bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2020–04–12
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. H2A monoubiquitination links glucose availability to epigenetic regulation of the endoplasmic reticulum stress response and cancer cell death.
  2. Melanoma-specific bcl-2 promotes a protumoral M2-like phenotype by tumor-associated macrophages.
  3. Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy.
  4. Hypoxia regulates the differentiation and anti-tumor effector functions of γδT cells in oral cancer.
  5. Glycolysis: a key player in the inflammatory response.
  6. The metabolic response to inflammation in astrocytes is regulated by nuclear factor-kappa B signaling.
  7. High cell density increases glioblastoma cell viability under glucose deprivation via degradation of the cystine/glutamate transporter xCT (SLC7A11).
  8. Annexin A2-STAT3-Oncostatin M receptor axis drives phenotypic and mesenchymal changes in glioblastoma.
  1. Cancer Res. 2020 Apr 09. pii: canres.3580.2019. [Epub ahead of print]
    H2A monoubiquitination links glucose availability to epigenetic regulation of the endoplasmic reticulum stress response and cancer cell death.
    Yilei Zhang, Jiejun Shi, Xiaoguang Liu, Zhenna Xiao, Guang Lei, Hyemin Lee, Pranavi Koppula, Weijie Cheng, Chao Mao, Li Zhuang, Li Ma, Wei Li, Boyi Gan.
      Epigenetic regulation of gene transcription has been shown to coordinate with nutrient availability, yet the mechanisms underlying this coordination remain incompletely understood. Here we show that glucose starvation suppresses histone 2A K119 monoubiquitination (H2Aub), a histone modification that correlates with gene repression. Glucose starvation suppressed H2Aub levels independently of energy stress-mediated AMPK activation and possibly through NADPH depletion and subsequent inhibition of BMI1, an integral component of polycomb repressive complex 1 (PRC1) that catalyzes H2Aub on chromatin. Integrated transcriptomic and epigenomic analyses linked glucose starvation-mediated H2Aub repression to the activation of genes involved in the endoplasmic reticulum (ER) stress response. We further showed that this epigenetic mechanism has a role in glucose starvation-induced cell death and that pharmacologic inhibition of glucose transporter 1 (GLUT1) and PRC1 synergistically promoted ER stress and suppressed tumor growth in vivo. Together, these results reveal a hitherto unrecognized epigenetic mechanism coupling glucose availability to the ER stress response.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-3580
  2. J Immunother Cancer. 2020 Apr;pii: e000489. [Epub ahead of print]8(1):
    Melanoma-specific bcl-2 promotes a protumoral M2-like phenotype by tumor-associated macrophages.
    Marta Di Martile, Valentina Farini, Francesca Maria Consonni, Daniela Trisciuoglio, Marianna Desideri, Elisabetta Valentini, Simona D'Aguanno, Maria Grazia Tupone, Simonetta Buglioni, Cristiana Ercolani, Enzo Gallo, Bruno Amadio, Irene Terrenato, Maria Laura Foddai, Antonio Sica, Donatella Del Bufalo.
       BACKGROUND: A bidirectional crosstalk between tumor cells and the surrounding microenvironment contributes to tumor progression and response to therapy. Our previous studies have demonstrated that bcl-2 affects melanoma progression and regulates the tumor microenvironment. The aim of this study was to evaluate whether bcl-2 expression in melanoma cells could influence tumor-promoting functions of tumor-associated macrophages, a major constituent of the tumor microenvironment that affects anticancer immunity favoring tumor progression.
    METHODS: THP-1 monocytic cells, monocyte-derived macrophages and melanoma cells expressing different levels of bcl-2 protein were used. ELISA, qRT-PCR and Western blot analyses were used to evaluate macrophage polarization markers and protein expression levels. Chromatin immunoprecipitation assay was performed to evaluate transcription factor recruitment at specific promoters. Boyden chamber was used for migration experiments. Cytofluorimetric and immunohistochemical analyses were carried out to evaluate infiltrating macrophages and T cells in melanoma specimens from patients or mice.
    RESULTS: Higher production of tumor-promoting and chemotactic factors, and M2-polarized activation was observed when macrophages were exposed to culture media from melanoma cells overexpressing bcl-2, while bcl-2 silencing in melanoma cells inhibited the M2 macrophage polarization. In agreement, the number of melanoma-infiltrating macrophages in vivo was increased, in parallel with a greater expression of bcl-2 in tumor cells. Tumor-derived interleukin-1β has been identified as the effector cytokine of bcl-2-dependent macrophage reprogramming, according to reduced tumor growth, decreased number of M2-polarized tumor-associated macrophages and increased number of infiltrating CD4+IFNγ+ and CD8+IFNγ+ effector T lymphocytes, which we observed in response to in vivo treatment with the IL-1 receptor antagonist kineret. Finally, in tumor specimens from patients with melanoma, high bcl-2 expression correlated with increased infiltration of M2-polarized CD163+ macrophages, hence supporting the clinical relevance of the crosstalk between tumor cells and microenvironment.
    CONCLUSIONS: Taken together, our results show that melanoma-specific bcl-2 controls an IL-1β-driven axis of macrophage diversion that establishes tumor microenvironmental conditions favoring melanoma development. Interfering with this pathway might provide novel therapeutic strategies.
    Keywords:  macrophages; melanoma; tumor microenvironment
    DOI:  https://doi.org/10.1136/jitc-2019-000489
  3. Front Oncol. 2020 ;10 231
    Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy.
    Fátima Baltazar, Julieta Afonso, Marta Costa, Sara Granja.
      To sustain their high proliferation rates, most cancer cells rely on glycolytic metabolism, with production of lactic acid. For many years, lactate was seen as a metabolic waste of glycolytic metabolism; however, recent evidence has revealed new roles of lactate in the tumor microenvironment, either as metabolic fuel or as a signaling molecule. Lactate plays a key role in the different models of metabolic crosstalk proposed in malignant tumors: among cancer cells displaying complementary metabolic phenotypes and between cancer cells and other tumor microenvironment associated cells, including endothelial cells, fibroblasts, and diverse immune cells. This cell metabolic symbiosis/slavery supports several cancer aggressiveness features, including increased angiogenesis, immunological escape, invasion, metastasis, and resistance to therapy. Lactate transport is mediated by the monocarboxylate transporter (MCT) family, while another large family of G protein-coupled receptors (GPCRs), not yet fully characterized in the cancer context, is involved in lactate/acidosis signaling. In this mini-review, we will focus on the role of lactate in the tumor microenvironment, from metabolic affairs to signaling, including the function of lactate in the cancer-cancer and cancer-stromal shuttles, as well as a signaling oncometabolite. We will also review the prognostic value of lactate metabolism and therapeutic approaches designed to target lactate production and transport.
    Keywords:  GPR81; lactate; lactate shuttles; metabolic fuel; monocarboxylate transporters; signaling molecule; warburg effect
    DOI:  https://doi.org/10.3389/fonc.2020.00231
  4. Clin Exp Immunol. 2020 Apr 07.
    Hypoxia regulates the differentiation and anti-tumor effector functions of γδT cells in oral cancer.
    Shalini Kashipathi Sureshbabu, Devendra Chaukar, Shubhada Vivek Chiplunkar.
      Hypoxia within the tumor microenvironment (TME) is a key factor contributing to immunosuppression in tumors, co-relating with poor treatment outcome and decreased overall survival in advanced oral cancer (OC) patients. Vδ2 is a dominant subset of gamma delta Tcells(γδT cells) present in the peripheral blood which exhibits potent anti-tumor cytotoxicity and is evolving as a key player of anti-cancer cellular therapy. However, the fate of γδT cells in hypoxic oral tumors remains elusive. In the present study, we compared the effect of hypoxia(1% O2 ) and normoxia(21% O2 ) on the expansion, proliferation, activation status,cytokine secretion and cytotoxicity of γδT cells isolated from OC patients and HI. Hypoxia exposed γδT cells exhibited reduced cytotoxicity against oral tumor cells. Our data demonstrated that hypoxia reduces the calcium efflux and the expression of degranulation marker CD107a in γδT cells which explains the decreased anti-tumor cytotoxicity of γδT cells observed under hypoxia. Hypoxia exposed γδT cells differentiated to γδT17 cells which corroborated our observations of increased γδT17 cells observed in the oral tumors. Co-culture of γδT cells with CD8 T cells in presence of hypoxia showed that PDL1high γδT cells brought about apoptosis of PD1high CD8 Tcells which could be significantly reversed upon blocking PD1. Thus, future immunotherapeutic treatment modality for oral cancer may use a combined approach of blocking the PD-1/PDL1 signaling and targeting HIF1α which may help in reversing hypoxia-induced immunosuppression.
    Keywords:  Tumor microenvironment; hypoxia-induced immune dysfunction; γδT cells ,γδT17
    DOI:  https://doi.org/10.1111/cei.13436
  5. FEBS J. 2020 Apr 07.
    Glycolysis: a key player in the inflammatory response.
    Gonzalo Soto-Heredero, Manuel M Gómez de Las Heras, Enrique Gabandé-Rodríguez, Jorge Oller, María Mittelbrunn.
      The inflammatory response involves the activation of several cell types to fight insults caused by a plethora of agents, and to maintain the tissue homeostasis. On the one hand, cells involved in the pro-inflammatory response, such as inflammatory M1 macrophages, Th1 and Th17 lymphocytes or activated microglia must rapidly provide energy to fuel inflammation, which is essentially accomplished by glycolysis and high lactate production. On the other hand, regulatory T cells or M2 macrophages, which are involved in immune regulation and resolution of inflammation, preferentially use fatty acid oxidation through the TCA cycle as a main source for energy production. Here we discuss the impact of glycolytic metabolism at the different steps of the inflammatory response. Finally, we review a wide variety of molecular mechanisms which could explain the relationship between glycolytic metabolites and the pro-inflammatory phenotype, including signalling events, epigenetic remodelling, post-transcriptional regulation and post-translational modifications. Inflammatory processes are a common feature of many age-associated diseases, such as cardiovascular and neurodegenerative disorders. The finding that immunometabolism could be a master regulator of inflammation broadens the avenue for treating inflammation-related pathologies through the manipulation of the vascular and immune cell metabolism.
    Keywords:  Ageing; Immune cells; Immunometabolism; Inflammation; Metabolites
    DOI:  https://doi.org/10.1111/febs.15327
  6. Glia. 2020 Apr 10.
    The metabolic response to inflammation in astrocytes is regulated by nuclear factor-kappa B signaling.
    Josephine L Robb, Nadia A Hammad, Paul G Weightman Potter, John K Chilton, Craig Beall, Kate L J Ellacott.
      Inflammation and metabolism are intrinsically linked with inflammatory stimuli inducing metabolic changes in cells and, in turn, metabolic capacity determining cellular inflammatory responses. Although well characterized in peripheral immune cells there is comparatively less known about these "immunometabolic" responses in astrocytes. In this study, we tested the hypothesis that the astrocytic inflammatory response driven by nuclear factor-kappa B (NF-κB) signaling is dependent on glycolytic metabolism. Using mouse primary cortical astrocyte cultures, we assessed changes in cellular metabolism after exposure to lipopolysaccharide (LPS), with cytokine ELISAs and immunoblotting being used to measure inflammatory responses. Results indicate temporally distinct metabolic adaptations to pro-inflammatory stimulation in astrocytes: 3 hr LPS treatment increased glycolysis but did not alter mitochondrial metabolism, while following 24 hr of LPS treatment we observed increased oxidative phosphorylation, and decreased glycolytic capacity and glucose uptake, partly due to reduced glucose transporter 1 expression. Inhibition of NF-κB signaling with the IKK-beta inhibitor TPCA-1 prevented the LPS induced changes to glycolysis and oxidative phosphorylation. Furthermore, TPCA-1 treatment altered both glycolysis and oxidative phosphorylation independently from inflammatory stimulation, indicating a role for NF-κB signaling in regulation of basal metabolism in astrocytes. Inhibition of glycolysis with 2-deoxyglucose significantly attenuated LPS-induced cytokine release and NF-κB phosphorylation, indicating that intact glycolysis is required for the full inflammatory response to LPS. Together our data indicate that astrocytes display immunometabolic responses to acute LPS stimulation which may represent a potential therapeutic target for neuroinflammatory disorders.
    Keywords:  astrocyte; glycolysis; inflammation; metabolism; nuclear factor-kappa B
    DOI:  https://doi.org/10.1002/glia.23835
  7. J Biol Chem. 2020 Apr 07. pii: jbc.RA119.012213. [Epub ahead of print]
    High cell density increases glioblastoma cell viability under glucose deprivation via degradation of the cystine/glutamate transporter xCT (SLC7A11).
    Itsuki Yamaguchi, Shige H Yoshimura, Hironori Katoh.
      The the cystine/glutamate transporter system xc- consists of the light-chain subunit xCT (SLC7A11) and the heavy-chain subunit CD98 (4F2hc or SLC3A2) and exchanges extracellular cystine for intracellular glutamate at the plasma membrane. The imported cystine is reduced to cysteine and used for synthesis of glutathione, which is one of the most important antioxidants in cancer cells. Because cancer cells have increased levels of reactive oxygen species (ROS), xCT, being responsible for cystine-glutamate exchange, is overexpressed in many cancers, including glioblastoma. However, under glucose-limited conditions, xCT overexpression induces ROS accumulation and cell death. Here, we report that cell survival under glucose deprivation depends on cell density. We found that a high cell density (HD) down-regulates xCT levels and increases cell viability under glucose deprivation. We also found that growth of glioblastoma cells at HD inactivates mTOR, and that treatment with the mTOR inhibitor Torin 1 of cells grown at low density (LD) down-regulates xCT and inhibits glucose deprivation-induced cell death. The lysosome inhibitor bafilomycin A1 (BafA1) suppressed xCT down-regulation in HD-cultured glioblastoma cells and in Torin 1-treated cells grown at LD. Additionally, BafA1 exposure or ectopic xCT expression restored glucose deprivation-induced cell death at HD. These results suggest that HD inactivates mTOR and promotes lysosomal degradation of xCT, leading to improved glioblastoma cell viability under glucose-limited conditions. Our findings provide evidence that the control of xCT protein expression via lysosomal degradation is an important mechanism for metabolic adaptation in glioblastoma cells.
    Keywords:  amino acid transport; cancer biology; cell biology; cell death; lysosome
    DOI:  https://doi.org/10.1074/jbc.RA119.012213
  8. Acta Neuropathol Commun. 2020 Apr 05. 8(1): 42
    Annexin A2-STAT3-Oncostatin M receptor axis drives phenotypic and mesenchymal changes in glioblastoma.
    Yuji Matsumoto, Tomotsugu Ichikawa, Kazuhiko Kurozumi, Yoshihiro Otani, Atsushi Fujimura, Kentaro Fujii, Yusuke Tomita, Yasuhiko Hattori, Atsuhito Uneda, Nobushige Tsuboi, Keisuke Kaneda, Keigo Makino, Isao Date.
      Glioblastoma (GBM) is characterized by extensive tumor cell invasion, angiogenesis, and proliferation. We previously established subclones of GBM cells with distinct invasive phenotypes and identified annexin A2 (ANXA2) as an activator of angiogenesis and perivascular invasion. Here, we further explored the role of ANXA2 in regulating phenotypic transition in GBM. We identified oncostatin M receptor (OSMR) as a key ANXA2 target gene in GBM utilizing microarray analysis and hierarchical clustering analysis of the Ivy Glioblastoma Atlas Project and The Cancer Genome Atlas datasets. Overexpression of ANXA2 in GBM cells increased the expression of OSMR and phosphorylated signal transducer and activator of transcription 3 (STAT3) and enhanced cell invasion, angiogenesis, proliferation, and mesenchymal transition. Silencing of OSMR reversed the ANXA2-induced phenotype, and STAT3 knockdown reduced OSMR protein expression. Exposure of GBM cells to hypoxic conditions activated the ANXA2-STAT3-OSMR signaling axis. Mice bearing ANXA2-overexpressing GBM exhibited shorter survival times compared with control tumor-bearing mice, whereas OSMR knockdown increased the survival time and diminished ANXA2-mediated tumor invasion, angiogenesis, and growth. Further, we uncovered a significant relationship between ANXA2 and OSMR expression in clinical GBM specimens, and demonstrated their correlation with tumor histopathology and patient prognosis. Our results indicate that the ANXA2-STAT3-OSMR axis regulates malignant phenotypic changes and mesenchymal transition in GBM, suggesting that this axis is a promising therapeutic target to treat GBM aggressiveness.
    Keywords:  ANXA2; Glioblastoma; Invasion; Mesenchymal transition; OSMR
    DOI:  https://doi.org/10.1186/s40478-020-00916-7
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