bims-unfpre Biomed News
on Unfolded protein response
Issue of 2025–06–08
seven papers selected by
Susan Logue, University of Manitoba
  1. Agr2 in cancer and beyond: unraveling its role during protein synthesis, ER stress, and as a predictive biomarker.
  2. Diabetes mellitus and the key role of endoplasmic reticulum stress in pancreatic β cells.
  3. High-throughput drug screening of clear cell ovarian cancer organoids reveal vulnerability to proteasome inhibitors and dinaciclib and identify AGR2 as a therapeutic target.
  4. Alcohol Disrupts Neural Differentiation Through Endoplasmic Reticulum Stress and PERK Pathway Activation.
  5. The role of 7-dehydrocholesterol in inducing ER stress and apoptosis of head and neck squamous cell carcinoma.
  6. Multiomics reveal biomolecular shifts and ER stress in sleep-restricted women affecting NSC functions.
  7. The effects of inhibiting IRE1α on the viability of ovarian granulosa cells.
  1. Mol Cell Biochem. 2025 Jun 05.
    Agr2 in cancer and beyond: unraveling its role during protein synthesis, ER stress, and as a predictive biomarker.
    Philip Salu, Katie M Reindl.
      Protein folding is an essential component of protein biosynthesis, allowing for post-translational modifications that ensure proper protein structure and function to support cellular physiology. The presence of unfolded proteins triggers cellular mechanisms to either remove the unfolded proteins or reduce protein synthesis. However, the accumulation of improperly folded proteins may lead to diseases, including neurological disorders and cancers. Indeed, cancer cells have a dysregulated protein synthesis capacity that enables them to survive in higher proliferative and growth states. The anterior gradient 2 (Agr2) protein is often overexpressed in multiple cancers to support the need for increased protein synthesis resulting from uncontrolled cell proliferation. Agr2 acts like a protein disulfide isomerase (PDI), catalyzing the formation of disulfide bonds in native proteins. Its expression in cancers has been associated with increased cell proliferation, metastasis, and invasion. Conversely, the lack of Agr2 has been associated with ER stress (ERS) and the activation of the unfolded protein response (UPR) pathway to restore cellular protein homeostasis. Furthermore, Agr2 can be secreted into the extracellular environment and has been detected in human urine and serum, highlighting its potential use as a cancer biomarker. This review discusses Agr2 and its role in protein synthesis and ERS. We examine recent developments regarding its detection and use as a biomarker and delve into emerging therapeutic strategies focused on targeting Agr2.
    Keywords:  Anterior gradient 2 (Agr2); Biomarker; Cancers; Endoplasmic reticulum stress; Protein disulfide isomerases; Protein synthesis
    DOI:  https://doi.org/10.1007/s11010-025-05318-8
  2. Nat Rev Endocrinol. 2025 Jun 04.
    Diabetes mellitus and the key role of endoplasmic reticulum stress in pancreatic β cells.
    Maria Lytrivi, Yue Tong, Enrico Virgilio, Xiaoyan Yi, Miriam Cnop.
      Insufficient insulin secretion by pancreatic β cells is central to the pathogenesis of diabetes mellitus. As insulin is synthesized in the endoplasmic reticulum (ER), perturbations in ER homeostasis lead to ER stress and activate the ER stress response. Over the past two decades, considerable data have accumulated on the role of β cell ER stress in diabetes mellitus. Several monogenic forms of diabetes mellitus are caused by excessive ER stress, perturbed ER stress response signalling or impaired ER-Golgi protein trafficking. These pathways are now recognized to contribute to β cell failure in both type 1 and type 2 diabetes mellitus. This Review considers the role of β cell ER stress in common forms of diabetes mellitus and examines whether it is a cause or a consequence of these diseases. The strong genetic evidence for a causal role of ER stress in 15 monogenic forms of diabetes mellitus is summarized, and the effects of ER stress on human β cell differentiation, function and survival are described. Although definitive proof is lacking that ER stress responses can be therapeutically targeted to improve β cell function in diabetes mellitus, existing and novel treatments that aim to restore ER homeostasis are also outlined.
    DOI:  https://doi.org/10.1038/s41574-025-01129-5
  3. Cancer Res Commun. 2025 Jun 03.
    High-throughput drug screening of clear cell ovarian cancer organoids reveal vulnerability to proteasome inhibitors and dinaciclib and identify AGR2 as a therapeutic target.
    Takuma Yoshimura, Takashi Kamatani, Aki Ookubo, Mio Takahashi, Manabu Itoh, Toshiki Ebisudani, Yohei Masugi, Tomomi Toyonaga, Junko Hamamoto, Keiko Saotome, Kensuke Sakai, Tomoko Yoshihama, Nobuko Moritoki, Shinsuke Shibata, Hiroyuki Yasuda, Toshiro Sato, Taka-Aki Sato, Daisuke Aoki, Wataru Yamagami, Tatsuhiko Tsunoda, Tatsuyuki Chiyoda.
      There are currently no effective treatments available for clear cell ovarian cancer (CCC). In this study, we aimed to identify effective drugs for CCC through high-throughput drug screening (HTDS) using ovarian cancer organoids and determine novel therapeutic targets based on the biological characteristics of CCC through omics analysis. An ovarian cancer organoid biobank was established, and HTDS was conducted using CCC organoids based on libraries of 361 and 4,560 compounds. The efficacy of the identified drugs was verified in in vitro and in vivo experiments using a patient-derived organoid xenograft mouse model. Transcriptome analysis was performed to identify genes related to the pathways targeted by the identified drugs in CCC and to assess their potential as therapeutic targets. Proteasome inhibitors and dinaciclib were extracted using HTDS and shown to inhibit tumorigenesis in vitro and in vivo. CCC, like multiple myeloma, exhibited activated endoplasmic reticulum (ER) stress and unfolded protein response (UPR), and treatment with proteasome inhibitors further enhanced ER stress and UPR, ultimately leading to cell death. Transcriptome analysis identified anterior gradient-2 (AGR2) as a key gene involved in UPR in CCC. CRISPR knockout of AGR2 suppressed cell proliferation, increased sensitivity to proteasome inhibitors, and reversed platinum resistance in CCC. AGR2 knockout also upregulated Schlafen 11, contributing to platinum sensitivity. ER stress and the UPR are activated in CCC, and proteasome inhibitors disrupt this balance, ultimately leading to cell death. AGR2 may serve as a potential therapeutic target in CCC.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-25-0024
  4. bioRxiv. 2025 May 22. pii: 2025.05.16.654531. [Epub ahead of print]
    Alcohol Disrupts Neural Differentiation Through Endoplasmic Reticulum Stress and PERK Pathway Activation.
    Zuohui Zhang, Wen Wen, Hong Lin, Di Hu, Hui Li, Jia Luo.
      Prenatal alcohol exposure (PAE) can lead to fetal alcohol spectrum disorder (FASD), a condition marked by developmental brain defects that result in neurobehavioral and cognitive impairments. However, the underlying molecular mechanisms remain poorly understood. Brain development is a highly regulated process, with neurogenesis playing a crucial role. A key stage in this process is neural differentiation, which is essential for proper brain function. This study aims to investigate how alcohol disrupts neural differentiation. NE-4C cells, a neural stem cell line derived from the mouse embryonic brain, were utilized as an in vitro model. As an in vivo model, pregnant mice were exposed to alcohol between gestation days 14 and 16, after which newly formed neurons in the ventricular zone (VZ) were analyzed. To examine the role of endoplasmic reticulum (ER) stress, tunicamycin (TM), and MANF-deficient NE-4C cells were employed. Neural differentiation was assessed using immunofluorescence, immunoblotting and flow cytometry. Alcohol impaired the differentiation of NE-4C cells into neurons and astrocytes without impacting cell migration. It also induced ER stress, preferably activating the PERK pathway. Similarly, ER stress caused by TM and MANF deficiency disrupted neural differentiation and activated PERK. Inhibiting PERK mitigated alcohol-induced impairment of neuronal differentiation. PAE decreased the number of newly formed neurons in the VZ of fetal brain while having little effects on cell survival and proliferation. Inhibiting PERK partially reversed the reduction of new neurons caused by PAE. Thus, alcohol-induced ER stress, particularly PERK activation, may contribute to impaired neurogenesis linked to FASD.
    DOI:  https://doi.org/10.1101/2025.05.16.654531
  5. Cancer Lett. 2025 May 31. pii: S0304-3835(25)00409-4. [Epub ahead of print] 217842
    The role of 7-dehydrocholesterol in inducing ER stress and apoptosis of head and neck squamous cell carcinoma.
    Bok-Soon Lee, Yea-In Park, Hengtian Liu, Sang Gyu Kim, Hyo Jeong Kim, Ji-Hye Choi, Si Hyun Rho, Joselyn Padilla, Jin Roh, Hyun Goo Woo, Hae Jin Seo, Man Ho Choi, Yu-Jin Jeong, Evan C Lien, Syed Hassan Mehdi, Dongjoon Lee, Donghoon Yoon, Chul-Ho Kim, Jiyoung Lee.
      Alterations of metabolic pathways that sustain cancer cell survival often offer promising therapeutic avenues. Here, we show that enhanced de novo cholesterol biosynthesis is crucial for the survival of head and neck squamous cell carcinoma (HNSCC). Transcriptomic analysis of HNSCC tissues identified profound dysregulation in steroid and cholesterol metabolism compared to normal tissues. Inhibition of two key enzymes, DHCR7 and DHCR24, which mediate cholesterol biosynthesis, induced apoptosis in HNSCC cells, even when cholesterol levels were restored. Metabolomic profiling revealed the accumulation of 7-dehydrocholesterol (7-DHC) upon DHCR7 or DHCR24 inhibition, triggering endoplasmic reticulum (ER) stress and promoting further cell death. These findings suggest that HNSCC cells adapt to ER stress by modulating 7-DHC levels through enhancing DHCR7 and DHCR24 levels, highlighting a metabolic vulnerability in HNSCC and demonstrating a direct link between cholesterol metabolism and ER stress in cancer cell viability.
    Keywords:  7-dehydrocholesterol; Cholesterol metabolism; DHCR24; DHCR7; ER stress; head and neck cancer
    DOI:  https://doi.org/10.1016/j.canlet.2025.217842
  6. iScience. 2025 May 16. 28(5): 112510
    Multiomics reveal biomolecular shifts and ER stress in sleep-restricted women affecting NSC functions.
    Vikas Malik, Xin Huang, Hongwei Zhou, Rebecca Bojar, Rajesh Kumar Soni, Donald W Landry, Sanja Jelic, Jianlong Wang.
      Adequate sleep (AS) is vital for physiological functions, yet a third of US adults sleep less than recommended. While circadian rhythms regulate adult stem cell functions, the impact of insufficient sleep remains unclear. We previously completed a clinical trial in healthy women in a randomized crossover design of 6-week periods with AS or mildly restricted sleep (RS; 1.5 h less). Here, we performed metabolomic and proteomic profiling of plasma samples. RS induced a stress-like state, highlighted by ER stress, heat shock, ubiquitination proteins, and amino acid biosynthesis. RS was strongly linked to disrupted neural development. Treating neural stem cells (NSCs) derived from human embryonic stem cells with RS-enriched metabolites disrupted G1 cell cycle phase and impaired differentiation into neurons, astrocytes, and oligodendrocytes. Our findings reveal how mild RS, mimicking "real-life" conditions, disrupts NSC divisions and differentiation, highlighting the critical role of sleep in adult stem cell regulation and neural development.
    Keywords:  Neuroscience; Omics; Stem cells research
    DOI:  https://doi.org/10.1016/j.isci.2025.112510
  7. Sci Rep. 2025 Jun 04. 15(1): 19512
    The effects of inhibiting IRE1α on the viability of ovarian granulosa cells.
    Chao Li, Yong-Peng Tan, Tie-Gang Meng, Di Gao, Ke Xu, You-Hui Lu, Li-Tao Yi, Shu-Chen Liu, Guang Wang, Qing-Yuan Sun, Xiao-Can Lei.
      IRE1α, a type I transmembrane protein characterized by a cytoplasmic serine/threonine kinase domain, is related to ER stress and ER function maintenance. In this study, 4µ8c, a highly effective selective inhibitor of IRE1α RNase, and APY29, an ATP competitive inhibitor, inhibiting IRE1α autophosphorylation and the kinase domain, were employed to elucidate the function of IRE1α on the proliferation of ovarian granulosa cells, with the ultimate goal of identifying novel strategies and methodologies for the prevention and treatment of associated diseases. Human ovarian granulosa cells (SVOG) cultured in vitro were treated with the IRE1α inhibitors 4µ8c and APY29. It was shown that inhibition of IRE1α reduced the cell ability of dealing with misfolded protein, triggered oxidative stress, altered mitochondrial membrane potential, and inflicted DNA damage, eventually lead to ovarian granulosa cell apoptosis.
    Keywords:  4µ8c; APY29; Cell apoptosis; Chaperones; IRE1α; Ovarian granulosa cells
    DOI:  https://doi.org/10.1038/s41598-025-03600-9
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