ORCID Profile
0000-0002-0503-7166
Current Organisation
University of Sydney
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Publisher: Springer Science and Business Media LLC
Date: 19-05-2023
DOI: 10.1007/S00018-023-04799-4
Abstract: Virilizer-like m 6 A methyltransferase-associated protein (VIRMA) maintains the stability of the m 6 A writer complex. Although VIRMA is critical for RNA m 6 A deposition, the impact of aberrant VIRMA expression in human diseases remains unclear. We show that VIRMA is lified and overexpressed in 15–20% of breast cancers. Of the two known VIRMA isoforms, the nuclear-enriched full-length but not the cytoplasmic-localised N-terminal VIRMA promotes m 6 A-dependent breast tumourigenesis in vitro and in vivo. Mechanistically, we reveal that VIRMA overexpression upregulates the m 6 A-modified long non-coding RNA, NEAT1 , which contributes to breast cancer cell growth. We also show that VIRMA overexpression enriches m 6 A on transcripts that regulate the unfolded protein response (UPR) pathway but does not promote their translation to activate the UPR under optimal growth conditions. Under stressful conditions that are often present in tumour microenvironments, VIRMA-overexpressing cells display enhanced UPR and increased susceptibility to death. Our study identifies oncogenic VIRMA overexpression as a vulnerability that may be exploited for cancer therapy.
Publisher: Elsevier BV
Date: 08-2007
Publisher: Springer Science and Business Media LLC
Date: 07-07-2020
DOI: 10.1186/S13046-020-01639-2
Abstract: Radiotherapy is the cornerstone of treatment of high-grade gliomas (HGGs). It eradicates tumor cells by inducing oxidative stress and subsequent DNA damage. Unfortunately, almost all HGGs recur locally within several months secondary to radioresistance with intricate molecular mechanisms. Therefore, unravelling specific underlying mechanisms of radioresistance is critical to elucidating novel strategies to improve the radiosensitivity of tumor cells, and enhance the efficacy of radiotherapy. This review addresses our current understanding of how hypoxia and the hypoxia-inducible factor 1 (HIF-1) signaling pathway have a profound impact on the response of HGGs to radiotherapy. In addition, intriguing links between hypoxic signaling, circadian rhythms and cell metabolism have been recently discovered, which may provide insights into our fundamental understanding of radioresistance. Cellular pathways involved in the hypoxic response, DNA repair and metabolism can fluctuate over 24-h periods due to circadian regulation. These oscillatory patterns may have consequences for tumor radioresistance. Timing radiotherapy for specific times of the day (chronoradiotherapy) could be beneficial in patients with HGGs and will be discussed.
Publisher: MDPI AG
Date: 19-07-2018
DOI: 10.3390/MD16070241
Abstract: Elements of the hypoxia inducible factor (HIF) transcriptional system, a key regulator of the cellular hypoxic response, are up-regulated in a range of cancer cells. HIF is fundamentally involved in tumor angiogenesis, invasion, and energy metabolism. Inhibition of the transcriptional activity of HIF may be of therapeutic benefit to cancer patients. We recently described the identification of two marine pyrroloiminoquinone alkaloids with potent activity in inhibiting the interaction between the oncogenic transcription factor HIF-1α and the coactivator protein p300. Herein, we present further characterization data for these two screening hits: discorhabdin H (1) and discorhabdin L (2), with a specific focus on their anti-angiogenic and anti-tumor effects. We demonstrated that only discorhabdin L (2) possesses excellent anti-angiogenic activity in inhibiting endothelial cell proliferation and tube formation, as well as decreasing microvessel outgrowth in the ex vivo rat aortic ring assay. We further showed that discorhabdin L (2) significantly inhibits in vivo prostate tumor growth in a LNCaP xenograft model. In conclusion, our findings suggest that discorhabdin L (2) represents a promising HIF-1α inhibitor worthy of further drug development.
Publisher: MDPI AG
Date: 20-09-2019
DOI: 10.3390/CLOCKSSLEEP1040034
Abstract: Circadian rhythms regulate many physiological and behavioral processes, including sleep, metabolism and cell ision, which have a 24-h oscillation pattern. Rhythmicity is generated by a transcriptional–translational feedback loop in in idual cells, which are synchronized by the central pacemaker in the brain and external cues. Epidemiological and clinical studies indicate that disruption of these rhythms can increase both tumorigenesis and cancer progression. Environmental changes (shift work, jet lag, exposure to light at night), mutations in circadian regulating genes, and changes to clock gene expression are recognized forms of disruption and are associated with cancer risk and/or cancer progression. Experimental data in animals and cell cultures further supports the role of the cellular circadian clock in coordinating cell ision and DNA repair, and disrupted cellular clocks accelerate cancer cell growth. This review will summarize studies linking circadian disruption to cancer biology and explore how such disruptions may be further altered by common characteristics of tumors including hypoxia and acidosis. We will highlight how circadian rhythms might be exploited for cancer drug development, including how delivery of current chemotherapies may be enhanced using chronotherapy. Understanding the role of circadian rhythms in carcinogenesis and tumor progression will enable us to better understand causes of cancer and how to treat them.
Publisher: American Chemical Society (ACS)
Date: 08-07-2005
DOI: 10.1021/OL051161G
Abstract: Described are the syntheses of 14 derivatives of the natural product Sansalvamide A, where two are more active against HCT 116 colon cancer cell lines than the natural product. These derivatives were synthesized using a combinatorial-type strategy that permits elucidation of the amino acid role in the cytotoxicity, and they lay the groundwork for development of new anticancer agents. [structure: see text]
Publisher: Elsevier BV
Date: 11-2004
Publisher: Oxford University Press (OUP)
Date: 27-07-2022
Abstract: Intermittent hypoxia is a key mechanism linking Obstructive Sleep Apnea (OSA) to cardiovascular disease (CVD). Oximetry analysis could enhance understanding of which OSA phenotypes are associated with CVD risk. The aim of this study was to compare associations of different oximetry patterns with incident CVD in men and women with OSA. Sleep Heart Health Study data were used for analysis. n = 2878 Participants (51.8% female mean age 63.5 ± 10.5 years) with OSA (Apnea Hypopnea Index [AHI] ≥ 5 events/h) and no pre-existing CVD at baseline or within the first 2 years of follow-up were included. Four oximetry analysis approaches were applied: desaturation characteristics, time series analysis, power spectral density, and non-linear analysis. Thirty-one resulting oximetry patterns were compared to incident CVD using proportional hazards regression models adjusted for age, race, smoking, BMI, and sex. There were no associations between OSA oximetry patterns and incident CVD in the total s le or in men. In women, there were some associations between incident CVD and time series analysis (e.g. SpO2 distribution standard deviation, HR 0.81, 95% CI 0.68–0.96, p = 0.014) and power spectral density oximetry patterns (e.g. Full frequency band mean HR 0.75 95% CI 0.59–0.95 p = 0.015). Comprehensive comparison of baseline oximetry patterns in OSA found none were related to development of CVD. There were no standout in idual oximetry patterns that appear to be candidates for CVD risk phenotyping in OSA, but some showed marginal relationships with CVD risk in women. Further work is required to understand whether OSA phenotypes can be used to predict susceptibility to cardiovascular disease.
Publisher: Wiley
Date: 11-07-2020
DOI: 10.1111/FEBS.15463
Publisher: American Chemical Society (ACS)
Date: 10-09-2005
DOI: 10.1021/OL0517325
Publisher: Springer Science and Business Media LLC
Date: 30-08-2016
DOI: 10.1038/NCOMMS12579
Abstract: Protein disulfide isomerase (PDI) is an oxidoreductase essential for folding proteins in the endoplasmic reticulum. The domain structure of PDI is a – b – b′ – x – a′ , wherein the thioredoxin-like a and a′ domains mediate disulfide bond shuffling and b and b′ domains are substrate binding. The b′ and a′ domains are connected via the x-linker, a 19-amino-acid flexible peptide. Here we identify a class of compounds, termed bepristats, that target the substrate-binding pocket of b′ . Bepristats reversibly block substrate binding and inhibit platelet aggregation and thrombus formation in vivo . Ligation of the substrate-binding pocket by bepristats paradoxically enhances catalytic activity of a and a′ by displacing the x-linker, which acts as an allosteric switch to augment reductase activity in the catalytic domains. This substrate-driven allosteric switch is also activated by peptides and proteins and is present in other thiol isomerases. Our results demonstrate a mechanism whereby binding of a substrate to thiol isomerases enhances catalytic activity of remote domains.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 02-02-2018
Abstract: We demonstrate mechanochemical regulation of platelet adhesion to von Willebrand factor in thrombosis and hemostasis.
Publisher: Mary Ann Liebert Inc
Date: 20-05-2013
Abstract: Protein action in nature is largely controlled by the level of expression and by post-translational modifications. Post-translational modifications result in a proteome that is at least two orders of magnitude more erse than the genome. There are three basic types of post-translational modifications: covalent modification of an amino acid side chain, hydrolytic cleavage or isomerization of a peptide bond, and reductive cleavage of a disulfide bond. This review addresses the modification of disulfide bonds. Protein disulfide bonds perform either a structural or a functional role, and there are two types of functional disulfide: the catalytic and allosteric bonds. The allosteric disulfide bonds control the function of the mature protein in which they reside by triggering a change when they are cleaved. The change can be in ligand binding, substrate hydrolysis, proteolysis, or oligomer formation. The allosteric disulfides are cleaved by oxidoreductases or by thiol/disulfide exchange, and the configurations of the disulfides and the secondary structures that they link share some recurring features. How these bonds are being identified using bioinformatics and experimental screens and what the future holds for this field of research are also discussed.
Publisher: American Chemical Society (ACS)
Date: 20-04-2015
DOI: 10.1021/JACS.5B02156
Publisher: MDPI AG
Date: 06-07-2021
DOI: 10.3390/IJMS22147265
Abstract: As the cornerstone of high-grade glioma (HGG) treatment, radiotherapy temporarily controls tumor cells via inducing oxidative stress and subsequent DNA breaks. However, almost all HGGs recur within months. Therefore, it is important to understand the underlying mechanisms of radioresistance, so that novel strategies can be developed to improve the effectiveness of radiotherapy. While currently poorly understood, radioresistance appears to be predominantly driven by altered metabolism and hypoxia. Glucose is a central macronutrient, and its metabolism is rewired in HGG cells, increasing glycolytic flux to produce energy and essential metabolic intermediates, known as the Warburg effect. This altered metabolism in HGG cells not only supports cell proliferation and invasiveness, but it also contributes significantly to radioresistance. Several metabolic drugs have been used as a novel approach to improve the radiosensitivity of HGGs, including dichloroacetate (DCA), a small molecule used to treat children with congenital mitochondrial disorders. DCA reverses the Warburg effect by inhibiting pyruvate dehydrogenase kinases, which subsequently activates mitochondrial oxidative phosphorylation at the expense of glycolysis. This effect is thought to block the growth advantage of HGGs and improve the radiosensitivity of HGG cells. This review highlights the main features of altered glucose metabolism in HGG cells as a contributor to radioresistance and describes the mechanism of action of DCA. Furthermore, we will summarize recent advances in DCA’s pre-clinical and clinical studies as a radiosensitizer and address how these scientific findings can be translated into clinical practice to improve the management of HGG patients.
Publisher: IEEE
Date: 07-2020
Publisher: American Physiological Society
Date: 10-2018
DOI: 10.1152/AJPREGU.00036.2018
Abstract: Obstructive sleep apnea (OSA) is common and linked to a variety of poor health outcomes. A key modulator of this disease is nocturnal intermittent hypoxia. There is striking epidemiological evidence that patients with OSA have higher rates of cancer and cancer mortality. Small-animal models demonstrate an important role for systemic intermittent hypoxia in tumor growth and metastasis, yet the underlying mechanisms are poorly understood. Emerging data indicate that intermittent hypoxia activates the hypoxic response and inflammatory pathways in a manner distinct from chronic hypoxia. However, there is significant heterogeneity in published methods for modeling hypoxic conditions, which are often lacking in physiological relevance. This is particularly important for studying key transcriptional mediators of the hypoxic and inflammatory responses such as hypoxia-inducible factor (HIF) and NF-κB. The relationship between HIF, the molecular clock, and circadian rhythm may also contribute to cancer risk in OSA. Building accurate in vitro models of intermittent hypoxia reflective of OSA is challenging but necessary to better elucidate underlying molecular pathways.
Publisher: Bio-Protocol, LLC
Date: 2019
Publisher: Elsevier BV
Date: 11-2022
Publisher: Wiley
Date: 17-10-2021
DOI: 10.1002/EHF2.13631
Abstract: Sleep apnoea and congestive heart failure (CHF) commonly co‐exist, but their interaction is unclear. Metabolomics may clarify their interaction and relationships to outcome. We assayed 372 circulating metabolites and lipids in 1919 and 1524 participants of the Framingham Heart Study (FHS) (mean age 54 ± 10 years, 53% women) and Women's Health Initiative (WHI) (mean age 67 ± 7 years), respectively. We used linear and Cox regression to relate plasma concentrations of metabolites and lipids to echocardiographic parameters CHF and its subtypes heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) and sleep indices. Adenine dinucleotide phosphate (ADP) associated with left ventricular (LV) fractional shortening phosphocreatine with LV wall thickness lysosomal storage molecule sphingomyelin 18:2 with LV mass and nicotine metabolite cotinine with time spent with an oxygen saturation less than 90% ( β = 2.3 min, P = 2.3 × 10 −5 ). Pro‐hypertrophic metabolite hydroxyglutarate partly mediated the association between LV wall thickness and HFpEF. Central sleep apnoea was significantly associated with HFpEF ( P = 0.03) but not HFrEF ( P = 0.5). There were three significant metabolite canonical variates, one of which conferred protection from cardiovascular death [hazard ratio = 0.3 (0.11, 0.81), P = 0.02]. Energetic metabolites were associated with cardiac function energy‐ and lipid‐storage metabolites with LV wall thickness and mass plasma levels of nicotine metabolite cotinine were associated with increased time spent with a sleep oxygen saturation less than 90%, a clinically significant marker of outcome, indicating a significant hazard for smokers who have sleep apnoea.
Publisher: Springer US
Date: 2008
Publisher: Cold Spring Harbor Laboratory
Date: 24-01-2019
DOI: 10.1101/521989
Abstract: Hypoxia Inducible Factor (HIF) is a transcription factor activated by low oxygen, which is common in solid tumours. HIF controls the expression of genes involved in angiogenesis, chemotherapy resistance and metastasis. The chaperone HSP90 (Heat Shock Protein 90) stabilizes the subunit HIF-1α and prevents degradation. Previously identified HSP90 inhibitors bind to the N-terminal pocket of HSP90 which blocks binding to HIF-1α, and produces HIF-1α degradation. N-terminal inhibitors have failed in the clinic as single therapy treatments due in part because they induce a heat shock response, which increases chemotherapy resistance. SM molecules are HSP90 inhibitors that bind to the C-terminus and do not activate the heat shock response. The effects of C-terminal HSP90 inhibitors on HIF-1α are unreported. Herein we show that SM compounds block binding between HSP90 and HIF-1α, leading to HIF-1α degradation through the proteasome using the PHD VHL pathway in hypoxic conditions. The SM compounds decrease HIF-1α target gene expression at the mRNA and protein level under hypoxia in colorectal cancer cells, leading to cell death, without inducing a heat shock response. Our results suggest that targeting the C-terminus of HSP90 blocks the hypoxic response and may be an effective anti-cancer strategy.
Publisher: American Society of Hematology
Date: 27-03-2014
DOI: 10.1182/BLOOD-2014-01-549816
Abstract: Most proteins in nature are chemically modified after they are made to control how, when, and where they function. The 3 core features of proteins are posttranslationally modified: amino acid side chains can be modified, peptide bonds can be cleaved or isomerized, and disulfide bonds can be cleaved. Cleavage of peptide bonds is a major mechanism of protein control in the circulation, as exemplified by activation of the blood coagulation and complement zymogens. Cleavage of disulfide bonds is emerging as another important mechanism of protein control in the circulation. Recent advances in our understanding of control of soluble blood proteins and blood cell receptors by functional disulfide bonds is discussed as is how these bonds are being identified and studied.
Publisher: Wiley
Date: 16-06-2010
DOI: 10.3322/CAAC.20075
Publisher: Elsevier BV
Date: 11-2013
Publisher: Wiley
Date: 24-04-2022
Abstract: Immune checkpoint inhibition with PD‐1/PD‐L1 blockade is a promising area in the field of anti‐cancer therapy. Although clinical data have revealed success of PD‐1/PD‐L1 blockade as monotherapy or in combination with CTLA‐4 or chemotherapy, the combination with radiotherapy could further boost anti‐tumour immunity and enhance clinical outcomes due to the immunostimulatory effects of radiation. However, the synergistic combination of PD‐1/PD‐L1 blockade and radiotherapy can be challenged by the complex nature of the tumour microenvironment (TME), including the presence of tumour hypoxia. Hypoxia is a major barrier to the effectiveness of both radiotherapy and PD‐1/PD‐L1 blockade immunotherapy. Thus, targeting the hypoxic TME is an attractive strategy to enhance the efficacy of the combination. Addition of compounds that directly or indirectly reduce hypoxia, to the combination of PD‐1/PD‐L1 inhibitors and radiotherapy may optimize the success of the combination and improve therapeutic outcomes. In this review, we will discuss the synergistic combination of PD‐1/PD‐L1 blockade and radiotherapy and highlight the role of hypoxic TME in impeding the success of both therapies. In addition, we will address the potential approaches for targeting tumour hypoxia and how exploiting these strategies could benefit the combination of PD‐1/PD‐L1 blockade and radiotherapy.
Publisher: IEEE
Date: 11-2021
Publisher: Springer Science and Business Media LLC
Date: 28-04-2014
Abstract: The downstream targets of hypoxia inducible factor-1 alpha (HIF-1α) play an important role in tumor progression and angiogenesis. Therefore, inhibition of HIF-mediated transcription has potential in the treatment of cancer. One attractive strategy for inhibiting HIF activity is the disruption of the HIF-1α 300 complex, as p300 is a crucial coactivator of hypoxia-inducible transcription. Several members of the epidithiodiketopiperazine (ETP) family of natural products have been shown to disrupt the HIF-1α 300 complex in vitro namely, gliotoxin, chaetocin, and chetomin. Here, we further characterized the molecular mechanisms underlying the antiangiogenic and antitumor effects of these ETPs using a preclinical model of prostate cancer. In the rat aortic ring angiogenesis assay, gliotoxin, chaetocin, and chetomin significantly inhibited microvessel outgrowth at a GI 50 of 151, 8, and 20 nM, respectively. In vitro co-immunoprecipitation studies in prostate cancer cell extracts demonstrated that these compounds disrupted the HIF-1α 300 complex. The downstream effects of inhibiting the HIF-1α 300 interaction were evaluated by determining HIF-1α target gene expression at the mRNA and protein levels. Dose-dependent decreases in levels of secreted VEGF were detected by ELISA in the culture media of treated cells, and the subsequent downregulation of VEGFA , LDHA , and ENO1 HIF-1α target genes were confirmed by semi-quantitative real-time PCR. Finally, treatment with ETPs in mice bearing prostate tumor xenografts resulted in significant inhibition of tumor growth. These results suggest that directly targeting the HIF-1α 300 complex with ETPs may be an effective approach for inhibiting angiogenesis and tumor growth.
Publisher: MDPI AG
Date: 21-01-2019
DOI: 10.3390/IJMS20020445
Abstract: Obstructive sleep apnea (OSA) affects a significant proportion of the population and is linked to increased rates of cancer development and a worse cancer outcome. OSA is characterized by nocturnal intermittent hypoxia and animal models of OSA-like intermittent hypoxia show increased tumor growth and metastasis. Advanced tumors typically have regions of chronic hypoxia, activating the transcription factor, HIF-1, which controls the expression of genes involved in cancer progression. Rapid intermittent hypoxia from OSA has been proposed to increase HIF-1 activity and this may occur in tumors. The effect of exposing a developing tumor to OSA-like intermittent hypoxia is largely unknown. We have built a cell-based model of physiological OSA tissue oxygenation in order to study the effects of intermittent hypoxia in HCT116 colorectal cancer cells. We found that HIF-1α increases following intermittent hypoxia and that the expression of HIF-target genes increases, including those involved in glycolysis, the hypoxic pathway and extracellular matrix remodeling. Expression of these genes acts as a ‘hypoxic’ signature which is associated with a worse prognosis. The total dose of hypoxia determined the magnitude of change in the hypoxic signature rather than the frequency or duration of hypoxia-reoxygenation cycles per se. Finally, transcription of HIF1A mRNA differs in response to chronic and intermittent hypoxia suggesting that HIF-1α may be regulated at the transcriptional level in intermittent hypoxia and not just by the post-translational oxygen-dependent degradation pathway seen in chronic hypoxia.
Publisher: Springer New York
Date: 2019
DOI: 10.1007/978-1-4939-9187-7_5
Abstract: The redox potential of a protein disulphide bond is one of the most important factors for determining the role of a disulphide bond. Disulphide bonds can have a stabilizing role for the structure of a protein or they can play a functional role which can regulate protein bioactivity. Determining the redox potential of disulphides can help distinguish the functional from the structural disulphide bonds. In this chapter, two methods for determining the redox potential of a protein disulphide bond are described. The first method uses maleimide-biotin labeling of free cysteine thiols and western blot densitometry to determine the fraction of reduced disulphide bond under various redox-buffering conditions. The second method uses differential cysteine labeling and tandem mass spectrometry to determine the redox potential.
Publisher: Springer Science and Business Media LLC
Date: 14-07-2023
Publisher: Cold Spring Harbor Laboratory
Date: 09-01-2019
DOI: 10.1101/515718
Abstract: Blood coagulation factor IXa (FIXa) activates factor X that leads to thrombin and fibrin formation and a stable thrombus. FIXa catalytic efficiency is markedly enhanced when bound to the co-factor, factor VIII (FVIII), and a negatively charged phospholipid surface in the tenase complex. Small redox active peptides and protein oxidoreductases have been shown previously to have some FIXa co-factor activity and thiol modifying agents have been reported to influence FVIII activity. These observations suggested that FIXa might contain an allosteric disulfide that is regulated by FVIII. This idea was tested by measuring the influence of FVIII on the redox state of FIXa disulfide bonds and the effect of plasma oxidoreductases on FIXa activity. The redox state of nine of the 11 disulfide bonds in FIXa was measured using differential cysteine labelling and mass spectrometry and all were oxidized in the protein, and this did not change upon binding of the enzyme to FVIII. All eight disulfide bonds in FVIII were also predominantly oxidized and this did not appreciably change upon FIXa binding. In addition, relevant protein reductants in the circulation inhibited rather than activated FIXa activity. In conclusion, we found no evidence that the co-factor function of FVIII involves a change in the redox state of one or more FIXa disulfide bonds.
Publisher: Cold Spring Harbor Laboratory
Date: 26-07-2021
DOI: 10.1101/2021.07.25.453726
Abstract: Cellular oxygen-sensing pathways are primarily regulated by hypoxia inducible factor-1 (HIF-1) in chronic hypoxia and are well studied. Intermittent hypoxia also occurs in many pathological conditions, yet little is known about its biological effects. In this study, we investigated how two proposed cellular oxygen sensing systems, HIF-1 and KDM4A-C, respond to cells exposed to intermittent hypoxia and compared to chronic hypoxia. We found that intermittent hypoxia increases HIF-1 activity through a pathway distinct from chronic hypoxia, involving the KDM4A, -B and -C histone lysine demethylases. Intermittent hypoxia increases the quantity and activity of KDM4A-C resulting in a decrease in H3K9 methylation. This contrasts with chronic hypoxia, which decreases KDM4A-C activity, leading to hypermethylation of H3K9. Demethylation of histones bound to the HIF1A gene in intermittent hypoxia increases HIF1A mRNA expression, which has the downstream effect of increasing overall HIF-1 activity and expression of HIF target genes. This study highlights how multiple oxygen-sensing pathways can interact to regulate and fine tune the cellular hypoxic response depending on the period and length of hypoxia.
Publisher: Elsevier BV
Date: 09-2009
Publisher: American Physiological Society
Date: 09-2020
DOI: 10.1152/AJPCELL.00305.2020
Abstract: Humans have internal circadian clocks that ensure that important physiological functions occur at specific times of the day. These molecular clocks are regulated at the genomic level and exist in most cells of the body. Multiple circadian resetting cues have been identified, including light, temperature, and food. Recently, oxygen has been identified as a resetting cue, and emerging science indicates that this occurs through interactions at the cellular level between the circadian transcription-translation feedback loop and the hypoxia-inducible pathway (hypoxia-inducible factor subject of the 2019 Nobel Prize in Physiology or Medicine). This review will cover recently identified relationships between HIF and proteins of the circadian clock. Interactions between the circadian clock and hypoxia could have wide-reaching implications for human diseases, and understanding the molecular mechanisms regulating these overlapping pathways may open up new strategies for drug discovery.
Publisher: Springer Science and Business Media LLC
Date: 17-05-2017
DOI: 10.1038/NCOMMS15245
Abstract: Lambda interferons ( IFNL , IFN-λ) are pro-inflammatory cytokines important in acute and chronic viral infection. Single-nucleotide polymorphisms rs12979860 and rs8099917 within the IFNL gene locus predict hepatitis C virus (HCV) clearance, as well as inflammation and fibrosis progression in viral and non-viral liver disease. The underlying mechanism, however, is not defined. Here we show that the rs12979860 CC genotype correlates with increased hepatic metallothionein expression through increased systemic zinc levels. Zinc interferes with IFN-λ3 binding to IFNL receptor 1 (IFNLR1), resulting in decreased antiviral activity and increased viral replication (HCV, influenza) in vitro . HCV patients with high zinc levels have low hepatocyte antiviral and inflammatory gene expression and high viral loads, confirming the inhibitory role of zinc in vivo . We provide the first evidence that zinc can act as a potent and specific inhibitor of IFN-λ3 signalling and highlight its potential as a target of therapeutic intervention for IFN-λ3-mediated chronic disease.
Publisher: Elsevier BV
Date: 04-2015
Publisher: American Chemical Society (ACS)
Date: 03-05-2016
Publisher: Cell Physiol Biochem Press GmbH and Co KG
Date: 06-09-2019
DOI: 10.33594/000000152
Abstract: Hypoxia Inducible Factor-1α (HIF-1α) is involved in cancer progression and is stabilized by the chaperone HSP90 (Heat Shock Protein 90), preventing degradation. Previously identified HSP90 inhibitors bind to the N-terminal pocket of HSP90, which blocks binding to HIF-1α and induces HIF-1α degradation. N-terminal inhibitors have failed in the clinic as single therapy treatments partially because they induce a heat shock response. SM molecules are HSP90 inhibitors that bind to the C-terminus of HSP90 and do not induce a heat shock response. The effects of these C-terminal inhibitors on HIF-1α are unreported. HCT116, MDA-MB-231, PC3, and HEK293T cells were treated with HSP90 inhibitors. qRT-PCR and western blotting was performed to assess mRNA and protein levels of HIF-1α, HSP- and RACK1-related genes. siRNA was used to knockdown RACK1, while MG262 was used to inhibit proteasome activity. Dimethyloxalylglycine (DMOG) was used to inhibit activity of the prolyl hydroxylases (PHDs). Anti-angiogenic activity of HSP90 inhibitors was assessed using a HUVEC tubule formation assay. We show that SM compounds decrease HIF-1α target expression at the mRNA and protein level under hypoxia in colorectal, breast and prostate cancer cells, leading to cell death, without inducing a heat shock response. Surprisingly, we found that when the C-terminal of HSP90 is inhibited, HIF-1α degradation occurs through the proteasome and prolyl hydroxylases in an oxygen-dependent manner even in very low levels of oxygen (tumor hypoxia levels). RACK1 was not required for proteasomal degradation of HIF-1α. Our results suggest that by targeting the C-terminus of HSP90 we can exploit the prolyl hydroxylase and proteasome pathway to induce HIF-1α degradation in hypoxic tumors.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Kristina Cook.