bims-istrec 2022-08-28 papers

bims-istrec

Biomed News

on Integrated stress response in cancer

Issue of 2022–08–28
thirteen papers selected by
the Vincenzo Ciminale lab, Istituto Oncologico Veneto

Restoring TRAILR2/DR5-Mediated Activation of Apoptosis upon Endoplasmic Reticulum Stress as a Therapeutic Strategy in Cancer.
Endoplasmic Reticulum Stress-Related Signature for Predicting Prognosis and Immune Features in Hepatocellular Carcinoma.
Epimedokoreanin B inhibits the growth of lung cancer cells through endoplasmic reticulum stress-mediated paraptosis accompanied by autophagosome accumulation.
Involvement of Bid in the crosstalk between ferroptotic agent-induced ER stress and TRAIL-induced apoptosis.
Artesunate Inhibits the Cell Growth in Colorectal Cancer by Promoting ROS-Dependent Cell Senescence and Autophagy.
The Glucose-Regulated Protein78 (GRP78) in the unfolded protein response (UPR) pathway: a potential therapeutic target for breast cancer.
Riboflavin (Vitamin B2) Deficiency Induces Apoptosis Mediated by Endoplasmic Reticulum Stress and the CHOP Pathway in HepG2 Cells.
Comprehensive analysis of the endoplasmic reticulum stress-related long non-coding RNA in bladder cancer.
Endoplasmic stress-inducing variants in carboxyl ester lipase and pancreatic cancer risk.
Local anesthetic lidocaine-inducible gene, growth differentiation factor-15 suppresses the growth of cancer cell lines.
METTL3 potentiates progression of cervical cancer by suppressing ER stress via regulating m6A modification of TXNDC5 mRNA.
Metabolic adaption of cancer cells toward autophagy: Is there a role for ER-phagy?
Anti-tumor effects of dual PI3K-HDAC inhibitor CUDC-907 on activation of ROS-IRE1α-JNK-mediated cytotoxic autophagy in esophageal cancer.

Int J Mol Sci. 2022 Aug 12. pii: 8987. [Epub ahead of print]23(16):

Restoring TRAILR2/DR5-Mediated Activation of Apoptosis upon Endoplasmic Reticulum Stress as a Therapeutic Strategy in Cancer.

Rocío Mora-Molina, Abelardo López-Rivas.

  The uncontrolled proliferation of malignant cells in growing tumors results in the generation of different stressors in the tumor microenvironment, such as nutrient shortage, hypoxia and acidosis, among others, that disrupt endoplasmic reticulum (ER) homeostasis and may lead to ER stress. As a response to ER stress, both normal and tumor cells launch a set of signaling pathways known as the unfolded protein response (UPR) to restore ER proteostasis and maintain cell viability and function. However, under sustained ER stress, an apoptotic cell death process can be induced and this has been the subject of different review articles, although the role of the TRAIL-R2/DR5-activated extrinsic pathway of apoptosis has not yet been thoroughly summarized. In this Review, we provide an updated overview of the molecular mechanisms regulating cell fate decisions in tumor cells undergoing ER stress and discuss the role of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor 2 (TRAIL-R2/DR5) in the final outcome of UPR signaling. Particularly, we focus on the mechanisms controlling cellular FLICE-like inhibitory protein (FLIP) levels in tumor cells undergoing ER stress, which may represent a potential target for therapeutic intervention in cancer.

Keywords:  FLIP; TRAILR2/DR5; apoptosis; cancer; endoplasmic reticulum stress; extrinsic pathway; tumor microenvironment; unfolded protein response

DOI:  https://doi.org/10.3390/ijms23168987
J Immunol Res. 2022 ;2022 1366508

Endoplasmic Reticulum Stress-Related Signature for Predicting Prognosis and Immune Features in Hepatocellular Carcinoma.

Genhao Zhang, Jianping Sun.

Hepatocellular carcinoma (HCC) with cancer cells under endoplasmic reticulum (ER) stress has a poor prognosis. This study is aimed at discovering credible biomarkers for predicting the prognosis of HCC based on ER stress-related genes (ERSRGs). We constructed a novel four-ERSRG prognostic risk model, including PON1, AGR2, SSR2, and TMCC1, through a series of bioinformatic approaches, which can accurately predict survival outcomes in HCC patients. Higher risk scores were linked to later grade, recurrence, advanced TNM stage, later T stage, and HBV infection. In addition, 20 fresh frozen tumors and normal tissues from HCC patients were collected and used to validate the genes expressed in the signature by qRT-PCR and immunohistochemical (IHC) assays. Moreover, we found the ER stress-related signature could reflect the infiltration levels of different immune cells in the tumor microenvironment (TME) and forecast the efficacy of immune checkpoint inhibitor (ICI) treatment. Finally, we created a nomogram incorporating this ER stress-related signature. In conclusion, our constructed four-gene risk model associated with ER stress can accurately predict survival outcomes in HCC patients, and the model's risk score is associated with the poor clinical classification.

DOI: https://doi.org/10.1155/2022/1366508
Chem Biol Interact. 2022 Aug 23. pii: S0009-2797(22)00330-1. [Epub ahead of print] 110125

Epimedokoreanin B inhibits the growth of lung cancer cells through endoplasmic reticulum stress-mediated paraptosis accompanied by autophagosome accumulation.

Hao Zheng, Qingying Liu, Shuqi Wang, Xiaoqing Liu, Mengjiao Ma, Tao Shen, Xiaoning Wang, Dongmei Ren.

  Epimedokoreanin B (EKB) is a prenylated flavonoid isolated from Epimedium koreanum. In this article, we described the anti-cancerous effects of EKB and its underlying mechanism in human non-small cell lung cancer (NSCLC) A549 and NCI-H292 cells. EKB treatment inhibited cell proliferation and migration accompanied by cytoplasmic vacuolation in both cell lines. The cell death induced by EKB lacked the features of apoptosis like chromatin condensation, phosphatidyl serine exposure and caspase cleavage. The vacuoles stimulated by EKB predominantly derived from endoplasmic reticulum (ER) and mitochondria dilation, which are the characteristics of paraptosis. Down-regulation of Alix and up-regulation of ER stress-related proteins after EKB treatment further supported the occurrence of paraptosis. ER stress inhibitor 4-phenylbutyric acid (4-PBA) and protein synthesis inhibitor cycloheximide (CHX) treatment antagonized the vacuoles formation as well as cell death induced by EKB, indicating that ER stress was involved in EKB induced paraptosis. In addition, autophagosome accumulation accompanied with autophagy flux blocking was observed in EKB treated cells, this was consistent with the occurrence of ER stress. Collectively, EKB was demonstrated as a paraptosis-like cell death inducer in A549 and NCI-H292 cells. The inhibitory effect of EKB on lung cancer cell proliferation was further demonstrated in a zebrafish xenograft model. These findings raise the possibility that paraptosis inducers may be considered as alternative choices for lung cancer therapy.

Keywords:  Autophagosome accumulation; ER stress; Epimedokoreanin B; Paraptosis

DOI:  https://doi.org/10.1016/j.cbi.2022.110125
J Cell Physiol. 2022 Aug 22.

Involvement of Bid in the crosstalk between ferroptotic agent-induced ER stress and TRAIL-induced apoptosis.

Jin Hong Kim, Abdo J Najy, Jian Li, Xu Luo, Hyeong-Reh C Kim, Mohammad Haroon Asif Choudry, Yong J Lee.

  Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces death receptor-mediated extrinsic apoptosis, specifically in cancer cells, and Bid (BH3-interacting domain death agonist) plays an important role in TRAIL-induced apoptosis. Ferroptosis is a newly defined form of regulated cell death known to be distinct from other forms of cell death. However, our previous studies have shown that ferroptosis shares common pathways with other types of programmed cell death such as apoptosis. In this study, we investigated the role of Bid in the crosstalk between the ferroptotic agent-induced endoplasmic reticulum (ER) stress response and TRAIL-induced apoptosis. When human colorectal carcinoma HCT116 cells were treated with the ferroptosis-inducing agents artesunate and erastin in combination with TRAIL, TRAIL-induced activation of caspase-8 was enhanced, and subsequently, the truncation of Bid was increased. Similar results were observed when ovarian adenocarcinoma OVCAR-3 cells were treated with the ferroptotic agents in combination with TRAIL. Results from studies with Bid mutants reveal that the truncation of Bid and the presence of intact BH3 domains are critical for synergistic apoptosis. Nonfunctional Bid mutants were not able to activate the mitochondria-dependent apoptosis pathway, which is required for the conversion of p19 to p17, the active form of caspase-3. These results indicate that Bid plays a critical role in the crosstalk between the ferroptotic agent-induced ER stress response and TRAIL-induced apoptosis.

Keywords:  Bid; TRAIL cytotoxicity; apoptosis; endoplasmic reticulum stress; ferroptosis

DOI:  https://doi.org/10.1002/jcp.30863
Cells. 2022 Aug 09. pii: 2472. [Epub ahead of print]11(16):

Artesunate Inhibits the Cell Growth in Colorectal Cancer by Promoting ROS-Dependent Cell Senescence and Autophagy.

Zhiying Huang, Shu Gan, Xuerong Zhuang, Yao Chen, Linlin Lu, Ying Wang, Xiaoxiao Qi, Qian Feng, Qiuju Huang, Biaoyan Du, Rong Zhang, Zhongqiu Liu.

  Although artesunate has been reported to be a promising candidate for colorectal cancer (CRC) treatment, the underlying mechanisms and molecular targets of artesunate are yet to be explored. Here, we report that artesunate acts as a senescence and autophagy inducer to exert its inhibitory effect on CRC in a reactive oxygen species (ROS)-dependent manner. In SW480 and HCT116 cells, artesunate treatment led to mitochondrial dysfunction, drastically promoted mitochondrial ROS generation, and consequently inhibited cell proliferation by causing cell cycle arrest at G0/G1 phase as well as subsequent p16- and p21-mediated cell senescence. Senescent cells underwent endoplasmic reticulum stress (ERS), and the unfolded protein response (UPR) was activated via IRE1α signaling, with upregulated BIP, IRE1α, phosphorylated IRE1α (p-IRE1α), CHOP, and DR5. Further experiments revealed that autophagy was induced by artesunate treatment due to oxidative stress and ER stress. In contrast, N-Acetylcysteine (NAC, an ROS scavenger) and 3-Methyladenine (3-MA, an autophagy inhibitor) restored cell viability and attenuated autophagy in artesunate-treated cells. Furthermore, cellular free Ca2+ levels were increased and could be repressed by NAC, 3-MA, and GSK2350168 (an IRE1α inhibitor). In vivo, artesunate administration reduced the growth of CT26 cell-derived tumors in BALB/c mice. Ki67 and cyclin D1 expression was downregulated in tumor tissue, while p16, p21, p-IRE1α, and LC3B expression was upregulated. Taken together, artesunate induces senescence and autophagy to inhibit cell proliferation in colorectal cancer by promoting excessive ROS generation.

Keywords:  artesunate; autophagy; cell senescence; colorectal cancer; reactive oxygen species

DOI:  https://doi.org/10.3390/cells11162472
Anticancer Agents Med Chem. 2022 Aug 23.

The Glucose-Regulated Protein78 (GRP78) in the unfolded protein response (UPR) pathway: a potential therapeutic target for breast cancer.

Maryam Mohammad Sadeghipour, Seyedeh Atekeh Torabizadeh, Mojgan Noroozi Karimabad.

  Amongst all types of cancers, breast cancer is recognized as the most common cancer and a principal cause of morbidity and mortality in women. Endoplasmic reticulum (ER) stress pathways are primarily activated in cancer cells and activate a signaling network called the unfolded protein response (UPR). Many tumors, by activating the UPR pathway, allow to adapt and grow under stressful conditions. UPR is usually inactive in non-tumor cells, while it is active in tumor cells, so it is appropriate to develop new breast cancer therapies. A protein that regulates UPR is 78 KDa Glucose-Regulated Protein (GRP78). Usually, the GRP78 level in the cell is relatively low but increases significantly under stresses that affect the ER and calcium homeostasis, and increases resistance to chemotherapy. GRP78 drug suppressors could provide promising anticancer therapeutics. Therefore, understanding the molecular mechanism of GRP78 in cancer and identifying drugs that target GRP78 is essential for the treatment of breast cancer. In this review, we investigate the role of GRP78 in the pathogenesis of breast cancer.

Keywords:  Anticancer; Breast cancer; GRP78; Mechanism; UPR pathway

DOI:  https://doi.org/10.2174/1871520622666220823094350
Nutrients. 2022 Aug 16. pii: 3356. [Epub ahead of print]14(16):

Riboflavin (Vitamin B2) Deficiency Induces Apoptosis Mediated by Endoplasmic Reticulum Stress and the CHOP Pathway in HepG2 Cells.

Bo Zhang, Jun-Ting Cao, Yong-Bao Wu, Ke-Xin Gao, Ming Xie, Zheng-Kui Zhou, Jing Tang, Shui-Sheng Hou.

  Riboflavin is an essential micronutrient and a precursor of flavin mononucleotide and flavin adenine dinucleotide for maintaining cell homeostasis. Riboflavin deficiency (RD) induces cell apoptosis. Endoplasmic reticulum (ER) stress is considered to induce apoptosis, and C/EBP homologous protein (CHOP) is a key pathway involved in this process. However, whether RD-induced apoptosis is mediated by ER stress and the CHOP pathway remains unclear and needs further investigation. Therefore, the current study presents the effect of RD on ER stress and apoptosis in the human hepatoma cell line (HepG2). Firstly, cells were cultured in a RD medium (4.55 nM riboflavin) and a control (CON) medium (1005 nM riboflavin). We conducted an observation of cell microstructure characterization and determining apoptosis. Subsequently, 4-phenyl butyric acid (4-PBA), an ER stress inhibitor, was used in HepG2 cells to investigate the role of ER stress in RD-induced apoptosis. Finally, CHOP&nbsp;siRNA was transfected into HepG2 cells to validate whether RD triggered ER stress-mediated apoptosis by the CHOP pathway. The results show that RD inhibited cell proliferation and caused ER stress, as well as increased the expression of ER stress markers (CHOP, 78 kDa glucose-regulated protein, activating transcription factor 6) (p < 0.05). Furthermore, RD increased the cell apoptosis rate, enhanced the expression of proapoptotic markers (B-cell lymphoma 2-associated X, Caspase 3), and decreased the expression of the antiapoptotic marker (B-cell lymphoma 2) (p < 0.05). The 4-PBA treatment and CHOP knockdown markedly alleviated RD-induced cell apoptosis. These results demonstrate that RD induces cell apoptosis by triggering ER stress and the CHOP pathway.

Keywords:  CHOP pathway; apoptosis; endoplasmic reticulum stress; riboflavin deficiency

DOI:  https://doi.org/10.3390/nu14163356
Front Oncol. 2022 ;12 951631

Comprehensive analysis of the endoplasmic reticulum stress-related long non-coding RNA in bladder cancer.

Zhenyu Wu, Yue Wang, Mengxin Yan, Quan Liang, Bin Li, Guoliang Hou, Taolin Xia, Zhe Lin, Wenfeng Xu.

   Background: Bladder cancer is ranked the second most frequent tumor among urological malignancies. The research strived to establish a prognostic model based on endoplasmic reticulum stress (ERS)-related long non-coding RNA (lncRNA) in bladder cancer.
Methods: We extracted the ERS-related genes from the published research and bladder cancer data from the Cancer Genome Atlas database. ERS-related lncRNAs with prognostic significance were screened by univariate Cox regression, least absolute shrinkage and selection operator regression analysis and Kaplan-Meier method. Multivariate Cox analysis was leveraged to establish the risk score model. Moreover, an independent dataset, GSE31684, was used to validate the model's efficacy. The nomogram was constructed based on the risk score and clinical variables. Furthermore, the biological functions, gene mutations, and immune landscape were investigated to uncover the underlying mechanisms of the ERS-related signature. Finally, we employed external datasets (GSE55433 and GSE89006) and qRT-PCR to investigate the expression profile of these lncRNAs in bladder cancer tissues and cells.
Results: Six ERS-related lncRNAs were identified to be closely coupled with patients' prognosis. On this foundation, a risk score model was created to generate the risk score for each patient. The ERS-related risk score was shown to be an independent prognostic factor. And the results of GSE31684 dataset also supported this conclusion. Then, a nomogram was constructed based on risk scores and clinical characteristics, and proven to have excellent predictive value. Moreover, the gene function analysis demonstrated that ERS-related lncRNAs were closely linked to fatty extracellular matrix, cytokines, cell adhesion, and tumor pathways. Further analysis revealed the association of the 6-lncRNAs signature with gene mutations and immunity in bladder cancer. Finally, the external datasets and qRT-PCR verified high expressions of the ERS-related lncRNAs in bladder cancer tissues and cells.
Conclusions: Overall, our findings indicated that ERS-related lncRNAs, which may affect tumor pathogenesis in a number of ways, might be exploited to assess the prognosis of bladder cancer patients.

Keywords:  ERS; TCGA; bladder cancer; lncRNA; prognostic model

DOI:  https://doi.org/10.3389/fonc.2022.951631
Pancreatology. 2022 Aug 17. pii: S1424-3903(22)00475-6. [Epub ahead of print]

Endoplasmic stress-inducing variants in carboxyl ester lipase and pancreatic cancer risk.

Makoto Kawamoto, Takeichi Yoshida, Koji Tamura, Mohamad Dbouk, Marcia Irene Canto, Richard Burkhart, Jin He, Nicholas J Roberts, Alison P Klein, Michael Goggins.

   BACKGROUND: Endoplasmic reticulum (ER) stress-inducing variants in several pancreatic secretory enzymes have been associated with pancreatic disease. Multiple variants in CEL, encoding carboxyl ester lipase, are known to cause maturity-onset diabetes of the young (MODY8) but have not been implicated in pancreatic cancer risk.
METHODS: The prevalence of ER stress-inducing variants in the CEL gene was compared among pancreatic cancer cases vs. controls. Variants were identified by next-generation sequencing and confirmed by Sanger sequencing. Variants of uncertain significance (VUS) were assessed for their effect on the secretion of CEL protein and variants with reduced protein secretion were evaluated to determine if they induced endoplasmic reticulum stress.
RESULTS: ER stress-inducing CEL variants were found in 34 of 986 cases with sporadic pancreatic ductal adenocarcinoma, and 21 of 1045 controls (P = 0.055). Most of the variants were either the CEL-HYB1 variant, the I488T variant, or the combined CEL-HYB1/I488T variant; one case had a MODY8 variant.
CONCLUSION: This case/control analysis finds ER stress-inducing CEL variants are not associated with an increased likelihood of having pancreatic cancer.

Keywords:  CEL; Endoplasmic reticulum stress; Inherited susceptibility; Pancreatic cancer; Variant

DOI:  https://doi.org/10.1016/j.pan.2022.08.004
Sci Rep. 2022 Aug 25. 12(1): 14520

Local anesthetic lidocaine-inducible gene, growth differentiation factor-15 suppresses the growth of cancer cell lines.

Keiko Haraguchi-Suzuki, Reika Kawabata-Iwakawa, Toru Suzuki, Takashi Suto, Tomonori Takazawa, Shigeru Saito.

Administration of local anesthetics, such as lidocaine, in the perioperative period improves outcomes of cancer patients. However, its precise mechanism is still unresolved. The growth of human cancer cell lines, including HeLa cells, are suppressed by lidocaine treatment. We identified that growth differentiation factor-15 (GDF-15) was commonly upregulated in lidocaine-treated cancer cell lines. GDF-15 is a divergent member of the transforming growth factor-β (TGF-β) superfamily and it is produced as an unprocessed pro-protein form and then cleaved to generate a mature form. In lidocaine-treated HeLa cells, increased production of GDF-15 in the endoplasmic reticulum (ER) was observed and unprocessed pro-protein form of GDF-15 was secreted extracellularly. Further, lidocaine induced apoptosis and apoptosis-inducible Tribbles homologue 3 (TRIB3) was also commonly upregulated in lidocaine-treated cancer cell lines. In addition, transcription factor C/EBP homologous protein (CHOP), which is a positive regulator of not only GDF-15 but TRIB3 was also induced by lidocaine. Lidocaine-induced growth suppression and apoptosis was suppressed by knockdown of GDF-15 or TRIB3 expression by small interference RNA (siRNA). These observations suggest that lidocaine suppresses the growth of cancer cells through increasing GDF-15 and TRIB3 expression, suggesting its potential application as cancer therapy.

DOI: https://doi.org/10.1038/s41598-022-18572-3
Oncogene. 2022 Aug 20.

METTL3 potentiates progression of cervical cancer by suppressing ER stress via regulating m6A modification of TXNDC5 mRNA.

Qiu-Ying Du, Fu-Chun Huo, Wen-Qi Du, Xiao-Lin Sun, Xin Jiang, Lan-Sheng Zhang, Dong-Sheng Pei.

N6-methyladenosine (m6A) is the most abundant chemical modification on mRNA and plays significant roles in many bioprocesses. However, the functions of m6A on cervical cancer (CC) tumorigenesis remain unclear. Here we found methyltransferase-like 3 (METTL3), a core member of the m6A methyltransferase family, was greatly upregulated as an independent prognostic factor in CC. Mechanistically, the transcription factor ETS1 recruited P300 and WDR5 which separately mediated H3K27ac and H3K4me3 histone modification in the promoter of METTL3 and induced METTL3 transcription activation. Furthermore, we identified TXNDC5 as a target of METTL3-mediated m6A modification through MeRIP-seq, and revealed that METTL3-mediated TXNDC5 expression relied on the m6A reader-dependent manner. Functionally, we verified that METTL3 promoted proliferation and metastasis of CC cells by regulating of TXNDC5 expression through in vitro and in vivo experiments. In addition, our study verified the effect of METTL3/TXNDC5 axis on ER stress. Taken together, METTL3 facilitates the malignant progression of CC, suggesting that METTL3 might be a potential prognostic biomarker and therapeutic target for CC.

DOI: https://doi.org/10.1038/s41388-022-02435-2
Front Mol Biosci. 2022 ;9 930223

Metabolic adaption of cancer cells toward autophagy: Is there a role for ER-phagy?

Debora Gentile, Marianna Esposito, Paolo Grumati.

  Autophagy is an evolutionary conserved catabolic pathway that uses a unique double-membrane vesicle, called autophagosome, to sequester cytosolic components, deliver them to lysosomes and recycle amino-acids. Essentially, autophagy acts as a cellular cleaning system that maintains metabolic balance under basal conditions and helps to ensure nutrient viability under stress conditions. It is also an important quality control mechanism that removes misfolded or aggregated proteins and mediates the turnover of damaged and obsolete organelles. In this regard, the idea that autophagy is a non-selective bulk process is outdated. It is now widely accepted that forms of selective autophagy are responsible for metabolic rewiring in response to cellular demand. Given its importance, autophagy plays an essential role during tumorigenesis as it sustains malignant cellular growth by acting as a coping-mechanisms for intracellular and environmental stress that occurs during malignant transformation. Cancer development is accompanied by the formation of a peculiar tumor microenvironment that is mainly characterized by hypoxia (oxygen < 2%) and low nutrient availability. Such conditions challenge cancer cells that must adapt their metabolism to survive. Here we review the regulation of autophagy and selective autophagy by hypoxia and the crosstalk with other stress response mechanisms, such as UPR. Finally, we discuss the emerging role of ER-phagy in sustaining cellular remodeling and quality control during stress conditions that drive tumorigenesis.

Keywords:  ER stress; ER-phagy; UPR; autophagy; cancer; endoplasmic reticulum; hypoxia

DOI:  https://doi.org/10.3389/fmolb.2022.930223
Cell Biosci. 2022 Aug 21. 12(1): 135

Anti-tumor effects of dual PI3K-HDAC inhibitor CUDC-907 on activation of ROS-IRE1α-JNK-mediated cytotoxic autophagy in esophageal cancer.

Zheng Jian, Yichao Han, Wentian Zhang, Chengqiang Li, Wei Guo, Xijia Feng, Bin Li, Hecheng Li.

   BACKGROUND: PI3K-Akt pathway activation and the expression of histone deacetylases (HDACs) are highly increased in esophageal cancer, suggesting that inhibition of such targets may be a viable therapeutic strategy. Herein, we aimed to evaluate the anti-tumor effect of CUDC-907, a dual PI3K-HDAC inhibitor, in esophageal squamous cell carcinoma (ESCC).
METHODS: The anti-tumor effects of CUDC-907 in ESCC were evaluated using cell counting kit-8, flow cytometry, and western blot. mRNA-sequencing was used to explore the mechanism underlying CUDC-907 anti-tumor effects. The relations of reactive oxygen species (ROS), lipocalin 2 (LCN2), and CUDC-907 were determined by flow cytometry, rescue experiments, and western blot. The activation of the IRE1α-JNK-CHOP signal cascade was confirmed by western blot. The in vivo inhibitory effects of CUDC-907 were examined by a subcutaneous xenograft model in nude mice.
RESULTS: CUDC-907 displayed effective inhibition in the proliferation, migration, and invasion of ESCC cells. Through an mRNA-sequencing and functional enrichment analysis, autophagy was found to be associated with cancer cells death. CUDC-907 not only inhibited the PI3K-Akt-mTOR pathways to result in autophagy, but also induced ROS accumulation to activate IRE1α-JNK-CHOP-mediated cytotoxic autophagy by downregulating LCN2 expression. Consistently, the in vivo anti-tumor effects of CUDC-907 accompanied by the downregulated expression of p-mTOR and LCN2 and upregulated expression of p-IRE1α and LC3B-II were evaluated in a xenograft mouse model.
CONCLUSION: Our findings suggested the clinical development and administration of CUDC-907 might act as a novel treatment strategy for ESCC. A more in-depth understanding of the anti-tumor effect of CUDC-907 in ESCC will benefit the clinically targeted treatment of ESCC.

Keywords:  Autophagy; CDX; CUDC-907; Esophageal cancer; HDAC; PI3K-Akt

DOI:  https://doi.org/10.1186/s13578-022-00855-x