stress, angiogenesis, tumour metabolism, invasion and autophagy/ cell death. Finally, we discuss potential new and exciting approaches to
Hypoxia-induced chemoresistance in cancer cells: The role of not only HIF-1
Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia, 2015
The aim of this review is to provide the information about molecular basis of hypoxia-induced chemoresistance, focusing on the possibility of diagnostic and therapeutic use. Hypoxia is a common feature of tumors and represents an independent prognostic factor in many cancers. It is the result of imbalances in the intake and consumption of oxygen caused by abnormal vessels in the tumor and the rapid proliferation of cancer cells. Hypoxia-induced resistance to cisplatin, doxorubicin, etoposide, melphalan, 5-flouoruracil, gemcitabine, and docetaxel has been reported in a number of experiments. Adaptation of tumor cells to hypoxia has important biological effects. The most studied factor responsible for these effects is hypoxia-inducible factor-1 (HIF-1) that significantly contributes to the aggressiveness and chemoresistance of different tumors. The HIF-1 complex, induced by hypoxia, binds to target genes, thereby increasing the expression of many genes. In addition, the expression of ...
The Role of Hypoxia-Induced Factors in Tumor Progression
The Oncologist, 2004
Hypoxia is a common characteristic of locally advanced solid tumors that has been associated with diminished therapeutic response and, more recently, with malignant progression, that is, an increasing probability of recurrence, locoregional spread, and distant metastasis. Emerging evidence indicates that the effect of hypoxia on malignant progression is mediated by a series of hypoxiainduced proteomic and genomic changes activating angiogenesis, anaerobic metabolism, and other processes that enable tumor cells to survive or escape their oxygen-deficient environment. The transcription factor hypoxiainducible factor 1 (HIF-1) is a major regulator of tumor cell adaptation to hypoxic stress. Tumor cells with proteomic and genomic changes favoring survival under hypoxic conditions will proliferate, thereby further aggravating the hypoxia. The selection and expansion of new (and more aggressive) clones, which eventually become the dominant tumor cell type, lead to the establishment of a vicious circle of hypoxia and malignant progression.