bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2022‒05‒29
seven papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge
  1. Hidden Agenda - The Involvement of Endoplasmic Reticulum Stress and Unfolded Protein Response in Inflammation-Induced Muscle Wasting.
  2. Arsenic Activates the ER Stress-Associated Unfolded Protein Response via the Activating Transcription Factor 6 in Human Bronchial Epithelial Cells.
  3. Studies in Rats of Combined Muscle and Liver Perfusion and of Muscle Extract Indicate That Contractions Release a Muscle Hormone Directly Enhancing Hepatic Glycogenolysis.
  4. Dysfunction of the energy sensor NFE2L1 triggers uncontrollable AMPK signaling and glucose metabolism reprogramming.
  5. Developing dietary interventions as therapy for cancer.
  6. ATF6 Activation Reduces Amyloidogenic Transthyretin Secretion through Increased Interactions with Endoplasmic Reticulum Proteostasis Factors.
  7. NLRP3 Inflammasome Activation: A Therapeutic Target for Cerebral Ischemia-Reperfusion Injury.
  1. Front Immunol. 2022 ;13 878755
    Hidden Agenda - The Involvement of Endoplasmic Reticulum Stress and Unfolded Protein Response in Inflammation-Induced Muscle Wasting.
    Melanie Kny, Jens Fielitz.
      Critically ill patients at the intensive care unit (ICU) often develop a generalized weakness, called ICU-acquired weakness (ICUAW). A major contributor to ICUAW is muscle atrophy, a loss of skeletal muscle mass and function. Skeletal muscle assures almost all of the vital functions of our body. It adapts rapidly in response to physiological as well as pathological stress, such as inactivity, immobilization, and inflammation. In response to a reduced workload or inflammation muscle atrophy develops. Recent work suggests that adaptive or maladaptive processes in the endoplasmic reticulum (ER), also known as sarcoplasmic reticulum, contributes to this process. In muscle cells, the ER is a highly specialized cellular organelle that assures calcium homeostasis and therefore muscle contraction. The ER also assures correct folding of proteins that are secreted or localized to the cell membrane. Protein folding is a highly error prone process and accumulation of misfolded or unfolded proteins can cause ER stress, which is counteracted by the activation of a signaling network known as the unfolded protein response (UPR). Three ER membrane residing molecules, protein kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring protein 1a (IRE1a), and activating transcription factor 6 (ATF6) initiate the UPR. The UPR aims to restore ER homeostasis by reducing overall protein synthesis and increasing gene expression of various ER chaperone proteins. If ER stress persists or cannot be resolved cell death pathways are activated. Although, ER stress-induced UPR pathways are known to be important for regulation of skeletal muscle mass and function as well as for inflammation and immune response its function in ICUAW is still elusive. Given recent advances in the development of ER stress modifying molecules for neurodegenerative diseases and cancer, it is important to know whether or not therapeutic interventions in ER stress pathways have favorable effects and these compounds can be used to prevent or treat ICUAW. In this review, we focus on the role of ER stress-induced UPR in skeletal muscle during critical illness and in response to predisposing risk factors such as immobilization, starvation and inflammation as well as ICUAW treatment to foster research for this devastating clinical problem.
    Keywords:  endoplasmic reticulum stress; inflammation; intensive care unit acquired weakness; sepsis; unfolded protein response
    DOI:  https://doi.org/10.3389/fimmu.2022.878755
  2. Biomedicines. 2022 Apr 22. pii: 967. [Epub ahead of print]10(5):
    Arsenic Activates the ER Stress-Associated Unfolded Protein Response via the Activating Transcription Factor 6 in Human Bronchial Epithelial Cells.
    Priya Wadgaonkar, Zhuoyue Bi, Junmei Wan, Yao Fu, Qian Zhang, Bandar Almutairy, Wenxuan Zhang, Yiran Qiu, Chitra Thakur, Maik Hüttemann, Fei Chen.
      Arsenic is a well-known human carcinogen associated with a number of cancers, including lung cancers. We have previously shown that long-term exposure to an environmentally relevant concentration of inorganic arsenic (As3+) leads to the malignant transformation of the BEAS2B cells, and some of the transformed cells show cancer stem-like features (CSCs) with a significant upregulation of glycolysis and downregulation of mitochondrial oxidative phosphorylation. In the present report, we investigate the short-term effect of As3+ on the endoplasmic reticulum (ER) stress response-the "unfolded protein response (UPR)" and metabolism in human bronchial epithelial cell line BEAS-2B cells. Treatment of the cells with inorganic As3+ upregulated both glycolysis and mitochondrial respiration. Analysis of ER UPR signaling pathway using a real-time human UPR array revealed that As3+ induced a significant up-regulation of some UPR genes, including ATF6, CEBPB, MAPK10, Hsp70, and UBE2G2. Additional tests confirmed that the induction of ATF6, ATF6B and UBE2G2 mRNAs and/or proteins by As3+ is dose dependent. Chromosome immunoprecipitation and global sequencing indicated a critical role of Nrf2 in mediating As3+-induced expression of these UPR genes. In summary, our data suggest that As3+ is able to regulate the ER stress response, possibly through activating the ATF6 signaling.
    Keywords:  ATF6; ER stress; Nrf2; UPR; arsenic; metabolism
    DOI:  https://doi.org/10.3390/biomedicines10050967
  3. J Pers Med. 2022 May 20. pii: 837. [Epub ahead of print]12(5):
    Studies in Rats of Combined Muscle and Liver Perfusion and of Muscle Extract Indicate That Contractions Release a Muscle Hormone Directly Enhancing Hepatic Glycogenolysis.
    Xiao X Han, Jens J Holst, Henrik Galbo.
      BACKGROUND: Established neuroendocrine signals do not sufficiently account for the exercise-induced increase in glucose production. Using an innovative, yet classical cross-circulation procedure, we studied whether contracting muscle produces a factor that directly stimulates hepatic glycogenolysis.METHODS: Isolated rat hindquarters were perfused in series with isolated livers.
    RESULTS: Stimulation of the sciatic nerve of one or both legs resulted in an increase in force, which rapidly waned. During one-legged contractions, hepatic glucose production increased initially (from -0.9 ± 0.5 (mean ± SE) to 3.3 ± 0.7 µmol/min, p < 0.05). The peak did not differ significantly from that seen after 20 nM of epinephrine (5.1 ± 1.2 µmol/min, p > 0.05). In response to two-legged contractions, the increase in hepatic glucose production (to 5.4 ± 1.3 µmol/min) was higher (p < 0.05) and lasted longer than that seen during one-legged contractions. During contractions, peak hepatic glucose output exceeded concomitant hepatic lactate uptake (p < 0.05), and glucose output decreased to basal levels, while lactate uptake rose to a plateau. Furthermore, in separate experiments an increase in lactate supply to isolated perfused livers increased lactate uptake, but not glucose output. In intact rats, intra-arterial injection of extract made from mixed leg muscle elicited a prolonged increase (p < 0.05) in plasma glucose concentration (from 5.2 ± 0.1 mM to 8.3 ± 1.5 mM). In perfused livers, muscle extract increased glucose output dose dependently. Fractionation by chromatography of the extract showed that the active substance had a MW below 2000.
    CONCLUSION: This study provides evidence that contracting skeletal muscle may produce a hormone with a MW below 2000, which enhances hepatic glycogenolysis according to energy needs. Further chemical characterization is warranted.
    Keywords:  exercise; glucose; glucose turnover; liver; muscle contraction; myokine
    DOI:  https://doi.org/10.3390/jpm12050837
  4. Cell Death Dis. 2022 May 25. 13(5): 501
    Dysfunction of the energy sensor NFE2L1 triggers uncontrollable AMPK signaling and glucose metabolism reprogramming.
    Lu Qiu, Qiufang Yang, Wenshan Zhao, Yadi Xing, Peng Li, Xiaowen Zhou, Haoming Ning, Ranran Shi, Shanshan Gou, Yalan Chen, Wenjie Zhai, Yahong Wu, Guodong Li, Zhenzhen Chen, Yonggang Ren, Yanfeng Gao, Yiguo Zhang, Yuanming Qi.
      The antioxidant transcription factor NFE2L1 (also called Nrf1) acts as a core regulator of redox signaling and metabolism homeostasis, and thus, its dysfunction results in multiple systemic metabolic diseases. However, the molecular mechanism(s) by which NFE2L1 regulates glycose and lipid metabolism remains elusive. Here, we found that loss of NFE2L1 in human HepG2 cells led to a lethal phenotype upon glucose deprivation and NFE2L1 deficiency could affect the uptake of glucose. Further experiments revealed that glycosylation of NFE2L1 enabled it to sense the energy state. These results indicated that NFE2L1 can serve as a dual sensor and regulator of glucose homeostasis. The transcriptome, metabolome, and seahorse data further revealed that disruption of NFE2L1 could reprogram glucose metabolism to aggravate the Warburg effect in NFE2L1-silenced hepatoma cells, concomitant with mitochondrial damage. Co-expression and Co-immunoprecipitation experiments demonstrated that NFE2L1 could directly interact and inhibit AMPK. Collectively, NFE2L1 functioned as an energy sensor and negatively regulated AMPK signaling through directly interacting with AMPK. The novel NFE2L1/AMPK signaling pathway delineate the mechanism underlying of NFE2L1-related metabolic diseases and highlight the crosstalk between redox homeostasis and metabolism homeostasis.
    DOI:  https://doi.org/10.1038/s41419-022-04917-3
  5. Nat Rev Cancer. 2022 May 25.
    Developing dietary interventions as therapy for cancer.
    Samuel R Taylor, John N Falcone, Lewis C Cantley, Marcus D Goncalves.
      Cancer cells acquire distinct metabolic preferences based on their tissue of origin, genetic alterations and degree of interaction with systemic hormones and metabolites. These adaptations support the increased nutrient demand required for increased growth and proliferation. Diet is the major source of nutrients for tumours, yet dietary interventions lack robust evidence and are rarely prescribed by clinicians for the treatment of cancer. Well-controlled diet studies in patients with cancer are rare, and existing studies have been limited by nonspecific enrolment criteria that inappropriately grouped together subjects with disparate tumour and host metabolic profiles. This imprecision may have masked the efficacy of the intervention for appropriate candidates. Here, we review the metabolic alterations and key vulnerabilities that occur across multiple types of cancer. We describe how these vulnerabilities could potentially be targeted using dietary therapies including energy or macronutrient restriction and intermittent fasting regimens. We also discuss recent trials that highlight how dietary strategies may be combined with pharmacological therapies to treat some cancers, potentially ushering a path towards precision nutrition for cancer.
    DOI:  https://doi.org/10.1038/s41568-022-00485-y
  6. Cells. 2022 May 17. pii: 1661. [Epub ahead of print]11(10):
    ATF6 Activation Reduces Amyloidogenic Transthyretin Secretion through Increased Interactions with Endoplasmic Reticulum Proteostasis Factors.
    Jaleh S Mesgarzadeh, Isabelle C Romine, Ethan M Smith-Cohen, Julia M D Grandjean, Jeffery W Kelly, Joseph C Genereux, R Luke Wiseman.
      The extracellular aggregation of destabilized transthyretin (TTR) variants is implicated in the onset and pathogenesis of familial TTR-related amyloid diseases. One strategy to reduce the toxic, extracellular aggregation of TTR is to decrease the population of aggregation-prone proteins secreted from mammalian cells. The stress-independent activation of the unfolded protein response (UPR)-associated transcription factor ATF6 preferentially decreases the secretion and subsequent aggregation of destabilized, aggregation-prone TTR variants. However, the mechanism of this reduced secretion was previously undefined. Here, we implement a mass-spectrometry-based interactomics approach to identify endoplasmic reticulum (ER) proteostasis factors involved in ATF6-dependent reductions in destabilized TTR secretion. We show that ATF6 activation reduces amyloidogenic TTR secretion and subsequent aggregation through a mechanism involving ER retention that is mediated by increased interactions with ATF6-regulated ER proteostasis factors including BiP and PDIA4. Intriguingly, the PDIA4-dependent retention of TTR is independent of both the single TTR cysteine residue and the redox activity of PDIA4, indicating that PDIA4 retains destabilized TTR in the ER through a redox-independent mechanism. Our results define a mechanistic basis to explain the ATF6 activation-dependent reduction in destabilized, amyloidogenic TTR secretion that could be therapeutically accessed to improve treatments of TTR-related amyloid diseases.
    Keywords:  ATF6; ER proteostasis; amyloid disease; extracellular proteostasis; protein aggregation; protein disulfide isomerase (PDI); unfolded protein response (UPR)
    DOI:  https://doi.org/10.3390/cells11101661
  7. Front Mol Neurosci. 2022 ;15 847440
    NLRP3 Inflammasome Activation: A Therapeutic Target for Cerebral Ischemia-Reperfusion Injury.
    Lixia Wang, Wei Ren, Qingjuan Wu, Tianzhu Liu, Ying Wei, Jiru Ding, Chen Zhou, Houping Xu, Sijin Yang.
      Millions of patients are suffering from ischemic stroke, it is urgent to figure out the pathogenesis of cerebral ischemia-reperfusion (I/R) injury in order to find an effective cure. After I/R injury, pro-inflammatory cytokines especially interleukin-1β (IL-1β) upregulates in ischemic brain cells, such as microglia and neuron. To ameliorate the inflammation after cerebral I/R injury, nucleotide-binding oligomerization domain (NOD), leucine-rich repeat (LRR), and pyrin domain-containing protein 3 (NLRP3) inflammasome is well-investigated. NLRP3 inflammasomes are complicated protein complexes that are activated by endogenous and exogenous danger signals to participate in the inflammatory response. The assembly and activation of the NLRP3 inflammasome lead to the caspase-1-dependent release of pro-inflammatory cytokines, such as interleukin (IL)-1β and IL-18. Furthermore, pyroptosis is a pro-inflammatory cell death that occurs in a dependent manner on NLRP3 inflammasomes after cerebral I/R injury. In this review, we summarized the assembly and activation of NLRP3 inflammasome; moreover, we also concluded the pivotal role of NLRP3 inflammasome and inhibitors, targeting the NLRP3 inflammasome in cerebral I/R injury.
    Keywords:  NLRP3 inflammasome activation; cerebral I/R injury; ischemic stroke; mitochondrion; pyroptosis
    DOI:  https://doi.org/10.3389/fnmol.2022.847440
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