ORCID Profile
0000-0002-4791-7292
Current Organisation
University of Nottingham
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Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22515507
Abstract: S3. HIF1α and hypoxia-dependent effects on transcription and protein levels.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22515516.V1
Abstract: S1. Blocking O-GlcNAcylation in vivo by inducing shOGT or alloxan treatment qualitatively reduces EZH2 immunoreactivity after irradiation.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22515504
Abstract: S4. Hypoxic regulation of glucose transporters and creatine kinases validation by PCR and western blot analysis.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22515510.V1
Abstract: S2. (A) Kaplan-Meier analysis of overall survival of 440 colon adenocarcinoma patients TGCA cohort. Patient group with highest quartile showed a reduced five-year survival. (B) Heatmap illustrating the correlative gene expression profile of creatine kinase enzymes (KCRU, KCRM, KCRB) and glucose transporters (GTR1, GTR3, GTR14) compared to 47 genes representing a "hypoxia signature" based on 337 CODREAD colorectal cancer patients.
Publisher: Proceedings of the National Academy of Sciences
Date: 20-07-2015
Abstract: Acidic pH may distinguish aggressive from more indolent cancers. The limitation on testing this hypothesis to date has been the difficulty of measuring acidic pH in cancers. Here we show that retention of the pH low insertion peptide (pHLIP) Variant 3 (Var3) reflects acidic pH. Using pHLIP Var3, we show its ability to detect cancer with a low false-positive rate in a genetically engineered model of murine breast cancer, paving the way for testing this probe in clinical situations.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22515492
Abstract: S7. WTN, KON, WTH, and KOH HCT116 cell proliferation after 5 days in two O2 conditions, 21% and 1% for cells knocked down for GTR3, GTR14, and HIF2α.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22515495.V1
Abstract: S6. Phosphocreatine/Creatine ratio per cell in WTN, KON, WTH, and KOH.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22515510
Abstract: S2. (A) Kaplan-Meier analysis of overall survival of 440 colon adenocarcinoma patients TGCA cohort. Patient group with highest quartile showed a reduced five-year survival. (B) Heatmap illustrating the correlative gene expression profile of creatine kinase enzymes (KCRU, KCRM, KCRB) and glucose transporters (GTR1, GTR3, GTR14) compared to 47 genes representing a "hypoxia signature" based on 337 CODREAD colorectal cancer patients.
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.CMET.2012.10.017
Abstract: Metabolic reprogramming of cancer cells provides energy and multiple intermediates critical for cell growth. Hypoxia in tumors represents a hostile environment that can encourage these transformations. We report that glycogen metabolism is upregulated in tumors in vivo and in cancer cells in vitro in response to hypoxia. In vitro, hypoxia induced an early accumulation of glycogen, followed by a gradual decline. Concordantly, glycogen synthase (GYS1) showed a rapid induction, followed by a later increase of glycogen phosphorylase (PYGL). PYGL depletion and the consequent glycogen accumulation led to increased reactive oxygen species (ROS) levels that contributed to a p53-dependent induction of senescence and markedly impaired tumorigenesis in vivo. Metabolic analyses indicated that glycogen degradation by PYGL is important for the optimal function of the pentose phosphate pathway. Thus, glycogen metabolism is a key pathway induced by hypoxia, necessary for optimal glucose utilization, which represents a targetable mechanism of metabolic adaptation.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22515486.V1
Abstract: Supplementary materials and methods
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22515507.V1
Abstract: S3. HIF1α and hypoxia-dependent effects on transcription and protein levels.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22515495
Abstract: S6. Phosphocreatine/Creatine ratio per cell in WTN, KON, WTH, and KOH.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.C.6541104
Abstract: Abstract Hypoxia-inducible factor 1α is a key regulator of the hypoxia response in normal and cancer tissues. It is well recognized to regulate glycolysis and is a target for therapy. However, how tumor cells adapt to grow in the absence of HIF1α is poorly understood and an important concept to understand for developing targeted therapies is the flexibility of the metabolic response to hypoxia via alternative pathways. We analyzed pathways that allow cells to survive hypoxic stress in the absence of HIF1α, using the HCT116 colon cancer cell line with deleted HIF1α versus control. Spheroids were used to provide a 3D model of metabolic gradients. We conducted a metabolomic, transcriptomic, and proteomic analysis and integrated the results. These showed surprisingly that in three-dimensional growth, a key regulatory step of glycolysis is Aldolase A rather than phosphofructokinase. Furthermore, glucose uptake could be maintained in hypoxia through upregulation of GLUT14, not previously recognized in this role. Finally, there was a marked adaptation and change of phosphocreatine energy pathways, which made the cells susceptible to inhibition of creatine metabolism in hypoxic conditions. Overall, our studies show a complex adaptation to hypoxia that can bypass HIF1α, but it is targetable and it provides new insight into the key metabolic pathways involved in cancer growth. Implications: Under hypoxia and HIF1 blockade, cancer cells adapt their energy metabolism via upregulation of the GLUT14 glucose transporter and creatine metabolism providing new avenues for drug targeting. /
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22515498
Abstract: S5. Statistical significance for mRNA PCR data.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22515519
Abstract: S8. WTN, KON, WTH, and KOH HCT116 cell proliferation after 5 days in two O2 conditions,21% and 1% for cells knocked down for GTR3, GTR14 , and HIF2α
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22515516
Abstract: S1. Blocking O-GlcNAcylation in vivo by inducing shOGT or alloxan treatment qualitatively reduces EZH2 immunoreactivity after irradiation.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22515519.V1
Abstract: S8. WTN, KON, WTH, and KOH HCT116 cell proliferation after 5 days in two O2 conditions,21% and 1% for cells knocked down for GTR3, GTR14 , and HIF2α
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22515498.V1
Abstract: S5. Statistical significance for mRNA PCR data.
Publisher: American Association for Cancer Research (AACR)
Date: 30-06-2016
DOI: 10.1158/0008-5472.CAN-15-1862
Abstract: Tumor hypoxia is associated clinically with therapeutic resistance and poor patient outcomes. One feature of tumor hypoxia is activated expression of carbonic anhydrase IX (CA9), a regulator of pH and tumor growth. In this study, we investigated the hypothesis that impeding the reuptake of bicarbonate produced extracellularly by CA9 could exacerbate the intracellular acidity produced by hypoxic conditions, perhaps compromising cell growth and viability as a result. In 8 of 10 cancer cell lines, we found that hypoxia induced the expression of at least one bicarbonate transporter. The most robust and frequent inductions were of the sodium-driven bicarbonate transporters SLC4A4 and SLC4A9, which rely upon both HIF1α and HIF2α activity for their expression. In cancer cell spheroids, SLC4A4 or SLC4A9 disruption by either genetic or pharmaceutical approaches acidified intracellular pH and reduced cell growth. Furthermore, treatment of spheroids with S0859, a small-molecule inhibitor of sodium-driven bicarbonate transporters, increased apoptosis in the cell lines tested. Finally, RNAi-mediated attenuation of SLC4A9 increased apoptosis in MDA-MB-231 breast cancer spheroids and dramatically reduced growth of MDA-MB-231 breast tumors or U87 gliomas in murine xenografts. Our findings suggest that disrupting pH homeostasis by blocking bicarbonate import might broadly relieve the common resistance of hypoxic tumors to anticancer therapy. Cancer Res 76(13) 3744–55. ©2016 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 31-05-2012
DOI: 10.1158/1078-0432.CCR-11-1877
Abstract: Purpose: Bevacizumab, an anti-VEGFA antibody, inhibits the developing vasculature of tumors, but resistance is common. Antiangiogenic therapy induces hypoxia and we observed increased expression of hypoxia-regulated genes, including carbonic anhydrase IX (CAIX), in response to bevacizumab treatment in xenografts. CAIX expression correlates with poor prognosis in most tumor types and with worse outcome in bevacizumab-treated patients with metastatic colorectal cancer, malignant astrocytoma, and recurrent malignant glioma. Experimental Design: We knocked down CAIX expression by short hairpin RNA in a colon cancer (HT29) and a glioblastoma (U87) cell line which have high hypoxic induction of CAIX and overexpressed CAIX in HCT116 cells which has low CAIX. We investigated the effect on growth rate in three-dimensional (3D) culture and in vivo, and examined the effect of CAIX knockdown in combination with bevacizumab. Results: CAIX expression was associated with increased growth rate in spheroids and in vivo. Surprisingly, CAIX expression was associated with increased necrosis and apoptosis in vivo and in vitro. We found that acidity inhibits CAIX activity over the pH range found in tumors (pK = 6.84), and this may be the mechanism whereby excess acid self-limits the build-up of extracellular acid. Expression of another hypoxia inducible CA isoform, CAXII, was upregulated in 3D but not two-dimensional culture in response to CAIX knockdown. CAIX knockdown enhanced the effect of bevacizumab treatment, reducing tumor growth rate in vivo. Conclusion: This work provides evidence that inhibition of the hypoxic adaptation to antiangiogenic therapy enhances bevacizumab treatment and highlights the value of developing small molecules or antibodies which inhibit CAIX for combination therapy. Clin Cancer Res 18(11) 3100–11. ©2012 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22515492.V1
Abstract: S7. WTN, KON, WTH, and KOH HCT116 cell proliferation after 5 days in two O2 conditions, 21% and 1% for cells knocked down for GTR3, GTR14, and HIF2α.
Publisher: Public Library of Science (PLoS)
Date: 12-02-2014
Publisher: American Association for Cancer Research (AACR)
Date: 07-2019
DOI: 10.1158/1541-7786.MCR-18-0315
Abstract: Under hypoxia and HIF1 blockade, cancer cells adapt their energy metabolism via upregulation of the GLUT14 glucose transporter and creatine metabolism providing new avenues for drug targeting.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22515489.V1
Abstract: S8. Hydrophilic metabolites detection and identification performed by LC/MS QTOF nanoflow using AMRT comparison.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22515489
Abstract: S8. Hydrophilic metabolites detection and identification performed by LC/MS QTOF nanoflow using AMRT comparison.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22515486
Abstract: Supplementary materials and methods
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22515504.V1
Abstract: S4. Hypoxic regulation of glucose transporters and creatine kinases validation by PCR and western blot analysis.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Alan McIntyre.