The dual role of GPX4 in breast cancer: mechanisms of therapeutic resistance and potential for novel targeted therapies

Angela NG, Hyuna S, Kimberly DM, Joan LK, Lisa AN, Adair M, et al. Breast Cancer Statistics, 2022. CA Cancer J Clin. 2022;72:524–41.

Article  Google Scholar 

Ye F, Dewanjee S, Li Y, Jha N, Chen Z, Kumar A, et al. Advancements in clinical aspects of targeted therapy and immunotherapy in breast cancer. Mol Cancer. 2023;22:105.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Madhuchhanda R, Amy MF, Gary AU, Aparna M. Molecular classification of breast cancer. PET Clin. 2023;18:441–58.

Article  Google Scholar 

Fiorenza DR, Bruno M, Maria Carmen DS, Antonella F, Lorenza M, Riccardo Ray C. et al. Rethinking breast cancer follow-up based on individual risk and recurrence management. Cancer Treat Rev. 2022;109:102434.

Article  Google Scholar 

Harshini S, Sangilimuthu Alagar KS, Extensive Y. review on breast cancer its etiology, progression, prognostic markers, and treatment. Med Oncol. 2023;40:238.

Article  Google Scholar 

Lining Z, Wansong Z, Hao Z, Rutao L. Kidney Toxicity and Response of Selenium Containing Protein-glutathione Peroxidase (Gpx3) to CdTe QDs on Different Levels. Toxicol Sci. 2018;168:201–8.

Google Scholar 

Leopold F, Stefano T, Laura O. The glutathione peroxidase family: Discoveries and mechanism. Free Radic Biol Med. 2022;187:113–22.

Article  Google Scholar 

Kamari W, Rachid S. The Selenoprotein Glutathione Peroxidase 4: From molecular mechanisms to novel therapeutic opportunities. Biomedicines. 2022;10:891.

Article  Google Scholar 

Xie Y, Kang R, Klionsky D, Tang D. GPX4 in cell death, autophagy, and disease. Autophagy. 2023;19:2621–38.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Liu Y, Wan Y, Jiang Y, Zhang L, Cheng W. GPX4: The hub of lipid oxidation, ferroptosis, disease and treatment. Biochim et Biophys Acta Rev cancer. 2023;1878:188890.

Article  CAS  Google Scholar 

Kirill B, Joseph MH, Zhipeng L, Leslie M, Breanna F, Peter HT, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019;575:688–92.

Article  Google Scholar 

Mutian J, Danhui Q, Chunyuan Z, Li C, Zhongxia Y, Wenwen W. et al. Redox homeostasis maintained by GPX4 facilitates STING activation. Nat Immunol. 2020;21:727–35.

Article  Google Scholar 

Vaishali A, Hardeep Singh T, Ayşegül V, Falak T, Mukerrem Betul Y, Katrin S. et al. Role of Reactive Oxygen Species in Cancer Progression: Molecular Mechanisms and Recent Advancements. Biomolecules. 2019;9:735.

Article  Google Scholar 

Dunyaporn T, Jerome A, Peng H. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?. Nat Rev Drug Discov. 2009;8:579–91.

Article  Google Scholar 

Chiara G, Isaac SH, Tak WM. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov. 2013;12:931–47.

Article  Google Scholar 

Jihye Y, Edouard M, Changyuan L, Kaitlyn NB, Adam K, Keith R. et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science. 2015;350:1391–96.

Article  Google Scholar 

Jing C, Zhijie O, Tiantian G, Yuwei Y, Anmei S, Huiqin X. et al. Ginkgolide B alleviates oxidative stress and ferroptosis by inhibiting GPX4 ubiquitination to improve diabetic nephropathy. Biomed Pharmacother. 2022;156:113953.

Article  Google Scholar 

Yu'e L, Shiping L, Lei-Lei W, Liang Y, Lixue Y, Jinghan W. The diversified role of mitochondria in ferroptosis in cancer. Cell Death Dis. 2023;14:519.

Article  Google Scholar 

Chong Z, Jie L, Ketao Z, Huohui O, Ke S, Qingbo L. et al. SHARPIN promotes cell proliferation of cholangiocarcinoma and inhibits ferroptosis via p53/SLC7A11/GPX4 signaling. Cancer Sci. 2022;113:3766–75.

Article  Google Scholar 

Yin Y, Zhian C, Hao Z, Cailing C, Ming Z, Joseph Y. et al. Selenium-GPX4 axis protects follicular helper T cells from ferroptosis. Nat Immunol. 2021;22:1127–39.

Article  Google Scholar 

Kuo S, Xujie W, Yunwei W, Yanhui J, Yue Z, Kejia W, et al. miR-125b-5p in adipose derived stem cells exosome alleviates pulmonary microvascular endothelial cells ferroptosis via Keap1/Nrf2/GPX4 in sepsis lung injury. Redox Biol. 2023;62:102655.

Article  Google Scholar 

Kim N, Andreas S, Nobuhiko K, Vishva MD. Cell death. Cell. 2024;187:235–56.

Article  Google Scholar 

Lorenzo G, Ilio V, Stuart AA, John MA, Dieter A, Patrizia A. et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25:486–41.

Article  Google Scholar 

Rumani S, Anthony L, Kristopher S. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat Rev Mol Cell Biol. 2019;20:175–93.

Article  Google Scholar 

Ran Q, Liang H, Gu M, Qi W, Walter CA, Roberts LJ 2nd, et al. Transgenic mice overexpressing glutathione peroxidase 4 are protected against oxidative stress-induced apoptosis. J Biol Chem. 2004;279:55137–46.

Article  CAS  PubMed  Google Scholar 

Huei-Sheng H, Wen Chang C, Ching Jiunn C. Involvement of reactive oxygen species in arsenite-induced downregulation of phospholipid hydroperoxide glutathione peroxidase in human epidermoid carcinoma A431 cells. Free Radic Biol Med. 2002;33:864–73.

Yansong X, Daniel ET, Wei Hong T, Callum K, Si Ming M. Emerging Activators and Regulators of Inflammasomes and Pyroptosis. Trends Immunol. 2019;40:1035–52.

Yang W, SriRamaratnam R, Welsch M, Shimada K, Skouta R, Viswanathan V, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156:317–31.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Regina B-F, Matilde M. Glutathione peroxidases. Biochim Biophys Acta. 2012;1830:3289–303.

Xiaoguang L, Kellen O, Yilei Z, Esther WL, Jiejun S, Xiaoshan Z, et al. Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer. Nat Cell Biol. 2020;22:476–86.

Scott JD, Kathryn ML, Michael RL, Rachid S, Eleina MZ, Caroline EG, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

Dana EC, Junying Y. Necroptosis as an alternative form of programmed cell death. Curr Opin Cell Biol. 2010;22:263–8.

Bersuker K, Hendricks J, Li Z, Magtanong L, Ford B, Tang P, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019;575:688–92.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Behrouz H, Peter V, Tom VB. Targeting ferroptosis to iron out cancer. Cancer Cell. 2019;35:830–49.

Sha R, Xu Y, Yuan C, Sheng X, Wu Z, Peng J, et al. Predictive and prognostic impact of ferroptosis-related genes ACSL4 and GPX4 on breast cancer treated with neoadjuvant chemotherapy. EBioMedicine. 2021;71:103560.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jose Pedro FA, Manuela S, Bettina P, Yulia YT, Vladimir AT, Victoria JH, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014;16:1180–91.

Le J, Ning K, Tongyuan L, Shang-Jui W, Tao S, Hanina H, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520:57–62.

Brent RS, José Pedro FA, Hülya B, Ashley IB, Marcus C, Scott JD, et al. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and Disease. Cell. 2017;171:273–85.

Vasanthi SV, Matthew JR, Harshil DD, Shubhroz G, Ossia ME, Brinton S-L, et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature. 2017;547:453–7.

Jinxin X, Huiming H, Xuejiao W, Peng T, Lishan O, Longyan W, et al. Boswellia carterii n-hexane extract suppresses breast cancer growth via induction of ferroptosis by downregulated GPX4 and upregulated transferrin. Sci Rep. 2024;14:14307.

Bowen L, Zixian W, Zhiyue W, Fangqi X, Jinhua Y, Baiqiang L, et al. Fusobacterium nucleatum induces oxaliplatin resistance by inhibiting ferroptosis through E-cadherin/β-catenin/GPX4 axis in colorectal cancer. Free Radic Biol Med. 2024;220:125–38.

Minglang G, Kai L, Yu D, Zilong L, Congkuan S, Wenjie W, et al. Eriocitrin inhibits epithelial-mesenchymal transformation (EMT) in lung adenocarcinoma cells via triggering ferroptosis. Aging. 2023;15:10089–104.

Park M, Kim D, Ko S, Kim A, Mo K, Yoon H. Breast cancer metastasis: mechanisms and therapeutic implications. Int J Mol Sci. 2022;23:6806.

Forcina G, Dixon S. GPX4 at the crossroads of lipid homeostasis and ferroptosis. Proteomics. 2019;19:e1800311.

Article  PubMed  Google Scholar 

Ding Y, Chen X, Liu C, Ge W, Wang Q, Hao X, et al. Identification of a small molecule as inducer of ferroptosis and apoptosis through ubiquitination of GPX4 in triple negative breast cancer cells. J Hematol Oncol. 2021;14:19.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhang X, Sui S, Wang L, Li H, Zhang L, Xu S, et al. Inhibition of tumor propellant glutathione peroxidase 4 induces ferroptosis in cancer cells and enhances anticancer effect of cisplatin. J Cell Physiol. 2020;235:3425–37.

Article  CAS  PubMed  Google Scholar 

Lv C, Qu H, Zhu W, Xu K, Xu A, Jia B, et al. Low-Dose Paclitaxel inhibits tumor cell growth by regulating glutaminolysis in colorectal carcinoma cells. Front Pharm. 2017;8:244.

Article  Google Scholar 

Guo J, Xu B, Han Q, Zhou H, Xia Y, Gong C, et al. Ferroptosis: A novel anti-tumor action for Cisplatin. Cancer Res Treat. 2018;50:445–60.

Article  CAS  PubMed  Google Scholar 

Hangauer M, Viswanathan V, Ryan M, Bole D, Eaton J, Matov A, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature. 2017;551:247–50.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mattia Z, Valentina B-T, Maria Luisa DP, Marco F, Matilde M, Giovanni M, et al. Redox status in a model of cancer stem cells. Arch Biochem Biophys. 2016;617:120–8.

Si-Wei W, Chao G, Yi-Min Z, Li Y, Jia-Cheng L, Xiao-Yong H, et al. Current applications and future perspective of CRISPR/Cas9 gene editing in cancer. Mol Cancer. 2022;21:57.

Christine A, Sohyoung H, David AJ. Radiotherapy for cancer: present and future. Adv Drug Deliv Rev. 2017;109:1–2.

Shan L, Hai-Liang Z, Jing L, Zhi-Peng Y, Tian D, Li-Chao L, et al. Tubastatin A potently inhibits GPX4 activity to potentiate cancer radiotherapy through boosting ferroptosis. Redox Biol. 2023;62:102677.

Xueting L, Michael DG, Weimin W, Jiali Y, Jae Eun C, Long J, et al. Radiotherapy and Immunotherapy Promote Tumoral Lipid Oxidation and Ferroptosis via Synergistic Repression of SLC7A11. Cancer

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