bims-stacyt 2019-07-21 papers

bims-stacyt

Biomed News

on Paracrine crosstalk between cancer and the organism

Issue of 2019‒07‒21
eleven papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

The Cytokine TNF Promotes Transcription Factor SREBP Activity and Binding to Inflammatory Genes to Activate Macrophages and Limit Tissue Repair.
Multiple-Omics Techniques Reveal the Role of Glycerophospholipid Metabolic Pathway in the Response of Saccharomyces cerevisiae Against Hypoxic Stress.
XBP-1 Remodels Lipid Metabolism to Extend Longevity.
Inflammation and Cancer: Triggers, Mechanisms, and Consequences.
Acute and chronic hypoxia differentially predispose lungs for metastases.
Apigenin Protects Against Renal Tubular Epithelial Cell Injury and Oxidative Stress by High Glucose via Regulation of NF-E2-Related Factor 2 (Nrf2) Pathway.
UDP-glucose 6-dehydrogenase regulates hyaluronic acid production and promotes breast cancer progression.
Curcumin suppresses intestinal microvascular endothelial cells invasion and angiogenesis induced by activated platelets.
PRKCSH contributes to tumorigenesis by selective boosting of IRE1 signaling pathway.
Extracellular acidosis triggers a senescence-like phenotype in human melanoma cells.
Mutant p53 improves cancer cells' resistance to endoplasmic reticulum stress by sustaining activation of the UPR regulator ATF6.

Immunity. 2019 Jul 02. pii: S1074-7613(19)30275-4. [Epub ahead of print]

The Cytokine TNF Promotes Transcription Factor SREBP Activity and Binding to Inflammatory Genes to Activate Macrophages and Limit Tissue Repair.

Anthony Kusnadi, Sung Ho Park, Ruoxi Yuan, Tania Pannellini, Eugenia Giannopoulou, David Oliver, Theresa Lu, Kyung-Hyun Park-Min, Lionel B Ivashkiv.

  Cytokine tumor necrosis factor (TNF)-mediated macrophage polarization is important for inflammatory disease pathogenesis, but the mechanisms regulating polarization are not clear. We performed transcriptomic and epigenomic analysis of the TNF response in primary human macrophages and revealed late-phase activation of SREBP2, the master regulator of cholesterol biosynthesis genes. TNF stimulation extended the genomic profile of SREBP2 occupancy to include binding to and activation of inflammatory and interferon response genes independently of its functions in sterol metabolism. Genetic ablation of SREBP function shifted the balance of macrophage polarization from an inflammatory to a reparative phenotype in peritonitis and skin wound healing models. Genetic ablation of SREBP activity in myeloid cells or topical pharmacological inhibition of SREBP improved skin wound healing under homeostatic and chronic inflammatory conditions. Our results identify a function and mechanism of action for SREBPs in augmenting TNF-induced macrophage activation and inflammation and open therapeutic avenues for promoting wound repair.

Keywords:  SREBP2; TNF; cholesterol; epigenomics; inflammation; macrophage polarization; macrophages; tissue repair; transcriptomics; wound healing

DOI:  https://doi.org/10.1016/j.immuni.2019.06.005
Front Microbiol. 2019 ;10 1398

Multiple-Omics Techniques Reveal the Role of Glycerophospholipid Metabolic Pathway in the Response of Saccharomyces cerevisiae Against Hypoxic Stress.

Zhengchao Xia, Xuelin Zhou, Jingyi Li, Lei Li, Yi Ma, Yi Wu, Zhong Huang, Xiaorong Li, Pingxiang Xu, Ming Xue.

  Although the biological processes of organism under hypoxic stress had been elucidated, the whole physiological changes of Saccharomyces cerevisiae are still unclear. In this work, we investigated the changes of biological process of S. cerevisiae under hypoxia by the methods of transcriptomics, proteomics, metabolomics, and bioinformatics. The results showed that the expression of a total of 1017 mRNA in transcriptome, 213 proteins in proteome, and 51 metabolites in metabolome had been significantly changed between the hypoxia and normoxia conditions. Moreover, based on the integration of system-omics data, we found that the carbohydrate, amino acids, fatty acid biosynthesis, lipid metabolic pathway, and oxidative phosphorylation were significantly changed in hypoxic stress. Among these pathways, the glycerophospholipid metabolic pathway was remarkably up-regulated from the mRNA, protein, and metabolites levels under hypoxic stress, and the expression of relevant mRNA was also confirmed by the qPCR. The metabolites of glycerophospholipid pathway such as phosphatidylcholine, phosphatidylethanolamine, phosphoinositide, and phosphatidic acids probably maintained the stability of cell membranes against hypoxic stress to relieve the cell injury, and kept S. cerevisiae survive with energy production. These findings in the hypoxic omics and integrated networks provide very useful information for further exploring the molecular mechanism of hypoxic stress.

Keywords:  Saccharomyces cerevisiae; glycerophospholipid metabolism; hypoxia; metabolomics; proteomics; transcriptomics

DOI:  https://doi.org/10.3389/fmicb.2019.01398
Cell Rep. 2019 Jul 16. pii: S2211-1247(19)30830-7. [Epub ahead of print]28(3): 581-589.e4

XBP-1 Remodels Lipid Metabolism to Extend Longevity.

Soudabeh Imanikia, Ming Sheng, Cecilia Castro, Julian L Griffin, Rebecca C Taylor.

  The endoplasmic reticulum unfolded protein response (UPRER) is a cellular stress response that maintains homeostasis within the secretory pathway, regulates glucose and lipid metabolism, and influences longevity. To ask whether this role in lifespan determination depends upon metabolic intermediaries, we metabotyped C. elegans expressing the active form of the UPRER transcription factor XBP-1, XBP-1s, and found many metabolic changes. These included reduced levels of triglycerides and increased levels of oleic acid (OA), a monounsaturated fatty acid associated with lifespan extension in C. elegans. Here, we show that constitutive XBP-1s expression increases the activity of lysosomal lipases and upregulates transcription of the Δ9 desaturase FAT-6, which is required for the full lifespan extension induced by XBP-1s. Dietary OA supplementation increases the lifespan of wild-type, but not xbp-1s-expressing animals and enhances proteostasis. These results suggest that modulation of lipid metabolism by XBP-1s contributes to its downstream effects on protein homeostasis and longevity.

Keywords:  C. elegans; aging; lipids; metabolism; monounsaturated; neurons; proteostasis; signaling

DOI:  https://doi.org/10.1016/j.celrep.2019.06.057
Immunity. 2019 Jul 16. pii: S1074-7613(19)30295-X. [Epub ahead of print]51(1): 27-41

Inflammation and Cancer: Triggers, Mechanisms, and Consequences.

Florian R Greten, Sergei I Grivennikov.

  Inflammation predisposes to the development of cancer and promotes all stages of tumorigenesis. Cancer cells, as well as surrounding stromal and inflammatory cells, engage in well-orchestrated reciprocal interactions to form an inflammatory tumor microenvironment (TME). Cells within the TME are highly plastic, continuously changing their phenotypic and functional characteristics. Here, we review the origins of inflammation in tumors, and the mechanisms whereby inflammation drives tumor initiation, growth, progression, and metastasis. We discuss how tumor-promoting inflammation closely resembles inflammatory processes typically found during development, immunity, maintenance of tissue homeostasis, or tissue repair and illuminate the distinctions between tissue-protective and pro-tumorigenic inflammation, including spatiotemporal considerations. Defining the cornerstone rules of engagement governing molecular and cellular mechanisms of tumor-promoting inflammation will be essential for further development of anti-cancer therapies.

Keywords:  cancer; cell plasticity; cytokine; inflammation; mechanisms; metastasis; tumor microenvironment; tumor progression

DOI:  https://doi.org/10.1016/j.immuni.2019.06.025
Sci Rep. 2019 Jul 15. 9(1): 10246

Acute and chronic hypoxia differentially predispose lungs for metastases.

Moritz Reiterer, Renato Colaço, Pardis Emrouznejad, Anders Jensen, Helene Rundqvist, Randall S Johnson, Cristina Branco.

Oscillations in oxygen levels affect malignant cell growth, survival, and metastasis, but also somatic cell behaviour. In this work, we studied the effect of the differential expression of the two primary hypoxia inducible transcription factor isoforms, HIF-1α and HIF-2α, and pulmonary hypoxia to investigate how the hypoxia response of the vascular endothelium remodels the lung pre-metastatic niche. Molecular responses to acute versus chronic tissue hypoxia have been proposed to involve dynamic HIF stabilization, but the downstream consequences and the extent to which differential lengths of exposure to hypoxia can affect HIF-isoform activation and secondary organ pre-disposition for metastasis is unknown. We used primary pulmonary endothelial cells and mouse models with pulmonary endothelium-specific deletion of HIF-1α or HIF-2α, to characterise their roles in vascular integrity, inflammation and metastatic take after acute and chronic hypoxia. We found that acute hypoxic response results in increased lung metastatic tumours, caused by HIF-1α-dependent endothelial cell death and increased microvascular permeability, in turn facilitating extravasation. This is potentiated by the recruitment and retention of specific myeloid cells that further support a pro-metastatic environment. We also found that chronic hypoxia delays tumour growth to levels similar to those seen in normoxia, and in a HIF-2α-specific fashion, correlating with increased endothelial cell viability and vascular integrity. Deletion of endothelial HIF-2α rendered the lung environment more vulnerable to tumour cell seeding and growth. These results demonstrate that the nature of the hypoxic challenge strongly influences the nature of the endothelial cell response, and affects critical parameters of the pulmonary microenvironment, significantly impacting metastatic burden. Additionally, this work establishes endothelial cells as important players in lung remodelling and metastatic progression.

DOI: https://doi.org/10.1038/s41598-019-46763-y
Med Sci Monit. 2019 Jul 16. 25 5280-5288

Apigenin Protects Against Renal Tubular Epithelial Cell Injury and Oxidative Stress by High Glucose via Regulation of NF-E2-Related Factor 2 (Nrf2) Pathway.

Jichen Zhang, Xuemei Zhao, Hongling Zhu, Jingnan Wang, Junhua Ma, Mingjun Gu.

BACKGROUND Diabetic nephropathy (DN) is a disease characterized by oxidative stress and apoptosis of renal tubular epithelial cells driven by hyperglycemia. Apigenin is a flavonoid compound that possesses potent anti‑apoptotic properties. The present study aimed to explore the protective effects and underlying mechanisms of apigenin on renal tubular epithelial cells exposed to hyperglycemia. MATERIAL AND METHODS Human renal epithelial cell HK-2 were incubated to D-glucose to establish in vitro DN model. The cell viability, lactate dehydrogenase (LDH) release, apoptosis and oxidative stress were evaluated. qRT-PCR was performed to determine the mRNA levels of NF-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Western blot analysis was performed to measure the protein expressions of Nrf2. RESULTS In HK-2 cells, high glucose reduced cell viability in a concentration- and time-dependent manner. Apigenin suppressed the decrease in cell viability and increase in supernatant LDH release at 100 and 200 μM after 48-h treatment. Apigenin reduced apoptotic rate and pro-inflammatory cytokines production. Apigenin suppressed oxidative stress and increased mRNA expressions of Nrf2 and HO-1. Inhibition of Nrf2 using small interfering RNA (siRNA), or cotreatment with LY294002, an inhibitor of PI3K/Akt, abolished the protective effect on high glucose-induced injury, oxidative stress, and pro-inflammatory cytokines production by apigenin. LY294002 also attenuated the increase in Nrf2 protein by apigenin in high glucose-treated HK-2 cells. CONCLUSIONS Apigenin protects renal tubular epithelial cells against high glucose-induced injury through suppression of oxidative stress and inflammation via activation of the Nrf2 pathway.

DOI: https://doi.org/10.12659/MSM.915038
Oncogene. 2019 Jul 15.

UDP-glucose 6-dehydrogenase regulates hyaluronic acid production and promotes breast cancer progression.

James M Arnold, Franklin Gu, Chandrashekar R Ambati, Uttam Rasaily, Esmeralda Ramirez-Pena, Robiya Joseph, Mohan Manikkam, Rebeca San Martin, Christy Charles, Yinghong Pan, Sujash S Chatterjee, Petra Den Hollander, Chandandeep Nagi, Andrew G Sikora, David Rowley, Nagireddy Putluri, Balasubramanyam Karanam, Sendurai A Mani, Arun Sreekumar.

An improved understanding of the biochemical alterations that accompany tumor progression and metastasis is necessary to inform the next generation of diagnostic tools and targeted therapies. Metabolic reprogramming is known to occur during the epithelial-mesenchymal transition (EMT), a process that promotes metastasis. Here, we identify metabolic enzymes involved in extracellular matrix remodeling that are upregulated during EMT and are highly expressed in patients with aggressive mesenchymal-like breast cancer. Activation of EMT significantly increases production of hyaluronic acid, which is enabled by the reprogramming of glucose metabolism. Using genetic and pharmacological approaches, we show that depletion of the hyaluronic acid precursor UDP-glucuronic acid is sufficient to inhibit several mesenchymal-like properties including cellular invasion and colony formation in vitro, as well as tumor growth and metastasis in vivo. We found that depletion of UDP-glucuronic acid altered the expression of PPAR-gamma target genes and increased PPAR-gamma DNA-binding activity. Taken together, our findings indicate that the disruption of EMT-induced metabolic reprogramming affects hyaluronic acid production, as well as associated extracellular matrix remodeling and represents pharmacologically actionable target for the inhibition of aggressive mesenchymal-like breast cancer progression.

DOI: https://doi.org/10.1038/s41388-019-0885-4
Exp Ther Med. 2019 Aug;18(2): 1099-1106

Curcumin suppresses intestinal microvascular endothelial cells invasion and angiogenesis induced by activated platelets.

Su Xu, Zhao-Xiu Xu, Shuai Yan, Jin Le, Hao Chen, Lan Ming, Shu-Guang Xu, Tao Lin.

  The present study investigated the effects and mechanism by which curcumin suppresses intestinal microvascular endothelial cells (INMECs) invasion and angiogenesis induced by activated platelets. INMECs were obtained from healthy rats, and divided into five groups: Control, platelets, platelets +2.5 µM curcumin, platelets +5.0 µM curcumin and platelets +10.0 µM curcumin. Curcumin toxicity was determined and vascular endothelial growth factor (VEGF) concentrations of the five groups were measured using ELISA. The branch point numbers were measured using a capillary tube formation experiment, invasion cell numbers were evaluated with the Transwell assay, relative protein expression levels were measured with western blot assay and immunofluorescence staining of the nucleus. The 2.5, 5 and 10 µM curcumin concentrations were found to be suitable for INMECs. Curcumin significantly downregulated VEGF concentration, suppressed vascular lumen formation and inhibited invasion cell numbers in a dose-dependent manner. The α-smooth muscle actin, collagen I, E-cadherin, phosphorylated (p-) phosphoinositide 3-kinase (PI3K), p-protein kinase B (AKT), p-mammalian target of rapamycin (m-TOR) and hypoxia inducible factor subunit alpha (HIF-1α) protein expression levels of the curcumin-treated groups were significantly downregulated in a dose-dependent manner compared with the platelet group. HIF-1α protein expression levels in the nucleus of the curcumin-treated groups were significantly suppressed in a dose-dependent manner compared with the platelet group. In conclusion, curcumin suppressed INMEC invasion and angiogenesis induced by activated platelets via inhibiting the activation of the PI3K/AKT/mTOR pathway.

Keywords:  curcumin; intestinal microvascular endothelial cells; mammalian target of rapamycin; phosphoinositide 3-kinase; protein kinase B

DOI:  https://doi.org/10.3892/etm.2019.7662
Nat Commun. 2019 Jul 18. 10(1): 3185

PRKCSH contributes to tumorigenesis by selective boosting of IRE1 signaling pathway.

Gu-Choul Shin, Sung Ung Moon, Hong Seok Kang, Hyo-Sun Choi, Hee Dong Han, Kyun-Hwan Kim.

Unfolded protein response (UPR) is an adaptive mechanism that aims at restoring ER homeostasis under severe environmental stress. Malignant cells are resistant to environmental stress, which is largely due to an activated UPR. However, the molecular mechanisms by which different UPR branches are selectively controlled in tumor cells are not clearly understood. Here, we provide evidence that PRKCSH, previously known as glucosidase II beta subunit, functions as a regulator for selective activation of the IRE1α branch of UPR. PRKCSH boosts ER stress-mediated autophosphorylation and oligomerization of IRE1α through mutual interaction. PRKCSH contributes to the induction of tumor-promoting factors and to tumor resistance to ER stress. Increased levels of PRKCSH in various tumor tissues are positively correlated with the expression of XBP1-target genes. Taken together, our data provide a molecular rationale for selective activation of the IRE1α branch in tumors and adaptation of tumor cells to severe environmental stress.

DOI: https://doi.org/10.1038/s41467-019-11019-w
Pigment Cell Melanoma Res. 2019 Jul 16.

Extracellular acidosis triggers a senescence-like phenotype in human melanoma cells.

Ines Böhme, Anja Bosserhoff.

  Acidosis of the tumor microenvironment is a characteristic of solid tumors such as malignant melanoma. Main causes of the extracellular acidification are metabolic alterations in cancer cells. While numerous studies showed that acidosis promotes tumor invasiveness, metastasis and neoangiogenesis resulting in malignant progression, contrary data reported that acidosis induces cell apoptosis, inhibits cell proliferation and mediates cell autophagy. Here, we show that low pH (pH 6.7) induces senescent/quiescent phenotype in melanoma cells after long-time treatment defined by induction of SA-ß-galactosidase, upregulation of p21, G1 /G0 cell-cycle arrest and reduction of proliferation. Moreover, we revealed that extracellular acidosis triggers the inhibition of eIF2α and subsequently the activation of ATF4 expression, a key component of the integrated stress response (ISR), indicating an acid-mediated translation reprogramming. Interestingly, we also demonstrated that acidosis represses microphthalmia-associated transcription factor (MITF) and activates the expression of the receptor tyrosine kinase AXL. This MITFlow /AXLhigh phenotype is correlated with drug resistance and therapeutic outcome in melanoma. Our results suggest that acidosis is an important microenvironmental factor triggering phenotypic plasticity and promoting tumor progression. This article is protected by copyright. All rights reserved.

Keywords:  Dormancy; Extracellular acidosis - Tumor microenvironment - Melanoma - Senescence; Slow-cycling phenotype

DOI:  https://doi.org/10.1111/pcmr.12811
Oncogene. 2019 Jul 16.

Mutant p53 improves cancer cells' resistance to endoplasmic reticulum stress by sustaining activation of the UPR regulator ATF6.

Daria Sicari, Marco Fantuz, Arianna Bellazzo, Elena Valentino, Mattia Apollonio, Ilaria Pontisso, Francesca Di Cristino, Marco Dal Ferro, Silvio Bicciato, Giannino Del Sal, Licio Collavin.

Missense mutations in the TP53 gene are frequent in human cancers, giving rise to mutant p53 proteins that can acquire oncogenic properties. Gain of function mutant p53 proteins can enhance tumour aggressiveness by promoting cell invasion, metastasis and chemoresistance. Accumulating evidences indicate that mutant p53 proteins can also modulate cell homeostatic processes, suggesting that missense p53 mutation may increase resistance of tumour cells to intrinsic and extrinsic cancer-related stress conditions, thus offering a selective advantage. Here we provide evidence that mutant p53 proteins can modulate the Unfolded Protein Response (UPR) to increase cell survival upon Endoplasmic Reticulum (ER) stress, a condition to which cancer cells are exposed during tumour formation and progression, as well as during therapy. Mechanistically, this action of mutant p53 is due to enhanced activation of the pro-survival UPR effector ATF6, coordinated with inhibition of the pro-apoptotic UPR effectors JNK and CHOP. In a triple-negative breast cancer cell model with missense TP53 mutation, we found that ATF6 activity is necessary for viability and invasion phenotypes. Together, these findings suggest that ATF6 inhibitors might be combined with mutant p53-targeting drugs to specifically sensitise cancer cells to endogenous or chemotherapy-induced ER stress.

DOI: https://doi.org/10.1038/s41388-019-0878-3