bims-istrec 2022-12-18 papers

bims-istrec

Biomed News

on Integrated stress response in cancer

Issue of 2022–12–18
twelve papers selected by
the Vincenzo Ciminale lab, Istituto Oncologico Veneto

Lathyrol promotes ER stress-induced apoptosis and proliferation inhibition in lung cancer cells by targeting SERCA2.
Total flavonoids of Oldenlandia diffusa (Willd.) Roxb. suppresses the growth of hepatocellular carcinoma through endoplasmic reticulum stress-mediated autophagy and apoptosis.
ER stress-related mRNA-lncRNA co-expression gene signature predicts the prognosis and immune implications of esophageal cancer.
Canonical and Noncanonical ER Stress-Mediated Autophagy Is a Bite the Bullet in View of Cancer Therapy.
Apoptin causes apoptosis in HepG-2 cells via Ca2+ imbalance and activation of the mitochondrial apoptotic pathway.
Endoplasmic reticulum stress mediates nickel chloride-induced epithelial‑mesenchymal transition and migration of human lung cancer A549 cells through Smad2/3 and p38 MAPK activation.
Milk Exosomal miR-27b Worsen Endoplasmic Reticulum Stress Mediated Colorectal Cancer Cell Death.
Orphan Nuclear Receptor Nur77 Mediates the Lethal Endoplasmic Reticulum Stress and Therapeutic Efficacy of Cryptomeridiol in Hepatocellular Carcinoma.
Metabolic disorders sensitise endometrial carcinoma through endoplasmic reticulum stress.
Silver nanoparticle-induced alteration of mitochondrial and ER homeostasis affects human breast cancer cell fate.
Effect of Flammulina velutipes polysaccharides on endoplasmic reticulum stress-mediated apoptosis by activating PLC-IP3 pathway in HepG2 cells.
Cysteine dioxygenase 1 attenuates the proliferation via inducing oxidative stress and integrated stress response in gastric cancer cells.

Biomed Pharmacother. 2022 Dec 13. pii: S0753-3322(22)01512-8. [Epub ahead of print]158 114123

Lathyrol promotes ER stress-induced apoptosis and proliferation inhibition in lung cancer cells by targeting SERCA2.

Peng Chen, Yiqian Li, Zhou Zhou, Chuqi Pan, Linghui Zeng.

  Lathyrol is a natural product isolated from the traditional Chinese medicine Semen Euphorbiae with unknown anti-tumor effects. We found that lathyrol had significant inhibitory effect on lung cancer cells by inducing apoptosis and inhibiting proliferation. Subsequently, we demonstrated for the first time that endoplasmic reticulum (ER) stress is a key anti-tumor mechanism of lathyrol. Furthermore, we found that lathyrol can induce ER stress in lung cancer cells by upregulating the protein expression levels of GRP78, PERK, p-eIF2α, CHOP, and ATF4, and the inhibitory effect of lathyrol on lung cancer cells was significantly reversed when cells were pretreated with ER stress inhibitor. In addition, we found that inhibition of SERCA2 resulted in depletion of the ER Ca2+ pool followed by a sustained increase in cytoplasmic Ca2+ levels, eventually leading to ER stress induced tumor cell apoptosis and proliferation inhibition. Lathyrol targeted SERCA2 to cause a significant upregulation of Ca2+ levels, and the inhibitory effect of lathyrol on lung cancer cells was significantly reversed after pretreatment with SERCA2 agonist. Taken together, our data suggest that lathyrol exerts its anti-tumor effect primarily by targeting SERCA2. Our findings highlight the potential for lathyrol as a new candidate drug for the treatment of lung cancer.

Keywords:  ER stress; Lathyrol; Lung cancer; SERCA2

DOI:  https://doi.org/10.1016/j.biopha.2022.114123
Front Pharmacol. 2022 ;13 1019670

Total flavonoids of Oldenlandia diffusa (Willd.) Roxb. suppresses the growth of hepatocellular carcinoma through endoplasmic reticulum stress-mediated autophagy and apoptosis.

Huan Chen, Xiaofei Shang, Huixin Yuan, Qianqian Niu, Jing Chen, Shumin Luo, Weihua Li, Xiuhui Li.

  Hepatocellular Carcinoma (HCC) is one of the most common malignant tumors in the world. Although the current treatment methods for HCC are gradually increasing, its efficacy still cannot meet the medical needs of patients with liver cancer, and new and effective treatment strategies are urgently needed. The total flavonoids of Oldenlandia diffusa (FOD) are the main active components in Oldenlandia diffusa, which have anti-inflammatory, antioxidant and anti-tumor effects, but their mechanism of action in liver cancer is unclear. In this study, we examined the effect of FOD on HCC. Using both in vitro and in vivo models, we confirmed that FOD inhibited HCC proliferation and induced apoptosis and autophagy. Mechanistic studies have shown that FOD induces apoptosis and activates autophagy in HCC cells by inducing endoplasmic reticulum stress (ER stress) and activating the PERK-eIF2α-ATF4 signaling pathway. Taken together, our results suggest that FOD is a potential anticancer drug targeting ER stress for the treatment of HCC.

Keywords:  apoptosis; autophagy; endoplasmic reticulum stress; hepatocellular carcinoma; total flavonoids of Oldenlandia diffusa (Willd.)

DOI:  https://doi.org/10.3389/fphar.2022.1019670
Am J Transl Res. 2022 ;14(11): 8064-8084

ER stress-related mRNA-lncRNA co-expression gene signature predicts the prognosis and immune implications of esophageal cancer.

Feng Li, Jiahao Ma, Cheng Yan, Yonghua Qi.

BACKGROUND: Esophageal cancer (EC) is one of the most common malignant cancers in the world. Endoplasmic reticulum (ER) stress is an adaptive response to various stress conditions and has been implicated in the development of various types of cancer. Long noncoding RNAs (lncRNAs) refer to a group of noncoding RNAs (ncRNAs), which regulate gene expression by interacting with DNA, RNA and proteins. Accumulating evidence suggests that lncRNAs are critical regulators of gene expression in development, differentiation, and human diseases, such as cancers and heart diseases. However, the prognostic model of EC based on ER stress-related mRNA and lncRNA has not been reported.
METHODS: Firstly, we downloaded RNA expression profiles from The Cancer Genome Atlas (TCGA) and obtained ER stress-related genes from the Molecular Signature Database (MSigDB). Next, Weighted Correlation Network Analysis (WGCNA) co-expression analysis was used to identify survival-related ER stress-related modules. Prognostic models were developed using univariate and Least absolute shrinkage and selection operator (LASSO) regression analyses on the training set and validated on the test set. Afterwards, The Receiver Operating Characteristic (ROC) curve and nomogram were used to evaluate the performance of risk prediction models. Differentially expressed gene (DEG) and enrichment analysis were performed between different groups in order to identify the biological processes correlated with the risk score. Finally, the fraction of immune cell infiltration and the difference of tumor microenvironment were identified in high-risk and low-risk groups.
RESULTS: The WGCNA co-expression analysis identified 49 ER genes that are highly associated with EC prognosis. Using univariate Cox regression and LASSO regression analysis, we developed prognostic risk models based on nine signature genes (four mRNAs and five lncRNAs). Both in the training and in the test sets, the overall survival (OS) of EC patients in the high-risk group was significantly lower than that in the low-risk group. The Kaplan-Meier curve and the ROC curve demonstrate the prognostic model we built can precisely predict the survival with more than 70% accuracy. The correlation analysis between the risk score and the infiltration of immune cells showed that the model can indicate the state of the immune microenvironment in EC.
CONCLUSION: In this study, we developed a novel prognostic model for esophageal cancer based on ER stress-related mRNA-lncRNA co-expression profiles that could predict the prognosis, immune cell infiltration, and immunotherapy response in patients with EC. Our results also may provide clinicians with a quantitative tool to predict the survival time of patients and help them individualize treatment strategies for the patients with EC.

Keywords: Esophageal cancer; endoplasmic reticulum stress; lncRNA; mRNA; prognostic model
Cells. 2022 Nov 25. pii: 3773. [Epub ahead of print]11(23):

Canonical and Noncanonical ER Stress-Mediated Autophagy Is a Bite the Bullet in View of Cancer Therapy.

Rashedul Alam, Mohammad Fazlul Kabir, Hyung-Ryong Kim, Han-Jung Chae.

  Cancer cells adapt multiple mechanisms to counter intense stress on their way to growth. Tumor microenvironment stress leads to canonical and noncanonical endoplasmic stress (ER) responses, which mediate autophagy and are engaged during proteotoxic challenges to clear unfolded or misfolded proteins and damaged organelles to mitigate stress. In these conditions, autophagy functions as a cytoprotective mechanism in which malignant tumor cells reuse degraded materials to generate energy under adverse growing conditions. However, cellular protection by autophagy is thought to be complicated, contentious, and context-dependent; the stress response to autophagy is suggested to support tumorigenesis and drug resistance, which must be adequately addressed. This review describes significant findings that suggest accelerated autophagy in cancer, a novel obstacle for anticancer therapy, and discusses the UPR components that have been suggested to be untreatable. Thus, addressing the UPR or noncanonical ER stress components is the most effective approach to suppressing cytoprotective autophagy for better and more effective cancer treatment.

Keywords:  ER stress; UPR; autophagy; cancer therapy; tumerogenesis

DOI:  https://doi.org/10.3390/cells11233773
Cancer Med. 2022 Dec 14.

Apoptin causes apoptosis in HepG-2 cells via Ca2+ imbalance and activation of the mitochondrial apoptotic pathway.

Xiaoyang Yu, Tongxing Wang, Yue Li, Yiquan Li, Bing Bai, Jinbo Fang, Jicheng Han, Shanzhi Li, Zhiru Xiu, Zirui Liu, Xia Yang, Yaru Li, Guangze Zhu, Ningyi Jin, Chao Shang, Xiao Li, Yilong Zhu.

   BACKGROUND: Apoptin is derived from the chicken anemia virus and exhibits specific cytotoxic effects against tumor cells. Herein, we found that Apoptin induced a strong and lasting endoplasmic reticulum (ER) stress response, Ca2+ imbalance, and triggered the mitochondrial apoptotic pathway. The aim of this study was to explore the mechanisms by which Apoptin exhibited anti-tumor effects in HepG-2 cells.
METHODS: The intracellular levels of calcium (Ca2+ ) were induced by ER stress and determined by electron microscopy, flow cytometry, and fluorescence staining. The mitochondrial injury was determined by mitochondrial membrane potential and electron microscopy. Western blotting was used to investigate the levels of key proteins in ER stress and the apoptotic pathway in mitochondria. The relationship between Ca2+ levels and apoptosis in Apoptin-treated cells was analyzed using a Ca2+ chelator (BAPTA-AM), flow cytometry, and fluorescence staining. We also investigated the in vivo effects of Ca2+ imbalance on the mitochondrial apoptotic pathway using tumor tissues xenografted on nude mice.
RESULTS: This study showed that Apoptin induced a strong and long- lasting ER stress and injury, which subsequently led to an imbalance of cellular Ca2+ levels, a reduction in the mitochondrial membrane potential, a significant extent image in the mitochondrial structure, and an increase in the expression levels of Smac/Diablo and Cyto-C.
CONCLUSIONS: In summary, Apoptin induced apoptosis in HepG-2 cells via Ca2+ imbalance and activation of the mitochondrial apoptotic pathway. This study provided a new direction for antitumor research in Apoptin.

Keywords:  Ca2+ imbalance; apoptin; endoplasmic reticulum stress; mitochondria apoptosis pathway; mitochondria structural injury

DOI:  https://doi.org/10.1002/cam4.5528
Ecotoxicol Environ Saf. 2022 Dec 09. pii: S0147-6513(22)01238-6. [Epub ahead of print]249 114398

Endoplasmic reticulum stress mediates nickel chloride-induced epithelial‑mesenchymal transition and migration of human lung cancer A549 cells through Smad2/3 and p38 MAPK activation.

Mengping Yu, Feipeng Chen, Haopei Wang, Qianlei Fu, Lingzi Yan, Zhao Chen, Huijun Li, Miaomiao Jia, Dalong Yang, Xiaohui Hua, Tong Shen, Qixing Zhu, Chengfan Zhou.

   BACKGROUND: The endoplasmic reticulum (ER) is a cellular membrane-bound organelle whereby proteins are synthesized, folded and glycosylated. Due to intrinsic (e.g., genetic) and extrinsic (e.g., environmental stressors) perturbations, ER proteostasis can be deregulated within cells which triggers unfolded protein response (UPR) as an adaptive stress response that may impact the migration and invasion properties of cancer cells. However, the mechanisms underlying the nickel compounds on lung cancer cell migration and invasion remain uncertain.
OBJECTIVE: We aimed to study whether Nickel chloride (NiCl2) induces ER stress in lung cancer cells, and whether ER stress is involved in modulating epithelial-mesenchymal transition (EMT) and migration by Smads and MAPKs pathways activation following NiCl2 treatment.
METHODS: A549 cells were treated with NiCl2 to determine the cell viability using MTT assay. The wound healing assay was used to evaluate cell migration ability. ER ultrastructure was observed by transmission electron microscopy. Western blotting assay was performed to evaluate the protein levels of BIP, PERK, IRE-1α, XBP-1 s, and ATF6 for ER stress and UPR, E-cadherin and Vimentin for EMT, p-Smad2/3, p-ERK, p-JNK, and p-P38 for activation of Smads and MAPKs signaling pathways.
RESULTS: The expression levels of BIP, PERK, IRE-1α, XBP-1 s, and ATF6 were significantly increased following treatment with NiCl2 in time- and dose-effect relationship. The ER stress inhibitor 4-PBA downregulated the expression levels of the above five proteins, and reversed the decrease in E-cadherin protein level and the increase in vimentin protein expression and cell migration abilities caused by NiCl2. Furthermore, 4-PBA significantly reduced nickel chloride-induced Smad2/3 and p38 MAPK pathway activation, while not affected ERK and JNK MAPK pathways.
CONCLUSION: NiCl2 triggers ER stress and UPR in A549 cells. Moreover, 4-PBA alleviates NiCl2-induced EMT and migration ability of A549 cells possibly through the Smad2/3 and p38 MAPK pathways activation, rather than ERK and JNK MAPK pathways.

Keywords:  A549 cell; Endoplasmic reticulum stress; Epithelial-mesenchymal transition; Migration; Nickel chloride

DOI:  https://doi.org/10.1016/j.ecoenv.2022.114398
Nutrients. 2022 Nov 29. pii: 5081. [Epub ahead of print]14(23):

Milk Exosomal miR-27b Worsen Endoplasmic Reticulum Stress Mediated Colorectal Cancer Cell Death.

Elisa Martino, Anna Balestrieri, Luigi Mele, Celestino Sardu, Raffaele Marfella, Nunzia D'Onofrio, Giuseppe Campanile, Maria Luisa Balestrieri.

  The relationship between dietary constituents and the onset and prevention of colorectal cancer (CRC) is constantly growing. Recently, the antineoplastic profiles of milk and whey from Mediterranean buffalo (Bubalus bubalis) have been brought to attention. However, to date, compared to cow milk, the potential health benefits of buffalo milk exosome-miRNA are still little explored. In the present study, we profiled the exosomal miRNA from buffalo milk and investigated the possible anticancer effects in CRC cells, HCT116, and HT-29. Results indicated that buffalo milk exosomes contained higher levels of miR-27b, miR-15b, and miR-148a compared to cow milk. Mimic miR-27b transfection in CRC cells induced higher cytotoxic effects (p < 0.01) compared to miR-15b and miR-148a. Moreover, miR-27b overexpression in HCT116 and HT-29 cells (miR-27b+) induced apoptosis, mitochondrial reactive oxygen species (ROS), and lysosome accumulation. Exposure of miR-27b+ cells to the bioactive 3kDa milk extract aggravated the apoptosis rate (p < 0.01), mitochondrial stress (p < 0.01), and advanced endoplasmic reticulum (ER) stress (p < 0.01), via PERK/IRE1/XBP1 and CHOP protein modulation (p < 0.01). Moreover, GSK2606414, the ER-inhibitor (ER-i), decreased the apoptosis phenomenon and XBP1 and CHOP modulation in miR-27b+ cells treated with milk (p < 0.01 vs. miR-27b++Milk), suggesting the ER stress as a cell-death-aggravating mechanism. These results support the in vitro anticancer activity of 3kDa milk extract and unveil the contribution of miR-27b in the promising beneficial effect of buffalo milk in CRC prevention.

Keywords:  colorectal cancer; endoplasmic reticulum stress; exogenous miRNA; milk

DOI:  https://doi.org/10.3390/nu14235081
Cells. 2022 Dec 01. pii: 3870. [Epub ahead of print]11(23):

Orphan Nuclear Receptor Nur77 Mediates the Lethal Endoplasmic Reticulum Stress and Therapeutic Efficacy of Cryptomeridiol in Hepatocellular Carcinoma.

Xudan Li, Quancheng Chen, Jie Liu, Shenjin Lai, Minda Zhang, Tidong Zhen, Hongyu Hu, Xiang Gao, Alice S T Wong, Jin-Zhang Zeng.

  Hepatocellular carcinoma (HCC) commonly possesses chronical elevation of IRE1α-ASK1 signaling. Orphan nuclear receptor Nur77, a promising therapeutic target in various cancer types, is frequently silenced in HCC. In this study, we show that cryptomeridiol (Bkh126), a naturally occurring sesquiterpenoid derivative isolated from traditional Chinese medicine Magnolia officinalis, has therapeutic efficacy in HCC by aggravating the pre-activated UPR and activating the silenced Nur77. Mechanistically, Nur77 is induced to sense IRE1α-ASK1-JNK signaling and translocate to the mitochondria, which leads to the loss of mitochondrial membrane potential (Δψm). The Bkh126-induced aggravation of ER stress and mitochondrial dysfunction result in increased cytotoxic product of reactive oxygen species (ROS). The in vivo anti-HCC activity of Bkh126 is superior to that of sorafenib, currently used to treat advanced HCC. Our study shows that Bkh126 induces Nur77 to connect ER stress to mitochondria-mediated cell killing. The identification of Nur77 as a molecular target of Bhk126 provides a basis for improving the leads for the further development of anti-HCC drugs.

Keywords:  ER stress; drug target; hepatocellular carcinoma; mitochondrial membrane potential; orphan nuclear receptor Nur77; sesquiterpenoid

DOI:  https://doi.org/10.3390/cells11233870
Cell Mol Biol Lett. 2022 Dec 16. 27(1): 110

Metabolic disorders sensitise endometrial carcinoma through endoplasmic reticulum stress.

Jingyi Zhou, Yanying Lin, Xiao Yang, Boqiang Shen, Juan Hao, Jiaqi Wang, Jianliu Wang.

   BACKGROUND: Metabolic disorder is considered a well-established risk factor for endometrial carcinoma (EC). However, the mechanism remains unclear. Insulin resistance and excessive flux of free fatty acids serve as fundamental pathogenic factors in metabolic disorders, including obesity and type 2 diabetes. The aim of this study was to test the correlation between insulin resistance and dyslipidaemia in EC and to determine the effect of insulin and saturated fatty acids on EC cells.
METHODS: A retrospective study on the medical records of patients with EC and RNA-seq from the TCGA database analysed with edgR and Gene Ontology (GO) were used to assess the correlation of dyslipidaemia and diabetes as well as obesity. Crystal violet assays and CCK-8 assays were used to detect the proliferation of EC cells, and Annexin V-PI was used to examine apoptosis. Transient changes in mitochondrial Ca2+ and reactive oxygen species (ROS) were monitored via confocal microscopy. DNA damage was assessed by comet assays. Changes in signalling pathways were detected via phospho-kinase array. western blotting was used to assess the molecular changes in endoplasmic reticulum (ER) stress and DNA damage.
RESULTS: We found that glucose metabolism disorders accompanied dyslipidaemia in patients with EC. As a key regulator of glucose metabolism disorders, insulin promoted DNA damage, ROS and Ca2+ homoeostasis imbalance in a panel of established EC cell lines. Interestingly, excessive insulin boosted saturated fatty acid-induced pro-apoptotic effects in EC cells. Furthermore, our data showed that insulin synergised with saturated fatty acids to activate the mechanistic target of rapamycin kinase/70 kDa ribosomal protein S6 kinase (mTOR/p70S6K) pathway and ER stress, resulting in Ca2+ release from ER and unfolded protein response (UPR) activation, which contributed to combined insulin and saturated fatty acid treatment-induced apoptosis and tumour progression.
CONCLUSIONS: Our data are the first to illustrate that impaired glucose metabolism accelerates dyslipidaemia-promoted EC progression, which is attributed to hyperinsulinaemia and saturated fatty acid-induced Ca2+ dyshomoeostasis and UPR activation in EC cells via ER stress.

Keywords:  Endometrial carcinoma; Endoplasmic reticulum stress; Insulin; Metabolic disorders; Saturated fatty acid

DOI:  https://doi.org/10.1186/s11658-022-00412-x
Toxicol Rep. 2022 ;9 1977-1984

Silver nanoparticle-induced alteration of mitochondrial and ER homeostasis affects human breast cancer cell fate.

Smita Dey, Leena Fageria, Ankita Sharma, Sudeshna Mukherjee, Surojit Pande, Rajdeep Chowdhury, Shibasish Chowdhury.

  Breast cancer is one of the most frequent forms of cancer. Although different treatment modalities are available, none has proved to be a game-changer. In this context, nanomedicine is one of the hot research areas, with different nano-formulations being explored as a therapeutic strategy against breast cancer. Herein, silver nanoparticles (AgNPs) have shown prospects with their anti-tumor properties and are currently being explored aggressively; however, the underlying molecular mechanisms of AgNP action remain to be unearthed. As part of this study, human breast cancer cells- MCF7 were exposed to AgNPs (∼9 nm), and the effect of the same was explored on mitochondrial and endoplasmic reticulum (ER) dynamicity. We observed that the AgNPs co-localize with mitochondria and cause mitochondrial membrane depolarization, ROS generation, and destabilized mitochondrial homeostasis. Also, the NPs were found to enhance ER stress. We further found that increased ER stress is linked to the disruption of mitochondrial dynamics. Overall, our study shows that the AgNPs can effectively cause apoptosis of MCF-7 cells by regulating the mitochondrial-ER dynamicity. The results provide an insight into the mechanisms via which AgNPs act and can be used in developing a potential chemotherapeutic agent.

Keywords:  Endoplasmic reticulum; Mitochondria; Silver nanoparticles

DOI:  https://doi.org/10.1016/j.toxrep.2022.10.017
J Food Sci. 2022 Dec 16.

Effect of Flammulina velutipes polysaccharides on endoplasmic reticulum stress-mediated apoptosis by activating PLC-IP3 pathway in HepG2 cells.

Miao Ding, Kai Lv, Dongliang Zhang, Wentao Fan, Ivan Stève Nguepi Tsopmejio, Zhouyu Jin, Hui Song.

  Flammulina velutipes polysaccharides (FVP) have been proven to induce apoptosis in HepG2 cells. It is well known that endoplasmic reticulum stress (ERS) is involved in apoptosis. However, ERS mediates FVP-induced apoptosis in HepG2 cells remains unclear. In our study, the results indicated that FVP caused ERS in HepG2 cells. They showed that FVP were water-soluble polysaccharides with the weight average molecular weight of 1972 kDa, which were mainly composed of mannose, gluconic acid, glucose, galactose, xylose and fructose in a molar ratio of 6.6 : 1.3 : 79.9 : 7.4 : 3.4 : 1.5. After FVP treatment, the expression levels of genes and proteins related to ERS were upregulated. The inhibition of ERS by 4-phenylbutyric acid (4-PBA) pretreatment could significantly reduce the role of FVP in inducing apoptosis. We further found the results of immunofluorescence and flow cytometry showing that Ca2+ in the ERS leaked out, and the intracellular Ca2+ concentration increased after FVP treatment. The pretreatment with the phospholipase C (PLC) inhibitor U73122 proved that FVP caused excessive intracellular Ca2+ concentration by activating the phospholipase C-inositol-1,4,5-triphosphate (PLC-IP3) pathway, resulting in ERS, and ultimately leading to apoptosis. In summary, our results indicated that FVP induced ERS-mediated apoptosis by activating PLC-IP3 pathway in HepG2 cells. PRACTICAL APPLICATION: This work may suggest that FVP could be used as an adjuvant therapy to anticancer drugs, providing new application prospects and possibilities.

Keywords:  Flammulina velutipes polysaccharides; HepG2 cells; apoptosis; endoplasmic reticulum stress

DOI:  https://doi.org/10.1111/1750-3841.16423
Cell Death Discov. 2022 Dec 16. 8(1): 493

Cysteine dioxygenase 1 attenuates the proliferation via inducing oxidative stress and integrated stress response in gastric cancer cells.

Gang Ma, Zhenzhen Zhao, Yang Qu, Fenglin Cai, Siya Liu, Han Liang, Rupeng Zhang, Jingyu Deng.

Whereas cysteine dioxygenase 1 (CDO1) expression is lost due to its hypermethylated promoter across a range of cancer types including gastric cancer (GC), its functions and molecular underpinnings remain largely unknown. Here we demonstrate that reduced CDO1 expression is indicative of unfavorable prognosis in patients with GC. CDO1 overexpression in GC cells markedly inhibits cellular proliferation in vitro and in vivo. Mechanistically, CDO1 exerts this cytostatic effect via increasing oxidative stress and thus activating integrated stress response (ISR) in GC cells. High throughput screening (HTS) of antioxidants library identifies that Engeletin, a flavanonol glycoside, blunts oxidative stress and the ISR to relieve the inhibitory effect of CDO1 on the proliferation in GC cells. Additionally, genetic disruption or pharmaceutical inhibition of the ISR boosts the growth in the GC cells with CDO1 expression. Our data uncover the molecular mechanisms underlying the cytostatic function of CDO1 in the proliferation of GC cells.

DOI: https://doi.org/10.1038/s41420-022-01277-x