bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2024–08–18
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. IFNγ-Induced Bcl3, PD-L1 and IL-8 Signaling in Ovarian Cancer: Mechanisms and Clinical Significance.
  2. Manipulating mannose metabolism as a potential anticancer strategy.
  3. Integrated stress response activator halofuginone protects mice from diabetes-like phenotypes.
  4. Macrophages dig into the obesity paradox in cancer.
  5. Hypoxic microenvironment promotes diabetic wound healing by polarizing macrophages to the M2 phenotype in vivo.
  6. Diet restriction enhances the effect of immune checkpoint block by inhibiting the intratumoral mTORC1/B7-H3 axis.
  7. Activation of PERK/eIF2α/ATF4/CHOP branch of endoplasmic reticulum stress response and cooperation between HIF-1α and ATF4 promotes Daprodustat-induced vascular calcification.
  8. Intracellular pH differentially regulates transcription of metabolic and signaling pathways in normal epithelial cells.
  1. Cancers (Basel). 2024 Jul 27. pii: 2676. [Epub ahead of print]16(15):
    IFNγ-Induced Bcl3, PD-L1 and IL-8 Signaling in Ovarian Cancer: Mechanisms and Clinical Significance.
    Suprataptha U Reddy, Fatema Zohra Sadia, Ales Vancura, Ivana Vancurova.
      IFNγ, a pleiotropic cytokine produced not only by activated lymphocytes but also in response to cancer immunotherapies, has both antitumor and tumor-promoting functions. In ovarian cancer (OC) cells, the tumor-promoting functions of IFNγ are mediated by IFNγ-induced expression of Bcl3, PD-L1 and IL-8/CXCL8, which have long been known to have critical cellular functions as a proto-oncogene, an immune checkpoint ligand and a chemoattractant, respectively. However, overwhelming evidence has demonstrated that these three genes have tumor-promoting roles far beyond their originally identified functions. These tumor-promoting mechanisms include increased cancer cell proliferation, invasion, angiogenesis, metastasis, resistance to chemotherapy and immune escape. Recent studies have shown that IFNγ-induced Bcl3, PD-L1 and IL-8 expression is regulated by the same JAK1/STAT1 signaling pathway: IFNγ induces the expression of Bcl3, which then promotes the expression of PD-L1 and IL-8 in OC cells, resulting in their increased proliferation and migration. In this review, we summarize the recent findings on how IFNγ affects the tumor microenvironment and promotes tumor progression, with a special focus on ovarian cancer and on Bcl3, PD-L1 and IL-8/CXCL8 signaling. We also discuss promising novel combinatorial strategies in clinical trials targeting Bcl3, PD-L1 and IL-8 to increase the effectiveness of cancer immunotherapies.
    Keywords:  Bcl3; IFNγ; IL-8; PD-L1; cancer immunotherapies; immune checkpoint blockade; ovarian cancer; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers16152676
  2. FEBS J. 2024 Aug 11.
    Manipulating mannose metabolism as a potential anticancer strategy.
    Yoichiro Harada.
      Cancer cells acquire metabolic advantages over their normal counterparts regarding the use of nutrients for sustained cell proliferation and cell survival in the tumor microenvironment. Notable among the metabolic traits in cancer cells is the Warburg effect, which is a reprogrammed form of glycolysis that favors the rapid generation of ATP from glucose and the production of biological macromolecules by diverting glucose into various metabolic intermediates. Meanwhile, mannose, which is the C-2 epimer of glucose, has the ability to dampen the Warburg effect, resulting in slow-cycling cancer cells that are highly susceptible to chemotherapy. This anticancer effect of mannose appears when its catabolism is compromised in cancer cells. Moreover, de novo synthesis of mannose within cancer cells has also been identified as a potential target for enhancing chemosensitivity through targeting glycosylation pathways. The underlying mechanisms by which alterations in mannose metabolism induce cancer cell vulnerability are just beginning to emerge. This review summarizes the current state of our knowledge of mannose metabolism and provides insights into its manipulation as a potential anticancer strategy.
    Keywords:  Warburg effect; cancer; chemotherapy; glucose; glycolysis; glycosylation; mannose; metabolism; tumor
    DOI:  https://doi.org/10.1111/febs.17230
  3. J Cell Biol. 2024 Oct 07. pii: e202405175. [Epub ahead of print]223(10):
    Integrated stress response activator halofuginone protects mice from diabetes-like phenotypes.
    Shashank Rai, Maria Szaruga, Aleksandra P Pitera, Anne Bertolotti.
      The integrated stress response (ISR) is a vital signaling pathway initiated by four kinases, PERK, GCN2, HRI and PKR, that ensure cellular resilience and protect cells from challenges. Here, we investigated whether increasing ISR signaling could rescue diabetes-like phenotypes in a mouse model of diet-induced obesity (DIO). We show that the orally available and clinically approved GCN2 activator halofuginone (HF) can activate the ISR in mouse tissues. We found that daily oral administration of HF increases glucose tolerance whilst reducing weight gain, insulin resistance, and serum insulin in DIO mice. Conversely, the ISR inhibitor GSK2656157, used at low doses to optimize its selectivity, aggravates glucose intolerance in DIO mice. Whilst loss of function mutations in mice and humans have revealed that PERK is the essential ISR kinase that protects from diabetes, our work demonstrates the therapeutic value of increasing ISR signaling by activating the related kinase GCN2 to reduce diabetes phenotypes in a DIO mouse model.
    DOI:  https://doi.org/10.1083/jcb.202405175
  4. Immunity. 2024 Aug 13. pii: S1074-7613(24)00362-5. [Epub ahead of print]57(8): 1731-1733
    Macrophages dig into the obesity paradox in cancer.
    Christopher S Nabel, Florian Gourgue, Matthew G Vander Heiden.
      Response to immune checkpoint blockade is increased in obesity-related cancers, but the mechanisms remain unclear. In a recent issue of Nature, Bader et al. report that obesity in mice induces macrophage PD-1 upregulation to promote tumor growth while potentiating immunotherapy responses.
    DOI:  https://doi.org/10.1016/j.immuni.2024.07.013
  5. J Mol Histol. 2024 Aug 10.
    Hypoxic microenvironment promotes diabetic wound healing by polarizing macrophages to the M2 phenotype in vivo.
    Feiyu Cai, Peng Wang, Mengling Yuan, Wenjiao Chen, Yi Liu.
       BACKGROUND: In diabetic wounds, M2 polarization of macrophages regulates the transition from an inflammatory phase to a proliferative phase. Prior investigations have demonstrated the potential of deferoxamine (DFO) in creating a localized hypoxic microenvironment, which could stimulate angiogenesis by promoting vascular endothelial growth factor (VEGF) secretion in diabetic wound healing. Nevertheless, there is still no clear information on whether this chemically induced hypoxic microenvironment modulates macrophage polarization to promote diabetic wound healing.
    METHODS: The 18 diabetic mice were randomly divided into three groups: a control group (n = 6), a 100µM DFO group (n = 6), and a 200µM DFO group (n = 6). Subsequently, a full-thickness wound with a diameter of 1.00 cm was created on the dorsal region of the diabetic mice. Observe wound closure regularly during treatment. At the end of the observation, tissue specimens were collected for a series of experiments and analyses, including hematoxylin and eosin (H&E), Masson, immunofluorescent, and immunohistochemical staining. The role and mechanism of DFO in regulating macrophage polarization were studied using RAW264.7 cells.
    RESULTS: In comparison to the control group, the administration of DFO notably facilitates wound healing in diabetic mice. In diabetic wounds, DFO increases blood supply by upregulating VEGF, which promotes angiogenesis. Additionally, The expression of HSP70 and CD206 were also upregulated by DFO in both vivo and in vitro, while iNOS expression was downregulated. Additionally, knk437 inhibited the expression of HSP70 in RAW264.7 cells, resulting in a reduction of M2 polarization and an increase in M1 polarization.
    CONCLUSION: The induction of a hypoxic microenvironment by DFO has been found to exert a substantial influence on the process of diabetic wound healing. DFO treatment enhances the capacity of diabetic wounds to stimulate angiogenesis and modulate macrophage polarization that may be associated with HSP70 expression, thereby expediting the transition of these wounds from an inflammatory to a proliferative state.
    Keywords:  Deferoxamine; Diabetic wounds; Heat shock proteins; Hypoxic microenvironment; Macrophage polarization
    DOI:  https://doi.org/10.1007/s10735-024-10244-y
  6. J Biochem Mol Toxicol. 2024 Aug;38(8): e23803
    Diet restriction enhances the effect of immune checkpoint block by inhibiting the intratumoral mTORC1/B7-H3 axis.
    Duqing Xiao, Tingting Liu, Youguang Pan.
      Immune checkpoint blockade therapy has demonstrated significant therapeutic efficacy in certain cancer types; however, the impact of dietary restriction remains scarcely reported in this context. This study aimed to investigate the influence of dietary restriction on anti-PDL-1 therapy and the interplay of immune cells within this context. Using an anti-PDL-1 regimen combined with dietary restrictions, tumor progression was assessed in LLC-bearing mice. Flow cytometry was employed to analyze immune cell infiltration and differentiation levels within the tumor microenvironment. The expression of mTORC1/B7-H3 in tumors subjected to dietary restriction was also examined. LLC tumors with elevated B7-H3 expression were validated in mice to determine its inhibitory effect on immune cell proliferation and differentiation. A CD3/B7-H3 chimeric antibody was developed for therapeutic intervention in B7-H3 overexpressing tumors, with subsequent T cell responses assessed through flow cytometry. Dietary restriction potentiated the effect of anti-PDL1 therapy by suppressing the intratumorally mTORC1/B7-H3 axis. In vivo experiments demonstrated that elevated B7-H3 expression in tumors reduced infiltration and activation of CD8 + T cells within the tumor, while it did not affect tumor-infiltrating Tregs. In vitro studies revealed that high B7-H3 expression influenced the proliferation and activation of CD8 + T cells within a Coculture system. The constructed CD3/B7-H3 chimeric antibody prominently activated TCR within B7-H3 overexpressing tumors and impeded tumor progression. The findings suggest that dietary restriction enhances the efficacy of immune checkpoint blockade by modulating the intratumoral mTORC1/B7-H3 axis.
    Keywords:  B7‐H3; PDL‐1; dietary restrictions; immune checkpoint block; mTORC1
    DOI:  https://doi.org/10.1002/jbt.23803
  7. Front Pharmacol. 2024 ;15 1399248
    Activation of PERK/eIF2α/ATF4/CHOP branch of endoplasmic reticulum stress response and cooperation between HIF-1α and ATF4 promotes Daprodustat-induced vascular calcification.
    Andrea Tóth, Gréta Lente, Dávid Máté Csiki, Enikő Balogh, Árpád Szöőr, Béla Nagy, Viktória Jeney.
      Introduction: Vascular calcification is accelerated in patients with chronic kidney disease (CKD) and increases the risk of cardiovascular events. CKD is frequently associated with anemia. Daprodustat (DPD) is a prolyl hydroxylase inhibitor for the treatment of CKD-associated anemia that enhances erythropoiesis through the activation of the hypoxia-inducible factor 1 (HIF-1) pathway. Studies showed that DPD promotes osteogenic differentiation of human aortic smooth muscle cells (HAoSMCs) and increases aorta calcification in mice with CKD. HIF-1 activation has been linked with endoplasmic reticulum (ER) stress; therefore, here we investigated the potential contribution of ER stress, particularly activating transcription factor 4 (ATF4), to the pro-calcification effect of DPD. Methods: Here, we used an adenine-induced CKD mouse model and HAoSMCs as an in vitro vascular calcification model to study the effect of DPD. Results: DPD treatment (15 mg/kg/day) corrects anemia but increases the expression of hypoxia (Glut1, VEGFA), ER stress (ATF4, CHOP, and GRP78), and osteo-/chondrogenic (Runx2, Sox9, BMP2, and Msx2) markers and accelerates aorta and kidney calcification in CKD mice. DPD activates the PERK/eIF2α/ATF4/CHOP pathway and promotes high phosphate-induced osteo-/chondrogenic differentiation of HAoSMCs. Inhibition of ER stress with 4-PBA or silencing of ATF4 attenuates HAoSMC calcification. DPD-induced ATF4 expression is abolished in the absence of HIF-1α; however, knockdown of ATF4 does not affect HIF-1α expression. Conclusion: We concluded that DPD induces ER stress in vitro and in vivo, in which ATF4 serves as a downstream effector of HIF-1 activation. Targeting ATF4 could be a potential therapeutic approach to attenuate the pro-calcific effect of DPD.
    Keywords:  ATF4; Daprodustat; chronic kidney disease (CKD); endoplasmic reticulum stress; hypoxia-inducible factor 1; prolyl hydroxylase inhibitor; vascular calcification
    DOI:  https://doi.org/10.3389/fphar.2024.1399248
  8. J Biol Chem. 2024 Aug 09. pii: S0021-9258(24)02159-8. [Epub ahead of print] 107658
    Intracellular pH differentially regulates transcription of metabolic and signaling pathways in normal epithelial cells.
    Ricardo Romero-Moreno, Brandon J Czowski, Lindsey Harris, Jessamine F Kuehn, Katharine A White.
      Intracellular pH (pHi) dynamics regulate normal cell function, and dysregulated pHi dynamics is an emerging hallmark of cancer (constitutively increased pHi) and neurodegeneration (constitutively decreased pHi). However, the molecular mechanisms by which pHi dynamics regulate cell biology are poorly understood. Here, we discovered that altering pHi in normal human breast epithelial cells triggers global transcriptional changes. We identified 176 genes differentially regulated by pHi, with pHi-dependent genes clustering in signaling and glycolytic pathways. Using various normal epithelial cell models, we showed pH-dependent Notch1 expression, with increased protein abundance at high pHi. This resulted in pH-dependent downstream signaling, with increased Notch1 signaling at high pHi. We also found that high pHi increased the expression of glycolytic enzymes and regulators of pyruvate fate, including lactate dehydrogenase and pyruvate dehydrogenase kinase. These transcriptional changes were sufficient to alter lactate production, with high pHi shifting these normal epithelial cells toward a glycolytic metabolism and increasing lactate production. Thus, pHi dynamics transcriptionally regulate signaling and metabolic pathways in normal epithelial cells. Our data reveal new molecular regulators of pHi-dependent biology and a role for increased pHi in driving the acquisition of cancer-associated signaling and metabolic changes in normal human epithelial cells.
    Keywords:  Intracellular pH; Notch1 signaling; glycolysis; lactate; metabolism; pyruvate
    DOI:  https://doi.org/10.1016/j.jbc.2024.107658
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