Endoplasmic Reticulum Stress-a Key Guardian in Cancer

Overview

Journal Cell Death Discov

Date 2024 Jul 30

PMID 39080273

Authors

Wenlong Zhang

Yidan Shi

Linda Oyang

Shiwen Cui

Shizhen Li

JinYun Li

Lin Liu

Yun Li

Mingjing Peng

Shiming Tan

Longzheng Xia

Jinguan Lin

Xuemeng Xu

Nayiyuan Wu

Qiu Peng

Yanyan Tang

Xia Luo

Qianjin Liao

Xianjie Jiang

Yujuan Zhou

Affiliations

Soon will be listed here.

Abstract

Endoplasmic reticulum stress (ERS) is a cellular stress response characterized by excessive contraction of the endoplasmic reticulum (ER). It is a pathological hallmark of many diseases, such as diabetes, obesity, and neurodegenerative diseases. In the unique growth characteristic and varied microenvironment of cancer, high levels of stress are necessary to maintain the rapid proliferation and metastasis of tumor cells. This process is closely related to ERS, which enhances the ability of tumor cells to adapt to unfavorable environments and promotes the malignant progression of cancer. In this paper, we review the roles and mechanisms of ERS in tumor cell proliferation, apoptosis, metastasis, angiogenesis, drug resistance, cellular metabolism, and immune response. We found that ERS can modulate tumor progression via the unfolded protein response (UPR) signaling of IRE1, PERK, and ATF6. Targeting the ERS may be a new strategy to attenuate the protective effects of ERS on cancer. This manuscript explores the potential of ERS-targeted therapies, detailing the mechanisms through which ERS influences cancer progression and highlighting experimental and clinical evidence supporting these strategies. Through this review, we aim to deepen our understanding of the role of ER stress in cancer development and provide new insights for cancer therapy.

Citing Articles

Artesunate alleviated murine ulcerative colitis by regulating immune response through inhibiting endoplasmic reticulum stress.

Yin S, Li L, Chen X, Wang J, Mao Y, Wang J Front Immunol. 2025; 16:1545468.

PMID: 40079012 PMC: 11897576. DOI: 10.3389/fimmu.2025.1545468.

Methylglyoxal Formation-Metabolic Routes and Consequences.

Vaskova J, Kovacova G, Pudelsky J, Palencar D, Mickova H Antioxidants (Basel). 2025; 14(2).

PMID: 40002398 PMC: 11852113. DOI: 10.3390/antiox14020212.

PERK-Olating Through Cancer: A Brew of Cellular Decisions.

Mazzolini L, Touriol C Biomolecules. 2025; 15(2).

PMID: 40001551 PMC: 11852789. DOI: 10.3390/biom15020248.

Routine Blood Tests as Predictive Tools for Differentiating Follicular Thyroid Carcinoma From Follicular Adenoma.

Wang J, Wang J, Liu H, Chen C Int J Gen Med. 2025; 18:733-744.

PMID: 39963518 PMC: 11830949. DOI: 10.2147/IJGM.S502626.

Relocating NSAIDs into the endoplasmic reticulum induces ER stress-mediated apoptosis in cancer cells.

Mishra T, Preeti , Ingle J, Saha A, Basu S RSC Med Chem. 2025; .

PMID: 39911136 PMC: 11791515. DOI: 10.1039/d4md00936c.

References

Grandjean J, Madhavan A, Cech L, Seguinot B, Paxman R, Smith E . Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming. Nat Chem Biol. 2020; 16(10):1052-1061. PMC: 7502540. DOI: 10.1038/s41589-020-0584-z. View

Cao Y, Trillo-Tinoco J, Sierra R, Anadon C, Dai W, Mohamed E . ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression. Nat Commun. 2019; 10(1):1280. PMC: 6426975. DOI: 10.1038/s41467-019-09263-1. View

Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K . ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev. 2002; 16(11):1345-55. PMC: 186318. DOI: 10.1101/gad.992302. View

Herrema H, Guan D, Choi J, Feng X, Hernandez M, Faruk F . FKBP11 rewires UPR signaling to promote glucose homeostasis in type 2 diabetes and obesity. Cell Metab. 2022; 34(7):1004-1022.e8. DOI: 10.1016/j.cmet.2022.06.007. View

Kaplan A, Stockwell B . Structural Elucidation of a Small Molecule Inhibitor of Protein Disulfide Isomerase. ACS Med Chem Lett. 2015; 6(9):966-971. PMC: 4603724. DOI: 10.1021/acsmedchemlett.5b00014. View

Kekupaa Knutson A, Williams A, Boisvert W, Shohet R . HIF in the heart: development, metabolism, ischemia, and atherosclerosis. J Clin Invest. 2021; 131(17). PMC: 8409592. DOI: 10.1172/JCI137557. View

Tang L, Xiong W, Zhang L, Wang D, Wang Y, Wu Y . circSETD3 regulates MAPRE1 through miR-615-5p and miR-1538 sponges to promote migration and invasion in nasopharyngeal carcinoma. Oncogene. 2020; 40(2):307-321. DOI: 10.1038/s41388-020-01531-5. View

Mohamed E, Sierra R, Trillo-Tinoco J, Cao Y, Innamarato P, Payne K . The Unfolded Protein Response Mediator PERK Governs Myeloid Cell-Driven Immunosuppression in Tumors through Inhibition of STING Signaling. Immunity. 2020; 52(4):668-682.e7. PMC: 7207019. DOI: 10.1016/j.immuni.2020.03.004. View

Guo J, Zhong X, Tan Q, Yang S, Liao J, Zhuge J . miR-301a-3p induced by endoplasmic reticulum stress mediates the occurrence and transmission of trastuzumab resistance in HER2-positive gastric cancer. Cell Death Dis. 2021; 12(7):696. PMC: 8277821. DOI: 10.1038/s41419-021-03991-3. View

10.

Adachi Y, Yamamoto K, Okada T, Yoshida H, Harada A, Mori K . ATF6 is a transcription factor specializing in the regulation of quality control proteins in the endoplasmic reticulum. Cell Struct Funct. 2008; 33(1):75-89. DOI: 10.1247/csf.07044. View

11.

Zhao Y, Wang Y, Zhang L, Wang W, Fahey T, Yao K . BRAF inhibition promotes ER stress-mediated cell death in uveal melanoma. Neoplasma. 2022; 69(5):1070-1078. DOI: 10.4149/neo_2022_220428N462. View

12.

Huang H, Gao Y, Liu A, Yang X, Huang F, Xu L . EIF3D promotes sunitinib resistance of renal cell carcinoma by interacting with GRP78 and inhibiting its degradation. EBioMedicine. 2019; 49:189-201. PMC: 6945244. DOI: 10.1016/j.ebiom.2019.10.030. View

13.

Zhao Y, Zhang W, Huo M, Wang P, Liu X, Wang Y . XBP1 regulates the protumoral function of tumor-associated macrophages in human colorectal cancer. Signal Transduct Target Ther. 2021; 6(1):357. PMC: 8526672. DOI: 10.1038/s41392-021-00761-7. View

14.

Lu C, Shi W, Hu W, Zhao Y, Zhao X, Dong F . Endoplasmic reticulum stress promotes breast cancer cells to release exosomes circ_0001142 and induces M2 polarization of macrophages to regulate tumor progression. Pharmacol Res. 2022; 177:106098. DOI: 10.1016/j.phrs.2022.106098. View

15.

Kim T, Lee S, Kim M, Cheon C, Ko S . Kaempferol induces autophagic cell death via IRE1-JNK-CHOP pathway and inhibition of G9a in gastric cancer cells. Cell Death Dis. 2018; 9(9):875. PMC: 6115440. DOI: 10.1038/s41419-018-0930-1. View

16.

Shen J, Prywes R . ER stress signaling by regulated proteolysis of ATF6. Methods. 2005; 35(4):382-9. DOI: 10.1016/j.ymeth.2004.10.011. View

17.

Chen J, Lei C, Zhang H, Huang X, Yang Y, Liu J . RPL11 promotes non-small cell lung cancer cell proliferation by regulating endoplasmic reticulum stress and cell autophagy. BMC Mol Cell Biol. 2023; 24(1):7. PMC: 9985270. DOI: 10.1186/s12860-023-00469-2. View

18.

Thommen D, Schumacher T . T Cell Dysfunction in Cancer. Cancer Cell. 2018; 33(4):547-562. PMC: 7116508. DOI: 10.1016/j.ccell.2018.03.012. View

19.

Feng Y, Tung C, Su Y, Tsao C, Wu T . Proteomic Profile of Sorafenib Resistance in Hepatocellular Carcinoma; GRP78 Expression Is Associated With Inferior Response to Sorafenib. Cancer Genomics Proteomics. 2019; 16(6):569-576. PMC: 6885357. DOI: 10.21873/cgp.20159. View

20.

Salaroglio I, Panada E, Moiso E, Buondonno I, Provero P, Rubinstein M . PERK induces resistance to cell death elicited by endoplasmic reticulum stress and chemotherapy. Mol Cancer. 2017; 16(1):91. PMC: 5427528. DOI: 10.1186/s12943-017-0657-0. View