bims-unfpre Biomed News
on Unfolded protein response
Issue of 2023–04–09
fiveteen papers selected by
Susan Logue, University of Manitoba
  1. The NK cell receptor NKp46 recognizes ecto-calreticulin on ER-stressed cells.
  2. PERK prevents rhodopsin degradation during retinitis pigmentosa by inhibiting IRE1-induced autophagy.
  3. HiBiT-SpyTag: A Minimal Tag for Covalent Protein Capture and Degrader Development.
  4. The dynamic role of endoplasmic reticulum stress in chronic liver disease.
  5. X-box Binding Protein 1: An Adaptor in the Pathogenesis of Atherosclerosis.
  6. Emerging evidence for poxvirus-mediated unfolded protein response: Lumpy skin disease virus maintains self-replication by activating PERK and IRE1 signaling.
  7. Normal tissue homeostasis and impairment of selective inflammatory responses in dendritic cells deficient for ATF6α.
  8. Endoplasmic reticulum stress contributes to pyroptosis through NF-κB/NLRP3 pathway in diabetic nephropathy.
  9. ER stress and the inflammatory response in allergic contact dermatitis.
  10. Musclin attenuates lipid deposition in hepatocytes through SIRT7/autophagy-mediated suppression of ER stress.
  11. Endoplasmic Reticulum Stress in Osteoarthritis: A Novel Perspective on the Pathogenesis and Treatment.
  12. The unfolded protein response transcription factor XBP1s ameliorates Alzheimer's disease by improving synaptic function and proteostasis.
  13. Wild-type and mutant p53 in cancer-related ferroptosis. A matter of stress management?
  14. Macrolide antibiotics activate the integrated stress response and promote tumor proliferation.
  15. Tumor microenvironment signaling and therapeutics in cancer progression.
  1. Nature. 2023 Apr 05.
    The NK cell receptor NKp46 recognizes ecto-calreticulin on ER-stressed cells.
    Sumit Sen Santara, Dian-Jang Lee, Ângela Crespo, Jun Jacob Hu, Caitlin Walker, Xiyu Ma, Ying Zhang, Sourav Chowdhury, Karla F Meza-Sosa, Mercedes Lewandrowski, Haiwei Zhang, Marjorie Rowe, Arthur McClelland, Hao Wu, Caroline Junqueira, Judy Lieberman.
      Natural killer (NK) cell kill infected, transformed and stressed cells when an activating NK cell receptor is triggered1. Most NK cells and some innate lymphoid cells express the activating receptor NKp46, encoded by NCR1, the most evolutionarily ancient NK cell receptor2,3. Blockage of NKp46 inhibits NK killing of many cancer targets4. Although a few infectious NKp46 ligands have been identified, the endogenous NKp46 cell surface ligand is unknown. Here we show that NKp46 recognizes externalized calreticulin (ecto-CRT), which translocates from the endoplasmic reticulum (ER) to the cell membrane during ER stress. ER stress and ecto-CRT are hallmarks of chemotherapy-induced immunogenic cell death5,6, flavivirus infection and senescence. NKp46 recognition of the P domain of ecto-CRT triggers NK cell signalling and NKp46 caps with ecto-CRT in NK immune synapses. NKp46-mediated killing is inhibited by knockout or knockdown of CALR, the gene encoding CRT, or CRT antibodies, and is enhanced by ectopic expression of glycosylphosphatidylinositol-anchored CRT. NCR1)-deficient human (and Nrc1-deficient mouse) NK cells are impaired in the killing of ZIKV-infected, ER-stressed and senescent cells and ecto-CRT-expressing cancer cells. Importantly, NKp46 recognition of ecto-CRT controls mouse B16 melanoma and RAS-driven lung cancers and enhances tumour-infiltrating NK cell degranulation and cytokine secretion. Thus, NKp46 recognition of ecto-CRT as a danger-associated molecular pattern eliminates ER-stressed cells.
    DOI:  https://doi.org/10.1038/s41586-023-05912-0
  2. J Cell Biol. 2023 May 01. pii: e202208147. [Epub ahead of print]222(5):
    PERK prevents rhodopsin degradation during retinitis pigmentosa by inhibiting IRE1-induced autophagy.
    Ning Zhao, Ning Li, Tao Wang.
      Chronic endoplasmic reticulum (ER) stress is the underlying cause of many degenerative diseases, including autosomal dominant retinitis pigmentosa (adRP). In adRP, mutant rhodopsins accumulate and cause ER stress. This destabilizes wild-type rhodopsin and triggers photoreceptor cell degeneration. To reveal the mechanisms by which these mutant rhodopsins exert their dominant-negative effects, we established an in vivo fluorescence reporter system to monitor mutant and wild-type rhodopsin in Drosophila. By performing a genome-wide genetic screen, we found that PERK signaling plays a key role in maintaining rhodopsin homeostasis by attenuating IRE1 activities. Degradation of wild-type rhodopsin is mediated by selective autophagy of ER, which is induced by uncontrolled IRE1/XBP1 signaling and insufficient proteasome activities. Moreover, upregulation of PERK signaling prevents autophagy and suppresses retinal degeneration in the adRP model. These findings establish a pathological role for autophagy in this neurodegenerative condition and indicate that promoting PERK activity could be used to treat ER stress-related neuropathies, including adRP.
    DOI:  https://doi.org/10.1083/jcb.202208147
  3. ACS Chem Biol. 2023 Apr 05.
    HiBiT-SpyTag: A Minimal Tag for Covalent Protein Capture and Degrader Development.
    Tiffany Tsang, Fidel Huerta, Yingpeng Liu, Jianwei Che, Rebecca J Metivier, Silas Ferrao, Katherine A Donovan, Lyn H Jones, Breanna L Zerfas, Radosław P Nowak.
      The ability to rapidly and selectively modulate cellular protein levels using small molecules is essential for studying complex biological systems. Degradation tags, such as dTAG, allow for selective protein removal with a specific degrader molecule, but their utility is limited by the large tag size (>12 kDa) and the low efficiency of fusion product gene knock-in. Here, we describe the development of a short 24 amino acid peptide tag that enables cell-based quantification and covalent functionalization of proteins to which it is fused. The minimalistic peptide, termed HiBiT-SpyTag, incorporates the HiBiT peptide for protein level quantification and SpyTag, which forms a spontaneous isopeptide bond in the presence of the SpyCatcher protein. Transient expression of dTAG-SpyCatcher efficiently labels HiBiT-SpyTag-modified BRD4 or IRE1α in cells, and subsequent treatment with the dTAG13 degrader results in efficient protein removal without the need for full dTAG knock-in. We also demonstrate the utility of HiBiT-SpyTag for validating the degradation of the endoplasmic reticulum (ER) stress sensor IRE1α, which led to the development of the first PROTAC degrader of the protein. Our modular HiBiT-SpyTag system represents a valuable tool for the efficient development of degraders and for studying other proximity-induced pharmacology.
    DOI:  https://doi.org/10.1021/acschembio.3c00084
  4. Am J Pathol. 2023 Apr 05. pii: S0002-9440(23)00121-9. [Epub ahead of print]
    The dynamic role of endoplasmic reticulum stress in chronic liver disease.
    Kaitlyn G Jackson, Grayson W Way, Jing Zeng, Marissa K Lipp, Huiping Zhou.
      Chronic liver disease (CLD) is a major worldwide public health threat, with an estimated prevalence of 1.5 billion individuals suffering from CLD in 2020. Chronic activation of endoplasmic reticulum (ER) stress-related pathways is recognized to substantially contribute to the pathological progression of CLD. The ER is an intracellular organelle that folds proteins into their correct 3-dimensional shapes. ER-associated enzymes and chaperone proteins highly regulate this process. Perturbations in protein folding lead to misfolded or unfolded protein accumulation in the ER lumen, resulting in ER stress and concomitant activation of the unfolded protein response (UPR). The adaptive UPR is a set of signal transduction pathways evolved in mammalian cells that attempts to reestablish ER protein homeostasis by reducing protein load and increasing ER-associated degradation. However, maladaptive UPR responses in CLD occur due to prolonged UPR activation, leading to concomitant inflammation and cell death. This review assesses the current understanding of the cellular and molecular mechanisms that regulate ER stress and the UPR in the progression of different liver diseases and the potential pharmacological and biological interventions which target the UPR.
    DOI:  https://doi.org/10.1016/j.ajpath.2023.03.009
  5. Aging Dis. 2023 Apr 01. 14(2): 350-369
    X-box Binding Protein 1: An Adaptor in the Pathogenesis of Atherosclerosis.
    Tao Wang, Jia Zhou, Xiao Zhang, Yujie Wu, Kehan Jin, Yilin Wang, Ran Xu, Ge Yang, Wenjing Li, Liqun Jiao.
      Atherosclerosis (AS), the formation of fibrofatty lesions in the vessel wall, is the primary cause of heart disease and stroke and is closely associated with aging. Disrupted metabolic homeostasis is a primary feature of AS and leads to endoplasmic reticulum (ER) stress, which is an abnormal accumulation of unfolded proteins. By orchestrating signaling cascades of the unfolded protein response (UPR), ER stress functions as a double-edged sword in AS, where adaptive UPR triggers synthetic metabolic processes to restore homeostasis, whereas the maladaptive response programs the cell to the apoptotic pathway. However, little is known regarding their precise coordination. Herein, an advanced understanding of the role of UPR in the pathological process of AS is reviewed. In particular, we focused on a critical mediator of the UPR, X-box binding protein 1 (XBP1), and its important role in balancing adaptive and maladaptive responses. The XBP1 mRNA is processed from the unspliced isoform (XBP1u) to the spliced isoform of XBP1 (XBP1s). Compared with XBP1u, XBP1s predominantly functions downstream of inositol-requiring enzyme-1α (IRE1α) and transcript genes involved in protein quality control, inflammation, lipid metabolism, carbohydrate metabolism, and calcification, which are critical for the pathogenesis of AS. Thus, the IRE1α/XBP1 axis is a promising pharmaceutical candidate against AS.
    Keywords:  IRE1α; XBP1; atherosclerosis; endoplasmic reticulum stress; unfolded protein response
    DOI:  https://doi.org/10.14336/AD.2022.0824
  6. FASEB J. 2023 05;37(5): e22902
    Emerging evidence for poxvirus-mediated unfolded protein response: Lumpy skin disease virus maintains self-replication by activating PERK and IRE1 signaling.
    Jinlong Tan, Yinju Liu, Fan Yang, Guohua Chen, Yongxiang Fang, Xiaobing He, Zhongzi Lou, Huaijie Jia, Zhizhong Jing, Weike Li.
      The monkeypox epidemic has attracted global attention to poxviruses. The cytoplasmic replication of poxviruses requires extensive protein synthesis, challenging the capacity of the endoplasmic reticulum (ER). However, the role of the ER in the life cycle of poxviruses is unclear. In this study, we demonstrate that infection with the lumpy skin disease virus (LSDV), a member of the poxvirus family, causes ER stress in vivo and in vitro, further facilitating the activation of the unfolded protein response (UPR). Although UPR activation aids in the restoration of the cellular environment, its significance in the LSDV life cycle remains unclear. Furthermore, the significance of ER imbalance for viral replication is also unknown. We show that LSDV replication is hampered by an unbalanced ER environment. In addition, we verify that the LSDV replication depends on the activation of PERK-eIF2α and IRE1-XBP1 signaling cascades rather than ATF6, implying that global translation and reduced XBP1 cleavage are deleterious to LSDV replication. Taken together, these findings indicate that LSDV is involved in the repression of global translational signaling, ER chaperone transcription, and ATF6 cleavage from the Golgi into the nucleus, thereby maintaining cell homeostasis; moreover, PERK and IRE1 activation contribute to LSDV replication. Our findings suggest that targeting UPR elements may be applied in response to infection from LSDV or even other poxviruses, such as monkeypox.
    Keywords:  cell signaling; endoplasmic reticulum stress; lumpy skin disease virus; poxvirus; unfolded protein response
    DOI:  https://doi.org/10.1096/fj.202300028R
  7. Front Cell Dev Biol. 2023 ;11 1089728
    Normal tissue homeostasis and impairment of selective inflammatory responses in dendritic cells deficient for ATF6α.
    Francisca Gutiérrez-Ballesteros, Jonathan Morales-Reyes, Dominique Fernández, Antonia Geisse, Amada Arcaya, Felipe Flores-Santibañez, María Rosa Bono, Fabiola Osorio.
      The initiation of adaptive immunity relies on the performance of dendritic cells (DCs), which are specialized leukocytes with professional antigen presenting capabilities. As such, the molecular mechanisms safeguarding DC homeostasis are matter of intense research. Sensors of the unfolded protein response (UPR) of the endoplasmic reticulum, a three-pronged signaling pathway that maintains the fidelity of the cellular proteome, have emerged as regulators of DC biology. The archetypical example is the IRE1/XBP1s axis, which supports DC development and survival of the conventional type 1 DC (cDC1) subtype. However, the role of additional UPR sensors in DC biology, such as the ATF6α branch, has not been clearly elucidated. Even though Xbp1 is transcriptionally induced by ATF6α under ER stress, it is unclear if cDCs also co-opt the ATF6α branch in tissues. Here, we examine the role of ATF6α in cDC homeostasis in vivo and upon innate stimulation in vitro. In steady state, animals lacking ATF6α in CD11c+ cells (Itgax Cre x Atf6 fl/fl mice) display normal cDC frequencies in spleen, intestine, liver, and lung. Also, ATF6α deficient cDCs express normal levels of Xbp1 mRNA and additional UPR components. However, a reduction of lung monocytes is observed in Itgax Cre x Atf6 fl/fl conditional deficient animals suggesting that ATF6α may play a role in the biology of monocyte subsets. Notably, in settings of DC activation, ATF6α contributes to the production of IL-12 and IL-6 to inflammatory stimuli. Thus, although ATF6α may be dispensable for tissue cDC homeostasis in steady state, the transcription factor plays a role in the acquisition of selective immunogenic features by activated DCs.
    Keywords:  ATF6; IL-12; IL-6; dendritic cells; immunity; proinflammatory cytokines; tissues; unfolded protein response
    DOI:  https://doi.org/10.3389/fcell.2023.1089728
  8. Life Sci. 2023 Apr 01. pii: S0024-3205(23)00290-4. [Epub ahead of print] 121656
    Endoplasmic reticulum stress contributes to pyroptosis through NF-κB/NLRP3 pathway in diabetic nephropathy.
    Quanwei Li, Kai Zhang, Limin Hou, Jianzhao Liao, Hui Zhang, Qingyue Han, Jianying Guo, Ying Li, Lianmei Hu, Jiaqiang Pan, Wenlan Yu, Zhaoxin Tang.
       AIMS: Diabetic nephropathy (DN) is known as a major microvascular complication in type 1 diabetes. Endoplasmic reticulum (ER) stress and pyroptosis play a critical role in the pathological process of DN, but their mechanism in DN has been litter attention.
    MAIN METHODS: Here, we firstly used large mammal beagles as DN model for 120 d to explored the mechanism of endoplasmic reticulum stress-mediated pyroptosis in DN. Meanwhile, 4-Phenylbutytic acid (4-PBA) and BYA 11-7082 were added in the MDCK (Madin-Daby canine kidney) cells by high glucose (HG) treatment. ER stress and pyroptosis related factors expression levels were analyzed by immunohistochemistry, immunofluorescence, western blotting, and quantitative real-time PCR assay.
    KEY FINDINGS: We identified that glomeruli atrophy, renal capsules were increased, and renal tubules thickened in diabetes. Masson and PAS staining resulted showed that the collagen fibers and glycogen were accumulated in kidney. Meanwhile, the ER stress and pyroptosis-related factors were significantly activated in vitro. Importantly, 4-PBA significantly inhibited the ER stress, which also alleviated the HG-induced pyroptosis in MDCK cells. Furthermore, BYA 11-7082 could reduce the expression levels of NLRP3 and GSDMD genes and proteins.
    SIGNIFICANCE: These data provide evidence for ER stress contributes to pyroptosis through NF-κΒ/ΝLRP3 pathway in canine type 1 diabetic nephropathy.
    Keywords:  Beagles; Endoplasmic reticulum stress; NF-κB/NLRP3 pathway; Pyroptosis; Type 1 diabetic nephropathy
    DOI:  https://doi.org/10.1016/j.lfs.2023.121656
  9. Eur J Immunol. 2023 Apr 04. e2249984
    ER stress and the inflammatory response in allergic contact dermatitis.
    Philipp R Esser, Michael Huber, Stefan F Martin.
      Maintaining homeostasis is central to organismal health. Deviation is detected by a variety of sensors that react to alarm signals arising from injury, infection and other inflammatory triggers. One important element of this alarm system is the innate immune system, which recognizes pathogen-/microbe- or damage-associated molecular patterns via pattern recognition receptors localized in the cytosol or in membranes of innate immune cells such as macrophages, dendritic cells and mast cells but also of T-cells, B-cells and epithelial cells. Activation of the innate immune system results in inflammation and is a pre-requisite for activation of the adaptive immune system. Another important element is represented by the unfolded protein response (UPR), a stress response of the endoplasmic reticulum. The UPR regulates proteostasis, and also contributes to the course of inflammatory diseases such as cancer, diabetes, obesity and neurodegenerative diseases. In addition, the UPR is instrumental in allergic contact dermatitis. This inflammatory skin disease, affecting 5-10% of the population, is caused by T-cells recognizing low-molecular weight organic chemicals and metal ions. In this Mini-review, we discuss the orchestration of inflammatory responses by the interplay of the innate immune system with cellular stress responses in allergic contact dermatitis, with a focus on the UPR. This article is protected by copyright. All rights reserved.
    Keywords:  skin ⋅ allergic contact dermatitis ⋅ inflammation ⋅ innate immunity ⋅ ER stress
    DOI:  https://doi.org/10.1002/eji.202249984
  10. Biochem Biophys Res Commun. 2023 Mar 31. pii: S0006-291X(23)00365-0. [Epub ahead of print]658 62-68
    Musclin attenuates lipid deposition in hepatocytes through SIRT7/autophagy-mediated suppression of ER stress.
    Wonjun Cho, Sung Woo Choi, Heeseung Oh, Fatih Baygutalp, A M Abd El-Aty, Ji Hoon Jeong, Jin-Ho Song, Yong Kyoo Shin, Tae Woo Jung.
      Musclin, an exercise-responsive myokine, has the ability to attenuate inflammation, oxidative stress, and apoptosis in cardiomyocytes under pathogenic conditions. While the potential benefits of musclin in the cardiovascular system have been well documented, its effects on hepatic endoplasmic reticulum (ER) stress and lipid metabolism are not fully understood. The present study showed that musclin treatment reduced lipid accumulation and lipogenic protein expression in primary hepatocytes exposed to palmitate. Palmitate treatment led to an increase in markers of ER stress, which was reversed by musclin treatment. Musclin treatment increased SIRT7 expression and markers of autophagy in a dose-dependent manner. Small interfering (si) RNA of SIRT7 or 3-methyladenine (3 MA) reduced the effects of musclin on lipogenic lipid deposition in hepatocytes under hyperlipidemic conditions. These findings suggest that musclin can suppress palmitate-induced ER stress by upregulating SIRT7 and autophagy signaling, thereby alleviating lipid accumulation in primary hepatocytes. The current study provides a potential therapeutic strategy for the treatment of liver diseases characterized by lipid accumulation and ER stress, such as nonalcoholic fatty liver disease (NAFLD).
    Keywords:  Hepatocyte; Lipogenesis; Musclin; NAFLD; Obesity
    DOI:  https://doi.org/10.1016/j.bbrc.2023.03.065
  11. Aging Dis. 2023 Apr 01. 14(2): 283-286
    Endoplasmic Reticulum Stress in Osteoarthritis: A Novel Perspective on the Pathogenesis and Treatment.
    Zeqin Wen, Qi Sun, Yunhan Shan, Wenqing Xie, Yilan Ding, Weiyang Wang, Ruixi Ye, Wenfeng Xiao, Yusheng Li.
      Osteoarthritis (OA), the most common degenerative joint disease, causes an enormous socioeconomic burden due to its disabling properties and high prevalence. Increasing evidence suggests that OA is a whole-joint disease involving cartilage degradation, synovitis, meniscal lesions, and subchondral bone remodeling. Endoplasmic reticulum (ER) stress is the accumulation of misfolded/unfolded proteins in the ER. Recent studies have found that ER stress is involved in the OA pathological changes by influencing the physiological function and survival of chondrocytes, fibroblast-like synoviocytes, synovial macrophages, meniscus cells, osteoblasts, osteoclasts, osteocytes, and bone marrow mesenchymal stem cells. Therefore, ER stress is an attractive and promising target for OA. However, although targeting ER stress has been proven to alleviate OA progression in vitro and in vivo, the treatments for OA remain in preclinical stage and require further investigation.
    Keywords:  cartilage degradation; endoplasmic reticulum stress; osteoarthritis; pathogenesis; treatment
    DOI:  https://doi.org/10.14336/AD.2022.0725
  12. Mol Ther. 2023 Apr 03. pii: S1525-0016(23)00161-2. [Epub ahead of print]
    The unfolded protein response transcription factor XBP1s ameliorates Alzheimer's disease by improving synaptic function and proteostasis.
    Claudia Duran-Aniotz, Natalia Poblete, Catalina Rivera-Krstulovic, Álvaro O Ardiles, Mei Li Díaz, Giovanni Tamburini, Carleen Mae P Sabusap, Yannis Gerakis, Felipe Cabral Miranda, Javier Diaz, Matias Fuentealba, Diego Arriagada, Ernesto Muñoz, Sandra Espinoza, Gabriela Martinez, Gabriel Quiroz, Danilo B Medinas, Darwin Contreras, Ricardo Piña, Mychael V Lourenco, Felipe C Ribeiro, Sergio T Ferreira, Carlos Rozas, Bernardo Morales, Lars Plate, Christian Gonzalez-Billault, Adrian G Palacios, Claudio Hetz.
      Alteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimer's disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER. Inositol requiring enzyme-1 (IRE1) operates as a central ER stress sensor, enabling the establishment of adaptive and repair programs through the control of the expression of the transcription factor X-Box binding protein 1 (XBP1). To artificially enforce the adaptive capacity of the UPR in the AD brain, we developed strategies to express the active form of XBP1 in the brain. Overexpression of XBP1 in the nervous system using transgenic mice reduced the load of amyloid deposits and preserved synaptic and cognitive function. Moreover, local delivery of XBP1 into the hippocampus of an AD mice using adeno-associated vectors improved different AD features. XBP1 expression corrected a large proportion of the proteomic alterations observed in the 5xFAD model, restoring the levels of several synaptic proteins and factors involved in actin cytoskeleton regulation and axonal growth. Our results illustrate the therapeutic potential of targeting UPR-dependent gene expression programs as a strategy to ameliorate AD features and sustain synaptic function.
    DOI:  https://doi.org/10.1016/j.ymthe.2023.03.028
  13. Front Genet. 2023 ;14 1148192
    Wild-type and mutant p53 in cancer-related ferroptosis. A matter of stress management?
    Marco Corazzari, Licio Collavin.
      Cancer cells within tumor masses are chronically exposed to stress caused by nutrient deprivation, oxygen limitation, and high metabolic demand. They also accumulate hundreds of mutations, potentially generating aberrant proteins that can induce proteotoxic stress. Finally, cancer cells are exposed to various damages during chemotherapy. In a growing tumor, transformed cells eventually adapt to these conditions, eluding the death-inducing outcomes of signaling cascades triggered by chronic stress. One such extreme outcome is ferroptosis, a form of iron-dependent non-apoptotic cell death mediated by lipid peroxidation. Not surprisingly, the tumor suppressor p53 is involved in this process, with evidence suggesting that it acts as a pro-ferroptotic factor and that its ferroptosis-inducing activity may be relevant for tumor suppression. Missense alterations of the TP53 gene are extremely frequent in human cancers and give rise to mutant p53 proteins (mutp53) that lose tumor suppressive function and can acquire powerful oncogenic activities. This suggests that p53 mutation provides a selective advantage during tumor progression, raising interesting questions on the impact of p53 mutant proteins in modulating the ferroptotic process. Here, we explore the role of p53 and its cancer-related mutants in ferroptosis, using a perspective centered on the resistance/sensitivity of cancer cells to exogenous and endogenous stress conditions that can trigger ferroptotic cell death. We speculate that an accurate molecular understanding of this particular axis may improve cancer treatment options.
    Keywords:  ER stress; UPR; autophagy; ferroptosis; hypoxia; p53 tumor suppressor; stress response pathways; unfolded protein response
    DOI:  https://doi.org/10.3389/fgene.2023.1148192
  14. Cell Stress. 2023 Apr;7(4): 20-33
    Macrolide antibiotics activate the integrated stress response and promote tumor proliferation.
    Xin Yu, Ai-Ling Tian, Ping Wang, Juanjuan Li, Juan Wu, Bei Li, Zhou Liu, Siqing Liu, Zhijie Gao, Si Sun, Shengrong Sun, Yi Tu, Qi Wu.
      Macrolide antibiotics are widely used antibacterial agents that are associated with autophagy inhibition. This study aimed to investigate the association between macrolide antibiotics and malignant tumors, as well as the effect on autophagy, reactive oxygen species (ROS) accumulation and integrated stress response (ISR). The meta-analysis indicated a modestly higher risk of cancer in macrolide antibiotic ever-users compared to non-users. Further experiments showed that macrolides block autophagic flux by inhibiting lysosomal acidification. Additionally, azithromycin, a representative macrolide antibiotic, induced the accumulation of ROS, and stimulated the ISR and the activation of transcription factor EB (TFEB) and TFE3 in a ROS-dependent manner. Finally, animal experiments confirmed that azithromycin promoted tumor progression in vivo, which could be receded by N-acetylcysteine, an inhibitor of ROS and ISR. Overall, this study reveals the potential role of macrolide antibiotics in malignant progression and highlights the need for further investigation into their effects.
    Keywords:  ER stress; ROS; autophagy; azithromycin; cancer; macrolide antibiotic
    DOI:  https://doi.org/10.15698/cst2023.04.278
  15. Cancer Commun (Lond). 2023 Apr 02.
    Tumor microenvironment signaling and therapeutics in cancer progression.
    Anshika Goenka, Fatima Khan, Bhupender Verma, Priyanka Sinha, Crismita C Dmello, Manasi P Jogalekar, Prakash Gangadaran, Byeong-Cheol Ahn.
      Tumor development and metastasis are facilitated by the complex interactions between cancer cells and their microenvironment, which comprises stromal cells and extracellular matrix (ECM) components, among other factors. Stromal cells can adopt new phenotypes to promote tumor cell invasion. A deep understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM interactions is needed to design effective intervention strategies that might interrupt these interactions. In this review, we describe the tumor microenvironment (TME) components and associated therapeutics. We discuss the clinical advances in the prevalent and newly discovered signaling pathways in the TME, the immune checkpoints and immunosuppressive chemokines, and currently used inhibitors targeting these pathways. These include both intrinsic and non-autonomous tumor cell signaling pathways in the TME: protein kinase C (PKC) signaling, Notch, and transforming growth factor (TGF-β) signaling, Endoplasmic Reticulum (ER) stress response, lactate signaling, Metabolic reprogramming, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and Siglec signaling pathways. We also discuss the recent advances in Programmed Cell Death Protein 1 (PD-1), Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4), T-cell immunoglobulin mucin-3 (TIM-3) and Lymphocyte Activating Gene 3 (LAG3) immune checkpoint inhibitors along with the C-C chemokine receptor 4 (CCR4)- C-C class chemokines 22 (CCL22)/ and 17 (CCL17), C-C chemokine receptor type 2 (CCR2)- chemokine (C-C motif) ligand 2 (CCL2), C-C chemokine receptor type 5 (CCR5)- chemokine (C-C motif) ligand 3 (CCL3) chemokine signaling axis in the TME. In addition, this review provides a holistic understanding of the TME as we discuss the three-dimensional and microfluidic models of the TME, which are believed to recapitulate the original characteristics of the patient tumor and hence may be used as a platform to study new mechanisms and screen for various anti-cancer therapies. We further discuss the systemic influences of gut microbiota in TME reprogramming and treatment response. Overall, this review provides a comprehensive analysis of the diverse and most critical signaling pathways in the TME, highlighting the associated newest and critical preclinical and clinical studies along with their underlying biology. We highlight the importance of the most recent technologies of microfluidics and lab-on-chip models for TME research and also present an overview of extrinsic factors, such as the inhabitant human microbiome, which have the potential to modulate TME biology and drug responses.
    Keywords:  3D-model; cancer therapy; gut microbiota; immune signaling; metabolism; signaling; tumor microenvironment
    DOI:  https://doi.org/10.1002/cac2.12416
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