bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2024–03–17
six papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. The Integrated Stress Response in metabolic adaptation.
  2. GFRAL Is Widely Distributed in the Brain and Peripheral Tissues of Mice.
  3. Endoplasmic reticulum stress enhances the expression of TLR3-induced TSLP by airway epithelium.
  4. Cancer cachexia reduces the efficacy of immune checkpoint inhibitors in cancer patients.
  5. Hypoxia and low-glucose environments co-induced HGDILnc1 promote glycolysis and angiogenesis.
  6. Multiple Myeloma Derived Extracellular Vesicle Uptake by Monocyte Cells Stimulates IL-6 and MMP-9 Secretion and Promotes Cancer Cell Migration and Proliferation.
  1. J Biol Chem. 2024 Mar 08. pii: S0021-9258(24)01646-6. [Epub ahead of print] 107151
    The Integrated Stress Response in metabolic adaptation.
    Hyung Don Ryoo.
      The Integrated Stress Response (ISR) refers to signaling pathways initiated by stress-activated eIF2‹ kinases. Distinct eIF2‹ kinases respond to different stress signals, including amino acid deprivation and mitochondrial stress. Such stress-induced eIF2‹ phosphorylation attenuates general mRNA translation and, at the same time, stimulates the preferential translation of specific downstream factors to orchestrate an adaptive gene expression program. In recent years, there have been significant new advances in our understanding of ISR during metabolic stress adaptation. Here, I discuss those advances, reviewing among others the ISR activation mechanisms in response to amino acid deprivation and mitochondrial stress. In addition, I review how ISR regulates the amino acid metabolic pathways and how changes in the ISR impact the physiology and pathology of various disease models.
    Keywords:  ATF4; GCN1; GCN2; HRI; Integrated Stress Response; amino acid deprivation; cysteine; eIF2‹; glutathione; mitochondrial stress; serine biosynthesis
    DOI:  https://doi.org/10.1016/j.jbc.2024.107151
  2. Nutrients. 2024 Mar 04. pii: 734. [Epub ahead of print]16(5):
    GFRAL Is Widely Distributed in the Brain and Peripheral Tissues of Mice.
    Karoline Fichtner, Hermann Kalwa, Miao-Miao Lin, Yuanyuan Gong, Anne Müglitz, Michael Kluge, Ute Krügel.
      In 2017, four independent publications described the glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as receptor for the growth differentiation factor 15 (GDF15, also MIC-1, NAG-1) with an expression exclusively in the mice brainstem area postrema (AP) and nucleus tractus solitarii (NTS) where it mediates effects of GDF15 on reduction of food intake and body weight. GDF15 is a cell stress cytokine with a widespread expression and pleiotropic effects, which both seem to be in contrast to the reported highly specialized localization of its receptor. This discrepancy prompts us to re-evaluate the expression pattern of GFRAL in the brain and peripheral tissues of mice. In this detailed immunohistochemical study, we provide evidence for a more widespread distribution of this receptor. Apart from the AP/NTS region, GFRAL-immunoreactivity was found in the prefrontal cortex, hippocampus, nucleus arcuatus and peripheral tissues including liver, small intestine, fat, kidney and muscle tissues. This widespread receptor expression, not taken into consideration so far, may explain the multiple effects of GDF-15 that are not yet assigned to GFRAL. Furthermore, our results could be relevant for the development of novel pharmacological therapies for physical and mental disorders related to body image and food intake, such as eating disorders, cachexia and obesity.
    Keywords:  GFRAL; brain; immunohistochemistry; peripheral tissue
    DOI:  https://doi.org/10.3390/nu16050734
  3. Am J Physiol Lung Cell Mol Physiol. 2024 Mar 12.
    Endoplasmic reticulum stress enhances the expression of TLR3-induced TSLP by airway epithelium.
    Prabuddha S Pathinayake, Alan C-Y Hsu, Kristy S Nichol, Jay C Horvat, Philip M Hansbro, Peter A Wark.
      Thymic stromal lymphopoietin (TSLP) is an epithelial-derived pleiotropic cytokine that regulates T-helper 2 (Th2) immune responses in the lung and plays a major role in severe uncontrolled asthma. Emerging evidence suggests a role for endoplasmic reticulum (ER) stress in the pathogenesis of asthma. In this study, we determined if ER stress and the unfolded protein response (UPR) signalling are involved in TSLP induction in the airway epithelium. For this, we treated human bronchial epithelial basal cells and differentiated primary bronchial epithelial cells with ER stress inducers and the TSLP mRNA and protein expression was determined. A series of siRNA gene knockdown experiments were conducted to determine the ER stress-induced TSLP signalling pathways. cDNA collected from asthmatic bronchial biopsies was used to determine the gene correlation between ER stress and TSLP. Our results show that ER stress signalling induces TSLP mRNA expression via the PERK-CHOP signalling pathway. AP-1 transcription factor is important in regulating this ER stress-induced TSLP mRNA induction, though ER stress alone cannot induce TSLP protein production. However, ER stress significantly enhances TLR3-induced TSLP protein secretion in the airway epithelium. TSLP and ER stress (PERK) mRNA expression positively correlates in bronchial biopsies from participants with asthma, particularly in neutrophilic asthma. In conclusion, these results suggest that ER stress primes TSLP which is then enhanced further upon TLR3 activation, which may induce severe asthma exacerbations. Targeting ER stress using pharmacological interventions may provide novel therapeutics for severe uncontrolled asthma.
    Keywords:  ER Stress; Severe Neutrophilic asthma; TSLP; Unfolded Protein Response
    DOI:  https://doi.org/10.1152/ajplung.00378.2023
  4. Aging (Albany NY). 2024 Mar 11. 16
    Cancer cachexia reduces the efficacy of immune checkpoint inhibitors in cancer patients.
    Yean Yu, Li Yan, Tianhui Huang, Zhenfu Wu, Juan Liu.
       OBJECTIVE: Cachexia, a multifactorial syndrome, is frequently noticed in cancer patients. A recent study has shown inconsistent findings about the relationship between cachexia and the efficiency of immune checkpoint inhibitors (ICIs). To analyze this disparity, we did a meta-analysis.
    METHODS: From the beginning of each database to July 2023, literature describing the association between cachexia and prognosis of ICI-treated patients with solid malignancies was systematically searched in three online databases. Estimates were pooled, and 95% confidence intervals (CIs) were generated.
    RESULTS: We analyzed a total of 12 articles, which included data from 1407 patients. The combined results of our analysis showed that cancer patients with cachexia had significantly worse overall survival (HR = 1.88, 95% CI: 1.59-2.22, p < 0.001), progression-free survival (HR = 1.84, 95% CI: 1.59-2.12, p < 0.001), and time to treatment failure (HR = 2.15, 95% CI: 1.32-3.50, p = 0.002). These findings were consistent in both univariate and multivariate analyses. Additionally, while not statistically significant, we observed a trend towards a lower objective response rate in cancer patients with cachexia compared to those without cachexia (OR = 0.59, 95% CI: 0.32-1.09, p = 0.093).
    CONCLUSION: Poor survival in cachexia patients suggests a negative relationship between cachexia and ICI efficacy. In clinical practice, the existence of cachexia should be estimated to choose individuals who may benefit from ICIs.
    Keywords:  cachexia; cancers; immune checkpoint inhibitors; non-small cell lung cancer
    DOI:  https://doi.org/10.18632/aging.205652
  5. Cell Death Discov. 2024 Mar 12. 10(1): 132
    Hypoxia and low-glucose environments co-induced HGDILnc1 promote glycolysis and angiogenesis.
    Qing-Wei Zhang, Xiao-Lu Lin, Zi-Hao Dai, Ran Zhao, Yi-Chao Hou, Qian Liang, Yan Zhang, Zhi-Zheng Ge.
      Small bowel vascular malformation disease (SBVM) commonly causes obscure gastrointestinal bleeding (OGIB). However, the pathogenetic mechanism and the role of lncRNAs in SBVM remain largely unknown. Here, we found that hypoxia and low-glucose environments co-augment angiogenesis and existed in SBVM. Mechanistically, hypoxia and low-glucose environments supported angiogenesis via activation of hypoxia and glucose deprivation-induced lncRNA (HGDILnc1) transcription by increasing binding of the NeuroD1 transcription factor to the HGDILnc1 promoter. Raised HGDILnc1 acted as a suppressor of α-Enolase 1 (ENO1) small ubiquitin-like modifier modification (SUMOylation)-triggered ubiquitination, and an activator of transcription of Aldolase C (ALDOC) via upregulation of Histone H2B lysine 16 acetylation (H2BK16ac) level in the promoter of ALDOC, and consequently promoting glycolysis and angiogenesis. Moreover, HGDILnc1 was clinically positively correlated with Neurogenic differentiation 1 (NeuroD1), ENO1, and ALDOC in SBVM tissues, and could function as a biomarker for SBVM diagnosis and therapy. These findings suggest that hypoxia and low-glucose environments were present in SBVM tissues, and co-augmented angiogenesis. Hypoxia and low-glucose environments co-induced HGDILnc1, which is higher expressed in SBVM tissue compared with normal tissue, could promoted glycolysis and angiogenesis.
    DOI:  https://doi.org/10.1038/s41420-024-01903-w
  6. Cancers (Basel). 2024 Feb 29. pii: 1011. [Epub ahead of print]16(5):
    Multiple Myeloma Derived Extracellular Vesicle Uptake by Monocyte Cells Stimulates IL-6 and MMP-9 Secretion and Promotes Cancer Cell Migration and Proliferation.
    Rebecca Sheridan, Kieran Brennan, Despina Bazou, Peter O'Gorman, David Matallanas, Margaret M Mc Gee.
      Multiple Myeloma (MM) is an incurable haematological malignancy caused by uncontrolled growth of plasma cells. MM pathogenesis is attributed to crosstalk between plasma cells and the bone marrow microenvironment, where extracellular vesicles (EVs) play a role. In this study, EVs secreted from a panel of MM cell lines were isolated from conditioned media by ultracentrifugation and fluorescently stained EVs were co-cultured with THP-1 monocyte cells. MM EVs from three cell lines displayed a differential yet dose-dependent uptake by THP-1 cells, with H929 EVs displaying the greatest EV uptake compared to MM.1s and U266 EVs suggesting that uptake efficiency is dependent on the cell line of origin. Furthermore, MM EVs increased the secretion of MMP-9 and IL-6 from monocytes, with H929 EVs inducing the greatest effect, consistent with the greatest uptake efficiency. Moreover, monocyte-conditioned media collected following H929 EV uptake significantly increased the migration and proliferation of MM cells. Finally, EV proteome analysis revealed differential cargo enrichment that correlates with disease progression including a significant enrichment of spliceosome-related proteins in H929 EVs compared to the U266 and MM.1s EVs. Overall, this study demonstrates that MM-derived EVs modulate monocyte function to promote tumour growth and metastasis and reveals possible molecular mechanisms involved.
    Keywords:  bone marrow microenvironment; cancer; extracellular vesicles; metastasis; multiple myeloma; spliceosome
    DOI:  https://doi.org/10.3390/cancers16051011
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