bims-stacyt 2020-03-08 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2020–03–08
ten papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Endoplasmic Reticulum Stress Signaling in Cancer Cells.
Chemical hypoxia induces pro-inflammatory signals in fat-laden hepatocytes and contributes to cellular crosstalk with Kupffer cells through extracellular vesicles.
Type I interferons and endoplasmic reticulum stress in health and disease.
Insulin-PI3K signalling: an evolutionarily insulated metabolic driver of cancer.
Proline biosynthesis is a vent for TGFβ-induced mitochondrial redox stress.
Infection-driven activation of transglutaminase 2 boosts glucose uptake and hexosamine biosynthesis in epithelial cells.
Targeting immunometabolism as an anti-inflammatory strategy.
Glucose regulates hypoxia-induced NLRP3 inflammasome activation in macrophages.
Tumor Microenvironment - Selective Pressures Boosting Cancer Progression.
Nucleotides released from palmitate-activated murine macrophages attract neutrophils.

Am J Pathol. 2020 Feb 26. pii: S0002-9440(20)30088-2. [Epub ahead of print]

Endoplasmic Reticulum Stress Signaling in Cancer Cells.

Scott A Oakes.

To survive, cancers cells must resist numerous internal and environmental insults associated with neoplasia that jeopardize proteostasis within the endoplasmic reticulum (ER). Solid and hematopoietic tumors often experience genomic instability, oncogene activation, increased protein secretion demands, and somatic mutations in proteins handled by the secretory pathway that impede their folding. Invasion or metastasis into foreign environments can expose tumor cells to hypoxia, oxidative stress, lack of growth signals, inadequate amino acid supplies, glucose deprivation, and lactic acidosis, all of which pose challenges for protein processing in the ER. Together, these conditions can promote the buildup of misfolded proteins in the ER to cause "ER stress," which then activates the unfolded protein response (UPR). An intracellular signaling network largely initiated by three ER transmembrane proteins, the UPR constantly surveils protein folding conditions within the ER lumen and when necessary initiates counteractive measures to maintain ER homeostasis. Under mild or moderate levels of ER stress, the homeostatic UPR (hUPR) sets in motion transcriptional and translational changes that promote cell adaption and survival. However, if these processes are unsuccessful at resolving ER stress, a terminal UPR (tUPR) program dominates and actively signals cell suicide. This article summarizes the mounting evidence that cancer cells are predisposed to ER stress and vulnerable to targeted interventions against ongoing UPR signaling.

DOI: https://doi.org/10.1016/j.ajpath.2020.01.010
Biochim Biophys Acta Mol Basis Dis. 2020 Feb 29. pii: S0925-4439(20)30098-3. [Epub ahead of print] 165753

Chemical hypoxia induces pro-inflammatory signals in fat-laden hepatocytes and contributes to cellular crosstalk with Kupffer cells through extracellular vesicles.

Alejandra Hernandez, Yana Geng, Rolando Sepulveda, Nancy Solis, Javiera Torres, Juan Pablo Arab, Francisco Barrera, Daniel Cabrera, Han Moshage, Marco Arrese.

   BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is associated to intermittent hypoxia (IH) and is an aggravating factor of non-alcoholic fatty liver disease (NAFLD). We investigated the effects of hypoxia in both in vitro and in vivo models of NAFLD.
METHODS: Primary rat hepatocytes treated with free fatty acids (FFA) were subjected to chemically induced hypoxia (CH) using the hypoxia-inducible factor-1 alpha (HIF-1α) stabilizer cobalt chloride (CoCl2). Triglyceride (TG) content, mitochondrial superoxide production, cell death rates, cytokine and inflammasome components gene expression and protein levels of cleaved caspase-1 were assessed. Also, Kupffer cells (KC) were treated with conditioned medium (CM) and extracellular vehicles (EVs) from hypoxic fat-laden hepatic cells. The choline deficient L-amino acid defined (CDAA)-feeding model used to assess the effects of IH on experimental NAFLD in vivo.
RESULTS: Hypoxia induced HIF-1α in cells and animals. Hepatocytes exposed to FFA and CoCl2 exhibited increased TG content and higher cell death rates as well as increased mitochondrial superoxide production and mRNA levels of pro-inflammatory cytokines and of inflammasome-components interleukin-1β, NLRP3 and ASC. Protein levels of cleaved caspase-1 increased in CH-exposed hepatocytes. CM and EVs from hypoxic fat-laden hepatic cells evoked a pro-inflammatory phenotype in KC. Livers from CDAA-fed mice exposed to IH exhibited increased mRNA levels of pro-inflammatory and inflammasome genes and increased levels of cleaved caspase-1.
CONCLUSION: Hypoxia promotes inflammatory signals including inflammasome/caspase-1 activation in fat-laden hepatocytes and contributes to cellular crosstalk with KC by release of EVs. These mechanisms may underlie the aggravating effect of OSAS on NAFLD. [Abstract word count: 257].

Keywords:  Fatty liver disease; Hepatology; Hypoxia, liver injury, steatosis, apoptosis; Nonalcoholic fatty liver disease

DOI:  https://doi.org/10.1016/j.bbadis.2020.165753
Int Rev Cell Mol Biol. 2020 ;pii: S1937-6448(19)30101-7. [Epub ahead of print]350 63-118

Type I interferons and endoplasmic reticulum stress in health and disease.

Jenny Sprooten, Abhishek D Garg.

  Type I interferons (IFNs) comprise of pro-inflammatory cytokines created, as well as sensed, by all nucleated cells with the main objective of blocking pathogens-driven infections. Owing to this broad range of influence, type I IFNs also exhibit critical functions in many sterile inflammatory diseases and immunopathologies, especially those associated with endoplasmic reticulum (ER) stress-driven signaling pathways. Indeed, over the years accumulating evidence has indicated that the presence of ER stress can influence the production, or sensing of, type I IFNs induced by perturbations like pattern recognition receptor (PRR) agonists, infections (bacterial, viral or parasitic) or autoimmunity. In this article we discuss the link between type I IFNs and ER stress in various diseased contexts. We describe how ER stress regulates type I IFNs production or sensing, or how type I IFNs may induce ER stress, in various circumstances like microbial infections, autoimmunity, diabetes, cancer and other ER stress-related contexts.

Keywords:  Chemokine; Danger signals; IRE1; Inflammation; Interferon-stimulated genes (ISGs); NF-κB; Oncolytic viruses; PERK; STING; Toll-like receptors (TLRs); Unfolded protein response (UPR)

DOI:  https://doi.org/10.1016/bs.ircmb.2019.10.004
Nat Rev Endocrinol. 2020 Mar 03.

Insulin-PI3K signalling: an evolutionarily insulated metabolic driver of cancer.

Benjamin D Hopkins, Marcus D Goncalves, Lewis C Cantley.

Cancer is driven by incremental changes that accumulate, eventually leading to oncogenic transformation. Although genetic alterations dominate the way cancer biologists think about oncogenesis, growing evidence suggests that systemic factors (for example, insulin, oestrogen and inflammatory cytokines) and their intracellular pathways activate oncogenic signals and contribute to targetable phenotypes. Systemic factors can have a critical role in both tumour initiation and therapeutic responses as increasingly targeted and personalized therapeutic regimens are used to treat patients with cancer. The endocrine system controls cell growth and metabolism by providing extracellular cues that integrate systemic nutrient status with cellular activities such as proliferation and survival via the production of metabolites and hormones such as insulin. When insulin binds to its receptor, it initiates a sequence of phosphorylation events that lead to activation of the catalytic activity of phosphoinositide 3-kinase (PI3K), a lipid kinase that coordinates the intake and utilization of glucose, and mTOR, a kinase downstream of PI3K that stimulates transcription and translation. When chronically activated, the PI3K pathway can drive malignant transformation. Here, we discuss the insulin-PI3K signalling cascade and emphasize its roles in normal cells (including coordinating cell metabolism and growth), highlighting the features of this network that make it ideal for co-option by cancer cells. Furthermore, we discuss how this signalling network can affect therapeutic responses and how novel metabolic-based strategies might enhance treatment efficacy for cancer.

DOI: https://doi.org/10.1038/s41574-020-0329-9
EMBO J. 2020 Mar 05. e103334

Proline biosynthesis is a vent for TGFβ-induced mitochondrial redox stress.

Simon Schwörer, Mirela Berisa, Sara Violante, Weige Qin, Jiajun Zhu, Ronald C Hendrickson, Justin R Cross, Craig B Thompson.

  The production and secretion of matrix proteins upon stimulation of fibroblasts by transforming growth factor-beta (TGFβ) play a critical role in wound healing. How TGFβ supports the bioenergetic cost of matrix protein synthesis is not fully understood. Here, we show that TGFβ promotes protein translation at least in part by increasing the mitochondrial oxidation of glucose and glutamine carbons to support the bioenergetic demand of translation. Surprisingly, we found that in addition to stimulating the entry of glucose and glutamine carbon into the TCA cycle, TGFβ induced the biosynthesis of proline from glutamine in a Smad4-dependent fashion. Metabolic manipulations that increased mitochondrial redox generation promoted proline biosynthesis, while reducing mitochondrial redox potential and/or ATP synthesis impaired proline biosynthesis. Thus, proline biosynthesis acts as a redox vent, preventing the TGFβ-induced increase in mitochondrial glucose and glutamine catabolism from generating damaging reactive oxygen species (ROS) when TCA cycle activity exceeds the ability of oxidative phosphorylation to convert mitochondrial redox potential into ATP. In turn, the enhanced synthesis of proline supports TGFβ-induced production of matrix proteins.

Keywords:  TGFβ; collagen; fibrosis; metabolism; proline

DOI:  https://doi.org/10.15252/embj.2019103334
EMBO J. 2020 Mar 05. e102166

Infection-driven activation of transglutaminase 2 boosts glucose uptake and hexosamine biosynthesis in epithelial cells.

Benoit Maffei, Marc Laverrière, Yongzheng Wu, Sébastien Triboulet, Stéphanie Perrinet, Magalie Duchateau, Mariette Matondo, Robert L Hollis, Charlie Gourley, Jan Rupp, Jeffrey W Keillor, Agathe Subtil.

  Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme with transamidating activity. We report here that both expression and activity of TG2 are enhanced in mammalian epithelial cells infected with the obligate intracellular bacteria Chlamydia trachomatis. Genetic or pharmacological inhibition of TG2 impairs bacterial development. We show that TG2 increases glucose import by up-regulating the transcription of the glucose transporter genes GLUT-1 and GLUT-3. Furthermore, TG2 activation drives one specific glucose-dependent pathway in the host, i.e., hexosamine biosynthesis. Mechanistically, we identify the glucosamine:fructose-6-phosphate amidotransferase (GFPT) among the substrates of TG2. GFPT modification by TG2 increases its enzymatic activity, resulting in higher levels of UDP-N-acetylglucosamine biosynthesis and protein O-GlcNAcylation. The correlation between TG2 transamidating activity and O-GlcNAcylation is disrupted in infected cells because host hexosamine biosynthesis is being exploited by the bacteria, in particular to assist their division. In conclusion, our work establishes TG2 as a key player in controlling glucose-derived metabolic pathways in mammalian cells, themselves hijacked by C. trachomatis to sustain their own metabolic needs.

Keywords:   Chlamydia ; GFPT ; O-GlcNAcylation; hexosamine biosynthesis; transglutaminase 2

DOI:  https://doi.org/10.15252/embj.2019102166
Cell Res. 2020 Mar 04.

Targeting immunometabolism as an anti-inflammatory strategy.

Eva M Pålsson-McDermott, Luke A J O'Neill.

The growing field of immunometabolism has taught us how metabolic cellular reactions and processes not only provide a means to generate ATP and biosynthetic precursors, but are also a way of controlling immunity and inflammation. Metabolic reprogramming of immune cells is essential for both inflammatory as well as anti-inflammatory responses. Four anti-inflammatory therapies, DMF, Metformin, Methotrexate and Rapamycin all work by affecting metabolism and/or regulating or mimicking endogenous metabolites with anti-inflammatory effects. Evidence is emerging for the targeting of specific metabolic events as a strategy to limit inflammation in different contexts. Here we discuss these recent developments and speculate on the prospect of targeting immunometabolism in the effort to develop novel anti-inflammatory therapeutics. As accumulating evidence for roles of an intricate and elaborate network of metabolic processes, including lipid, amino acid and nucleotide metabolism provides key focal points for developing new therapies, we here turn our attention to glycolysis and the TCA cycle to provide examples of how metabolic intermediates and enzymes can provide potential novel therapeutic targets.

DOI: https://doi.org/10.1038/s41422-020-0291-z
J Cell Physiol. 2020 Mar 01.

Glucose regulates hypoxia-induced NLRP3 inflammasome activation in macrophages.

Sachiko Watanabe, Fumitake Usui-Kawanishi, Tadayoshi Karasawa, Hiroaki Kimura, Ryo Kamata, Takanori Komada, Yoshiyuki Inoue, Nathan Mise, Tadashi Kasahara, Masafumi Takahashi.

  Although the intimate linkage between hypoxia and inflammation is well known, the mechanism underlying this linkage has not been fully understood. Nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is an intracellular multiprotein complex that regulates interleukin-1β (IL-1β) secretion and pyroptosis, and is implicated in the pathogenesis of sterile inflammatory diseases. Here, we investigated the regulatory mechanism of NLRP3 inflammasome activation in response to hypoxia in macrophages. Severe hypoxia (0.1% O2 ) induced the processing of pro-IL-1β, pro-caspase-1, and gasdermin D, as well as the release of IL-1β and lactate dehydrogenase in lipopolysaccharide (LPS)-primed murine macrophages, indicating that hypoxia induces NLRP3 inflammasome-driven inflammation and pyroptosis. NLRP3 deficiency and a specific caspase-1 blockade inhibited hypoxia-induced IL-1β release. Hypoxia-induced IL-1β release and cell death were augmented under glucose deprivation, and an addition of glucose in the media negatively regulated hypoxia-induced IL-1β release. Under hypoxia and glucose deprivation, hypoxia-induced glycolysis was not driven and subsequently, the intracellular adenosine triphosphates (ATPs) were depleted. Atomic absorption spectrometry analysis showed a reduction of intracellular K+ concentrations, indicating the K+ efflux occurring under hypoxia and glucose deprivation. Furthermore, hypoxia and glucose deprivation-induced IL-1β release was significantly prevented by inhibition of K+ efflux and KATP channel blockers. In vivo experiments further revealed that IL-1β production was increased in LPS-primed mice exposed to hypoxia (9.5% O2 ), which was prevented by a deficiency of NLRP3, an apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase-1. Our results demonstrate that NLRP3 inflammasome can sense intracellular energy crisis as a danger signal induced by hypoxia and glucose deprivation, and provide new insights into the mechanism underlying hypoxia-induced inflammation.

Keywords:  adenosine triphosphate; inflammation; interleukin-1; potassium efflux; pyroptosis

DOI:  https://doi.org/10.1002/jcp.29659
Adv Exp Med Biol. 2020 ;1219 35-49

Tumor Microenvironment - Selective Pressures Boosting Cancer Progression.

Sofia C Nunes.

  In 2018, 9.6 million deaths from cancer were estimated, being this disease the second leading cause of death worldwide. Notwithstanding all the efforts developed in prevention, diagnosis and new treatment approaches, chemoresistance seems to be inevitable, leading to cancer progression, recurrence and affecting the outcome of the disease. As more and more evidence support that cancer is an evolutionary and ecological process, this concept is rarely applied in the clinical context. In fact, cancer cells emerge and progress within an ecological niche - the tumor microenvironment - that is shared with several other cell types and that is continuously changing. Therefore, the tumor microenvironment imposes several selective pressures on cancer cells such as acidosis, hypoxia, competition for space and resources, immune predation and anti-cancer therapies, that cancer cells must be able to adapt to or will face extinction.In here, the role of the tumor microenvironment selective pressures on cancer progression will be discussed, as well as the targeting of its features/components as strategies to fight cancer.

Keywords:  Cancer; Evolution; Metabolic selection; Microenvironment

DOI:  https://doi.org/10.1007/978-3-030-34025-4_2
J Biol Chem. 2020 Mar 04. pii: jbc.RA119.010868. [Epub ahead of print]

Nucleotides released from palmitate-activated murine macrophages attract neutrophils.

Theresa H Tam, Kenny L Chan, Parastoo Boroumand, Zhi Liu, Joseph T Brozinick, Hai Hoang Bui, Kenneth Roth, C Brent Wakefield, Silvia Penuela, Philip J Bilan, Amira Klip.

  Obesity and elevation of circulating free fatty acids are associated with an accumulation and pro-inflammatory polarization of macrophages within metabolically active tissues such as adipose tissue, muscle, liver, and pancreas. Beyond macrophages, neutrophils also accumulate in adipose and muscle tissues during high fat diets and contribute to a state of local inflammation and insulin resistance. However, the mechanisms by which neutrophils are recruited to these tissues are largely unknown. Here, we used a cell culture system as proof-of-concept to show that upon exposure to a saturated fatty acid, palmitate, macrophages release nucleotides that attract neutrophils. Moreover, we find that palmitate upregulates pannexin-1 channels in macrophages that mediate the attraction of neutrophils, previously shown to allow transfer of nucleotides across membranes. These findings suggest that pro-inflammatory macrophages release nucleotides through pannexin-1, a process that may facilitate neutrophil recruitment into metabolic tissues during obesity.

Keywords:  chemotaxis; fatty acid; high fat diet; inflammation; macrophage; metabolic disorder; neutrophil; nucleotide; obesity; pannexin-1

DOI:  https://doi.org/10.1074/jbc.RA119.010868