bims-stacyt 2022-10-30 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2022–10–30
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Lipopolysaccharide-induced hypothalamic inflammation in cancer cachexia-anorexia is amplified by tumour-derived prostaglandin E2.
Limiting glutamine utilization activates a GCN2/TRAIL-R2/Caspase-8 apoptotic pathway in glutamine-addicted tumor cells.
Reprogramming Carbohydrate Metabolism in Cancer and Its Role in Regulating the Tumor Microenvironment.
A cell-based chemical-genetic screen for amino acid stress response inhibitors reveals torins reverse stress kinase GCN2 signaling.
Lactate dehydrogenases promote glioblastoma growth and invasion via a metabolic symbiosis.
Antibiotic-disrupted Ribosome Biogenesis Facilitates Tumor Chemokine Superinduction.
Nucleoside transporters and immunosuppressive adenosine signaling in the tumor microenvironment: Potential therapeutic opportunities.
Metabolic control of CD47 expression through LAT2-mediated amino acid uptake promotes tumor immune evasion.

J Cachexia Sarcopenia Muscle. 2022 Oct 27.

Lipopolysaccharide-induced hypothalamic inflammation in cancer cachexia-anorexia is amplified by tumour-derived prostaglandin E2.

Xiaolin Li, Tosca Holtrop, Fleur A C Jansen, Brennan Olson, Pete Levasseur, Xinxia Zhu, Mieke Poland, Winni Schalwijk, Renger F Witkamp, Daniel L Marks, Klaske van Norren.

   BACKGROUND: Cachexia-anorexia syndrome is a complex metabolic condition characterized by skeletal muscle wasting, reduced food intake and prominent involvement of systemic and central inflammation. Here, the gut barrier function was investigated in pancreatic cancer-induced cachexia mouse models by relating intestinal permeability to the degree of cachexia. We further investigated the involvement of the gut-brain axis and the crosstalk between tumour, gut and hypothalamus in vitro.
METHODS: Two distinct mouse models of pancreatic cancer cachexia (KPC and 4662) were used. Intestinal inflammation and permeability were assessed through fluorescein isothiocyanate dextran (FITC-dextran) and lipopolysaccharide (LPS), and hypothalamic and systemic inflammation through mRNA expression and plasma cytokines, respectively. To simulate the tumour-gut-brain crosstalk, hypothalamic (HypoE-N46) cells were incubated with cachexia-inducing tumour secretomes and LPS. A synthetic mimic of C26 secretome was produced based on its secreted inflammatory mediators. Each component of the mimic was systematically omitted to narrow down the key mediator(s) with an amplifying inflammation. To substantiate its contribution, cyclooxygenase-2 (COX-2) inhibitor was used.
RESULTS: In vivo experiments showed FITC-dextran was enhanced in the KPC group (362.3 vs. sham 111.4 ng/mL, P < 0.001). LPS was increased to 140.9 ng/mL in the KPC group, compared with sham and 4662 groups (115.8 and 115.8 ng/mL, P < 0.05). Hypothalamic inflammatory gene expression of Ccl2 was up-regulated in the KPC group (6.3 vs. sham 1, P < 0.0001, 4662 1.3, P < 0.001), which significantly correlated with LPS concentration (r = 0.4948, P = 0.0226). These data suggest that intestinal permeability is positively related to the cachexic degree. Prostaglandin E2 (PGE2) was confirmed to be present in the plasma and PGE2 concentration (log10) in the KPC group was much higher than in 4662 group (1.85 and 0.56 ng/mL, P < 0.001), indicating a role for PGE2 in pancreatic cancer-induced cachexia. Parallel to in vivo findings, in vitro experiments revealed that the cachexia-inducing tumour secretomes (C26, LLC, KPC and 4662) amplified LPS-induced hypothalamic IL-6 secretion (419%, 321%, 294%, 160%). COX-2 inhibitor to the tumour cells reduced PGE2 content (from 105 to 102 pg/mL) in the secretomes and eliminated the amplified hypothalamic IL-6 production. Moreover, results could be reproduced by addition of PGE2 alone, indicating that the increased hypothalamic inflammation is directly related to the PGE2 from tumour.
CONCLUSIONS: PGE2 secreted by the tumour may play a role in amplifying the effects of bacteria-derived LPS on the inflammatory hypothalamic response. The cachexia-inducing potential of tumour mice models parallels the loss of intestinal barrier function. Tumour-derived PGE2 might play a key role in cancer-related cachexia-anorexia syndrome via tumour-gut-brain crosstalk.

Keywords:  Cachexia; Cancer; Gut-brain axis; Hypothalamic inflammation; Prostaglandin

DOI:  https://doi.org/10.1002/jcsm.13093
Cell Death Dis. 2022 Oct 27. 13(10): 906

Limiting glutamine utilization activates a GCN2/TRAIL-R2/Caspase-8 apoptotic pathway in glutamine-addicted tumor cells.

Rosario Yerbes, Rocío Mora-Molina, F Javier Fernández-Farrán, Laura Hiraldo, Abelardo López-Rivas, Carmen Palacios.

Oncogenic transformation leads to changes in glutamine metabolism that make transformed cells highly dependent on glutamine for anabolic growth and survival. Herein, we investigated the cell death mechanism activated in glutamine-addicted tumor cells in response to the limitation of glutamine metabolism. We show that glutamine starvation triggers a FADD and caspase-8-dependent and mitochondria-operated apoptotic program in tumor cells that involves the pro-apoptotic TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2), but is independent of its cognate ligand TRAIL. In glutamine-depleted tumor cells, activation of the amino acid-sensing general control nonderepressible-2 kinase (GCN2) is responsible for TRAIL-R2 upregulation, caspase-8 activation, and apoptotic cell death. Interestingly, GCN2-dependent ISR signaling induced by methionine starvation also leads to TRAIL-R2 upregulation and apoptosis. Moreover, pharmacological inhibition of transaminases activates a GCN2 and TRAIL-R2-dependent apoptotic mechanism that is inhibited by non-essential amino acids (NEAA). In addition, metabolic stress upon glutamine deprivation also results in GCN2-independent FLICE-inhibitory protein (FLIP) downregulation facilitating caspase-8 activation and apoptosis. Importantly, downregulation of the long FLIP splice form (FLIPL) and apoptosis upon glutamine deprivation are inhibited in the presence of a membrane-permeable α-ketoglutarate. Collectively, our data support a model in which limiting glutamine utilization in glutamine-addicted tumor cells triggers a previously unknown cell death mechanism regulated by GCN2 that involves the TRAIL-R2-mediated activation of the extrinsic apoptotic pathway.

DOI: https://doi.org/10.1038/s41419-022-05346-y
Subcell Biochem. 2022 ;100 3-65

Reprogramming Carbohydrate Metabolism in Cancer and Its Role in Regulating the Tumor Microenvironment.

Swagata Adhikari, Deblina Guha, Chitra Mohan, Shravanti Mukherjee, Jessica K Tyler, Chandrima Das.

  Altered metabolism has become an emerging feature of cancer cells impacting their proliferation and metastatic potential in myriad ways. Proliferating heterogeneous tumor cells are surrounded by other resident or infiltrating cells, along with extracellular matrix proteins, and other secretory factors constituting the tumor microenvironment. The diverse cell types of the tumor microenvironment exhibit different molecular signatures that are regulated at their genetic and epigenetic levels. The cancer cells elicit intricate crosstalks with these supporting cells, exchanging essential metabolites which support their anabolic processes and can promote their survival, proliferation, EMT, angiogenesis, metastasis and even therapeutic resistance. In this context, carbohydrate metabolism ensures constant energy supply being a central axis from which other metabolic and biosynthetic pathways including amino acid and lipid metabolism and pentose phosphate pathway are diverged. In contrast to normal cells, increased glycolytic flux is a distinguishing feature of the highly proliferative cancer cells, which supports them to adapt to a hypoxic environment and also protects them from oxidative stress. Such rewired metabolic properties are often a result of epigenetic alterations in the cancer cells, which are mediated by several factors including, DNA, histone and non-histone protein modifications and non-coding RNAs. Conversely, epigenetic landscapes of the cancer cells are also dictated by their diverse metabolomes. Altogether, this metabolic and epigenetic interplay has immense potential for the development of efficient anti-cancer therapeutic strategies. In this book chapter we emphasize upon the significance of reprogrammed carbohydrate metabolism in regulating the tumor microenvironment and cancer progression, with an aim to explore the different metabolic and epigenetic targets for better cancer treatment.

Keywords:  Acetyl-CoA; Carbohydrate metabolism; DNMTs; Epigenetics; Glycolytic flux; HATs; HDACs; HDM; HMT; Hypoxia; Metabolic reprogramming; Metastasis; OXPHOS; Oncometabolites; SAM; Tumor microenvironment

DOI:  https://doi.org/10.1007/978-3-031-07634-3_1
J Biol Chem. 2022 Oct 20. pii: S0021-9258(22)01072-9. [Epub ahead of print] 102629

A cell-based chemical-genetic screen for amino acid stress response inhibitors reveals torins reverse stress kinase GCN2 signaling.

Johanna B Brüggenthies, Alessandra Fiore, Marion Russier, Christina Bitsina, Julian Brötzmann, Susanne Kordes, Sascha Menninger, Alexander Wolf, Elena Conti, Jan E Eickhoff, Peter J Murray.

  mTORC1 and GCN2 are serine/threonine kinases that control how cells adapt to amino acid availability. mTORC1 responds to amino acids to promote translation and cell growth while GCN2 senses limiting amino acids to hinder translation via eIF2α phosphorylation. GCN2 is an appealing target for cancer therapies because malignant cells can harness the GCN2 pathway to temper the rate of translation during rapid amino acid consumption. To isolate new GCN2 inhibitors, we created cell-based, amino acid limitation reporters via genetic manipulation of Ddit3 (encoding the transcription factor CHOP). CHOP is strongly induced by limiting amino acids and in this context, GCN2-dependent. Using leucine starvation as a model for essential amino acid sensing, we unexpectedly discovered ATP-competitive PI3 kinase-related kinase inhibitors, including ATR and mTOR inhibitors like torins, completely reversed GCN2 activation in a time-dependent way. Mechanistically, via inhibiting mTORC1-dependent translation, torins increased intracellular leucine, which was sufficient to reverse GCN2 activation and the downstream integrated stress response including stress-induced transcriptional factor ATF4 expression. Strikingly, we found that general translation inhibitors mirrored the effects of torins. Therefore, we propose that mTOR kinase inhibitors concurrently inhibit different branches of amino acid sensing by a dual mechanism involving direct inhibition of mTOR and indirect suppression of GCN2 that are connected by effects on the translation machinery. Collectively, our results highlight distinct ways of regulating GCN2 activity.

Keywords:  GCN2; amino acid starvation; integrated stress response; mTORC1; torins

DOI:  https://doi.org/10.1016/j.jbc.2022.102629
EMBO Mol Med. 2022 Oct 24. e15343

Lactate dehydrogenases promote glioblastoma growth and invasion via a metabolic symbiosis.

Joris Guyon, Ignacio Fernandez-Moncada, Claire M Larrieu, Cyrielle L Bouchez, Antonio C Pagano Zottola, Johanna Galvis, Tiffanie Chouleur, Audrey Burban, Kevin Joseph, Vidhya M Ravi, Heidi Espedal, Gro Vatne Røsland, Boutaina Daher, Aurélien Barre, Benjamin Dartigues, Slim Karkar, Justine Rudewicz, Irati Romero-Garmendia, Barbara Klink, Konrad Grützmann, Marie-Alix Derieppe, Thibaut Molinié, Nina Obad, Céline Léon, Giorgio Seano, Hrvoje Miletic, Dieter Henrik Heiland, Giovanni Marsicano, Macha Nikolski, Rolf Bjerkvig, Andreas Bikfalvi, Thomas Daubon.

  Lactate is a central metabolite in brain physiology but also contributes to tumor development. Glioblastoma (GB) is the most common and malignant primary brain tumor in adults, recognized by angiogenic and invasive growth, in addition to its altered metabolism. We show herein that lactate fuels GB anaplerosis by replenishing the tricarboxylic acid (TCA) cycle in absence of glucose. Lactate dehydrogenases (LDHA and LDHB), which we found spatially expressed in GB tissues, catalyze the interconversion of pyruvate and lactate. However, ablation of both LDH isoforms, but not only one, led to a reduction in tumor growth and an increase in mouse survival. Comparative transcriptomics and metabolomics revealed metabolic rewiring involving high oxidative phosphorylation (OXPHOS) in the LDHA/B KO group which sensitized tumors to cranial irradiation, thus improving mouse survival. When mice were treated with the antiepileptic drug stiripentol, which targets LDH activity, tumor growth decreased. Our findings unveil the complex metabolic network in which both LDHA and LDHB are integrated and show that the combined inhibition of LDHA and LDHB strongly sensitizes GB to therapy.

Keywords:  antiepileptic drug; energy metabolism; glioblastoma; invasion; lactate dehydrogenases

DOI:  https://doi.org/10.15252/emmm.202115343
Biochem Pharmacol. 2022 Oct 22. pii: S0006-2952(22)00397-5. [Epub ahead of print] 115303

Antibiotic-disrupted Ribosome Biogenesis Facilitates Tumor Chemokine Superinduction.

Ki-Hyung Kim, Arulkumar Nagappan, BoGyoung Song, Sehun Lim, Yuseok Moon.

  Upon exposure to internal or external stressors, ribosomes stand sentinel via modulation of ribosome assembly and protein translation. Ribosome-dependent cellular dysfunctions have been associated with pathophysiological processes during inflammation and tumorigenesis. In the present study, ribosome biogenesis was assessed to determine its effects on tumor chemokines, potentially contributing to cancer cell malignant features. In particular, ribosome biogenesis inhibition by antibiotic actinomycin D (ActD) enhanced the expression of chemokines in intestinal cancer cells under endoplasmic reticulum stress that governs multiple pro-tumoral reprogramming. Mechanistically, ribosome biogenesis inhibition superinduced proinflammatory chemokines via transcriptional and post-transcriptional regulation. Moreover, ribosomal stress-responsive p53 and its target macrophage inhibitory cytokine 1 (MIC-1) mediated chemokine superinduction by activating TGF-β-activated kinase 1 (TAK-1) and nuclear factor-kappa B (NF-κB) in intestinal cancer cells. Cancer cell-based regulation of chemokine induction via MIC-1 signaling was verified using clinical transcriptome datasets. Clinical tumor tissue-derived MIC-1 was a positive regulator of chemokines and genes involved in the ribosome biogenesis pathway, supporting the in vitro assessments. Moreover, MIC-1-correlated chemokine expressions predicted poor prognoses in patients with colorectal cancer. Ribosome-based chemokine regulation via MIC-1 signaling would provide novel insights into translational interventions against malignant inflammatory insults.

Keywords:  Cancer chemokines; Endoplasmic reticulum stress; MIC-1; Ribosome biogenesis; p53

DOI:  https://doi.org/10.1016/j.bcp.2022.115303
Pharmacol Ther. 2022 Oct 22. pii: S0163-7258(22)00194-2. [Epub ahead of print] 108300

Nucleoside transporters and immunosuppressive adenosine signaling in the tumor microenvironment: Potential therapeutic opportunities.

Tejinder Kaur, Brenna Weadick, Thomas A Mace, Kajal Desai, Hannah Odom, Rajgopal Govindarajan.

  Adenosine compartmentalization has a profound impact on immune cell function by regulating adenosine localization and, therefore, extracellular signaling capabilities, which suppresses immune cell function in the tumor microenvironment. Nucleoside transporters, responsible for the translocation and cellular compartmentalization of hydrophilic adenosine, represent an understudied yet crucial component of adenosine disposition in the tumor microenvironment. In this review article, we will summarize what is known regarding nucleoside transporter's function within the purinome in relation to currently devised points of intervention (i.e., ectonucleotidases, adenosine receptors) for cancer immunotherapy, alterations in nucleoside transporter expression reported in cancer, and potential avenues for targeting of nucleoside transporters for the desired modulation of adenosine compartmentalization and action. Further, we put forward that nucleoside transporters are an unexplored therapeutic opportunity, and modulation of nucleoside transport processes could attenuate the pathogenic buildup of immunosuppressive adenosine in solid tumors, particularly those enriched with nucleoside transport proteins.

Keywords:  Adenosine; Drug; Immunosuppression; Nucleoside; Receptor; Signaling; Transporter

DOI:  https://doi.org/10.1016/j.pharmthera.2022.108300
Nat Commun. 2022 Oct 23. 13(1): 6308

Metabolic control of CD47 expression through LAT2-mediated amino acid uptake promotes tumor immune evasion.

Zenan Wang, Binghao Li, Shan Li, Wenlong Lin, Zhan Wang, Shengdong Wang, Weida Chen, Wei Shi, Tao Chen, Hao Zhou, Eloy Yinwang, Wenkan Zhang, Haochen Mou, Xupeng Chai, Jiahao Zhang, Zhimin Lu, Zhaoming Ye.

Chemotherapy elicits tumor immune evasion with poorly characterized mechanisms. Here, we demonstrate that chemotherapy markedly enhances the expression levels of CD47 in osteosarcoma tissues, which are positively associated with patient mortality. We reveal that macrophages in response to chemotherapy secrete interleukin-18, which in turn upregulates expression of L-amino acid transporter 2 (LAT2) in tumor cells for substantially enhanced uptakes of leucine and glutamine, two potent stimulators of mTORC1. The increased levels of leucine and enhanced glutaminolysis activate mTORC1 and subsequent c-Myc-mediated transcription of CD47. Depletion of LAT2 or treatment of tumor cells with a LAT inhibitor downregulates CD47 with enhanced macrophage infiltration and phagocytosis of tumor cells, and sensitizes osteosarcoma to doxorubicin treatment in mice. These findings unveil a mutual regulation between macrophage and tumor cells that plays a critical role in tumor immune evasion and underscore the potential to intervene with the LAT2-mediated amino acid uptake for improving cancer therapies.

DOI: https://doi.org/10.1038/s41467-022-34064-4