bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2023–11–12
six papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Mitochondrial dysfunction decreases cisplatin sensitivity in gastric cancer cells through upregulation of integrated stress response and mitokine GDF15.
  2. New perspectives in cancer immunotherapy: targeting IL-6 cytokine family.
  3. IL-6/JAK2-dependent G6PD phosphorylation promotes nucleotide synthesis and supports tumor growth.
  4. Fumarate hydratase as a metabolic regulator of immunity.
  5. Breast adipose tissue-derived extracellular vesicles from obese women alter tumor cell metabolism.
  6. Hipoxia modulates the secretion of growth factors of human umbilical cord-derived mesenchymal stem cells.
  1. FEBS J. 2023 Nov 07.
    Mitochondrial dysfunction decreases cisplatin sensitivity in gastric cancer cells through upregulation of integrated stress response and mitokine GDF15.
    Sheng-Fan Wang, Yuh-Lih Chang, Ting-Yu Liu, Kuo-Hung Huang, Wen-Liang Fang, Anna Fen-Yau Li, Tien-Shun Yeh, Giun-Yi Hung, Hsin-Chen Lee.
      Gastric neoplasm is a high-mortality cancer worldwide. Chemoresistance is the obstacle against gastric cancer treatment. Mitochondrial dysfunction has been observed to promote malignant progression. However, the underlying mechanism is still unclear. The mitokine growth differentiation factor 15 (GDF15) is a significant biomarker for mitochondrial disorder and is activated by the integrated stress response (ISR) pathway. The serum level of GDF15 was found to be correlated with the poor prognosis of gastric cancer patients. In this study, we found that high GDF15 protein expression might increase disease recurrence in adjuvant chemotherapy-treated gastric cancer patients. Moreover, treatment with mitochondrial inhibitors, especially oligomycin (a complex V inhibitor) and salubrinal (an ISR activator), respectively, was found to upregulate GDF15 and enhance cisplatin insensitivity of human gastric cancer cells. Mechanistically, it was found that the activating transcription factor 4 (ATF4)-C/EBP homologous protein (CHOP) pathway has a crucial function in the heightened manifestation of GDF15. In addition, reactive oxygen species (ROS)-activated general control nonderepressible 2 (GCN2) mediates the oligomycin-induced ISR, and upregulates GDF15. The GDF15-glial cell-derived neurotrophic factor family receptor a-like (GFRAL)-ISR-cystine/glutamate transporter (xCT)-enhanced glutathione production was found to be involved in cisplatin resistance. These results suggest that mitochondrial dysfunction might enhance cisplatin insensitivity through GDF15 upregulation, and targeting mitokine GDF15-ISR regulation might be a strategy against cisplatin resistance of gastric cancer.
    Keywords:  Gastric cancer; chemoresistance; growth differentiation factor 15; integrated stress response; mitochondria
    DOI:  https://doi.org/10.1111/febs.16992
  2. J Immunother Cancer. 2023 Nov;pii: e007530. [Epub ahead of print]11(11):
    New perspectives in cancer immunotherapy: targeting IL-6 cytokine family.
    Maria Florencia Soler, Andrea Abaurrea, Peio Azcoaga, Angela M Araujo, Maria M Caffarel.
      Chronic inflammation has been recognized as a canonical cancer hallmark. It is orchestrated by cytokines, which are master regulators of the tumor microenvironment (TME) as they represent the main communication bridge between cancer cells, the tumor stroma, and the immune system. Interleukin (IL)-6 represents a keystone cytokine in the link between inflammation and cancer. Many cytokines from the IL-6 family, which includes IL-6, oncostatin M, leukemia inhibitory factor, IL-11, IL-27, IL-31, ciliary neurotrophic factor, cardiotrophin 1, and cardiotrophin-like cytokine factor 1, have been shown to elicit tumor-promoting roles by modulating the TME, making them attractive therapeutic targets for cancer treatment.The development of immune checkpoint blockade (ICB) immunotherapies has radically changed the outcome of some cancers including melanoma, lung, and renal, although not without hurdles. However, ICB shows limited efficacy in other solid tumors. Recent reports support that chronic inflammation and IL-6 cytokine signaling are involved in resistance to immunotherapy. This review summarizes the available preclinical and clinical data regarding the implication of IL-6-related cytokines in regulating the immune TME and the response to ICB. Moreover, the potential clinical benefit of combining ICB with therapies targeting IL-6 cytokine members for cancer treatment is discussed.
    Keywords:  Cytokines; Immune Checkpoint Inhibitors; Immunotherapy; Inflammation Mediators; Tumor Microenvironment
    DOI:  https://doi.org/10.1136/jitc-2023-007530
  3. Mol Metab. 2023 Nov 08. pii: S2212-8778(23)00170-9. [Epub ahead of print] 101836
    IL-6/JAK2-dependent G6PD phosphorylation promotes nucleotide synthesis and supports tumor growth.
    Xuemei Qiu, Hongping Ye, Xiaofei Li, Dan Li, Lu Jiang, Rui Liu, Zhe Zhao, Dan He.
      Tumor cells hijack inflammatory mechanisms to promote their own growth. IL-6 is one of the major cytokines, and is frequently upregulated in tumors. The pentose phosphate pathway (PPP) generates the indispensable building blocks to produce various nucleotides. However, whether and how PPP is timely tuned in response to IL-6 to support tumor growth remains largely unknown. Here we show that the metabolic flux of PPP and enzymatic activity of glucose-6-phosphate dehydrogenase (G6PD) is rapidly induced under IL-6 treatment, without obvious changes in G6PD expression level. Mechanistically, Janus kinase 2 (JAK2) phosphorylates G6PD Y437 under IL-6 treatment, which accentuates G6PD enzymatic activity by promoting G6PD binding with its substrate G6P. Further, JAK2-dependent G6PD Y437 phosphorylation is required for IL-6-induced nucleotide biosynthesis and tumor cell proliferation, and is associated with the progression of oral squamous cell carcinoma. Our findings report a new mechanism implicated in the crosstalk between tumor cells and inflammatory microenvironment, by which JAK2-dependent activation of G6PD governs nucleotide synthesis to support tumor cell proliferation, thereby highlighting its value as a potential anti-tumor target.
    Keywords:  G6PD; JAK2; nucleotide metabolism; pentose phosphate pathway; tumorigenesis
    DOI:  https://doi.org/10.1016/j.molmet.2023.101836
  4. Trends Cell Biol. 2023 Nov 06. pii: S0962-8924(23)00209-X. [Epub ahead of print]
    Fumarate hydratase as a metabolic regulator of immunity.
    Christian G Peace, Shane M O'Carroll, Luke A J O'Neill.
      Tricarboxylic acid (TCA) cycle metabolites have been implicated in modulating signalling pathways in immune cells. Notable examples include succinate and itaconate, which have pro- and anti-inflammatory roles, respectively. Recently, fumarate has emerged as having specific roles in macrophage activation, regulating the production of such cytokines as interleukin (IL)-10 and type I interferons (IFNs). Fumarate hydratase (FH) has been identified as a control point. Notably, FH loss in different models and cell types has been found to lead to DNA and RNA release from mitochondria which are sensed by cytosolic nucleic acid sensors including retinoic acid-inducible gene (RIG)-I, melanoma differentiation-associated protein (MDA)5, and cyclic GMP-AMP synthase (cGAS) to upregulate IFN-β production. These findings may have relevance in the pathogenesis and treatment of diseases associated with decreased FH levels such as systemic lupus erythematosus (SLE) or FH-deficient kidney cancer.
    Keywords:  immunometabolism; innate immunity; interferon; mitochondria
    DOI:  https://doi.org/10.1016/j.tcb.2023.10.005
  5. EMBO Rep. 2023 Nov 06. e57339
    Breast adipose tissue-derived extracellular vesicles from obese women alter tumor cell metabolism.
    Shuchen Liu, Alberto Benito-Martin, Fanny A Pelissier Vatter, Sarah Z Hanif, Catherine Liu, Priya Bhardwaj, Praveen Sethupathy, Alaa R Farghli, Phoebe Piloco, Paul Paik, Malik Mushannen, Xue Dong, David M Otterburn, Leslie Cohen, Rohan Bareja, Jan Krumsiek, Leona Cohen-Gould, Samuel Calto, Jason A Spector, Olivier Elemento, David C Lyden, Kristy A Brown.
      Breast adipose tissue is an important contributor to the obesity-breast cancer link. Extracellular vesicles (EVs) are nanosized particles containing selective cargo, such as miRNAs, that act locally or circulate to distant sites to modulate target cell functions. Here, we find that long-term education of breast cancer cells with EVs obtained from breast adipose tissue of women who are overweight or obese (O-EVs) results in increased proliferation. RNA-seq analysis of O-EV-educated cells demonstrates increased expression of genes involved in oxidative phosphorylation, such as ATP synthase and NADH: ubiquinone oxidoreductase. O-EVs increase respiratory complex protein expression, mitochondrial density, and mitochondrial respiration in tumor cells. The mitochondrial complex I inhibitor metformin reverses O-EV-induced cell proliferation. Several miRNAs-miR-155-5p, miR-10a-3p, and miR-30a-3p-which promote mitochondrial respiration and proliferation, are enriched in O-EVs relative to EVs from lean women. O-EV-induced proliferation and mitochondrial activity are associated with stimulation of the Akt/mTOR/P70S6K pathway, and are reversed upon silencing of P70S6K. This study reveals a new facet of the obesity-breast cancer link with human breast adipose tissue-derived EVs causing metabolic reprogramming of breast cancer cells.
    Keywords:  breast cancer; extracellular vesicles; mitochondrial respiration; obesity; proliferation
    DOI:  https://doi.org/10.15252/embr.202357339
  6. Biomedicine (Taipei). 2023 ;13(3): 49-56
    Hipoxia modulates the secretion of growth factors of human umbilical cord-derived mesenchymal stem cells.
    Arfianti Arfianti, Ulfah, Leopold S Hutabarat, G Agnes Ivana, Anisa D Budiarti, Nabilla S Sahara, Nicko P K Saputra.
       Background: Mesenchymal stem cell (MSC) has great potential as therapies due its ability to regenerate tissue damage and promote tissue homeostasis. Preconditioning of MSC in low oxygen concentration has been shown to affect the therapeutic potential of these cells. This study aimed to compare the characteristic and secretion of trophic factors of MSCs cultured under hypoxia and normoxia.
    Methods: MSCs were isolated from Wharton's jelly of human umbilical cord (UC) tissue by explant method and characterized by flow cytometry. Following 24 h of CoCl2-induced hypoxic culture, the viability and metabolic activity of MSC were analyzed by trypan blue exclusion test and methyl thiazolyl tetrazolium (MTT) assay, respectively. The secretion of hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) was assessed in conditioned medium using enzyme-linked immunosorbent assay (ELISA) method.
    Results: Flow cytometry analysis showed >99% of the population of MSCs cells were positive for CD73 and CD90 and > 62% were positive for CD105. While the cell viability of MSC was not affected by hypoxic cultured condition, the metabolic activity rate of these cells was decreased under hypoxic conditioning. In line with reduced metabolic activity, hypoxic human UC-derived MSC produced less HGF than normoxic counterpart. Compared to normoxic MSC, hypoxic preconditioned MSC secreted higher level of VEGF in the conditioned medium (p < 0.05).
    Conclusions: Hypoxia decreased the metabolic activity of MSCs associated with the modulation of HGF and VEGF secretions. It is suggested that hypoxia may also affect the therapeutic capacity of MSC cells.
    Keywords:  CoCl2; Hepatocyte growth factor; Hypoxia; Mesenchymal stem cell; Vascular endothelial growth factor
    DOI:  https://doi.org/10.37796/2211-8039.1416
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