Objective  To investigate the effect of epithelial-mesenchymal transition (EMT) on the sensitivity to ferroptosis inducers in lung cancer.

Methods  Bioinformatics analysis was utilized to as-sess the relationship between EMT-related genes and the sensitivity of multiple drugs. Cells with low expression of E-cadherin and high expression of N-cadherin or high expression of E-cadherin and low expression of N-cadherin were sorted by flow cytometry to simulate lung cancer epithelial and mesen-chymal cells. The sensitivity of different types of lung cancer cells to ferroptosis was compared by treat-ment with the ferroptosis inducer (GPX4) and endogenous ferroptosis inducers (IFN-γ combined with arachidonic acid).

Results  The resistance to ferroptosis inducers was positively correlated with the expression of E-cadherin and negatively correlated with the expression of vimentin, zinc finger E-box-binding homeobox 1 and zinc finger E-box-binding homeobox 2. Treatment with ferropto-sis-inducers revealed that lung cancer cells with low expression of E-cadherin and high expression of N-cadherin were more sensitive to ferroptosis. The ferroptosis inhibitor ferrostatin-1 could reverse the induction of ferroptosis by IFN-γ combined with arachidonic acid.

Conclusion  Lung cancer cells un-dergoing EMT are more sensitive to ferroptosis, which could potentially serve as a novel therapeutic strategy for the treatment of metastatic and treatment-resistant lung cancer.

1.Singh M, Yelle N, Venugopal C, et al. EMT: Mechanisms and therapeutic implications[J]. Pharmacol Ther, 2018, 182: 80-94. DOI: 10.1016/j.pharmthera.2017.08.009.

2.De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression[J]. Nat Rev Cancer, 2013, 13(2): 97-110. DOI: 10.1038/nrc3447.

3.Shibue T, Weinberg RA. EMT, CSCs, and drug resistance: the mechanistic link and clinical implica-tions[J]. Nat Rev Clin Oncol, 2017, 14(10): 611-629. DOI: 10.1038/nrclinonc.2017.44.

4.Taki M, Abiko K, Ukita M, et al. Tumor immune microenvironment during epithelial-mesenchymal tran-sition[J]. Clin Cancer Res, 2021, 27(17): 4669-4679. DOI: 10.1158/1078-0432.Ccr-20-4459.

5.Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149(5): 1060-1072. DOI: 10.1016/j.cell. 2012.03.042.

6.Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease[J]. Nat Rev Mol Cell Biol, 2021, 22(4): 266-282. DOI: 10.1038/s41580-020-00324-8.

7.Zhang C, Liu X, Jin S, et al. Ferroptosis in cancer therapy: a novel approach to reversing drug re-sistance[J]. Mol Cancer, 2022, 21(1): 47. DOI: 10.1186/s12943-022-01530-y.

8.Chen X, Li J, Kang R, et al. Ferroptosis: machinery and regulation[J]. Autophagy, 2021, 17(9): 2054-2081. DOI: 10.1080/15548627.2020.1810918.

9.Ebrahimi N, Adelian S, Shakerian S, et al. Crosstalk between ferroptosis and the epitheli-al-mesenchymal transition: implications for inflammation and cancer therapy[J]. Cytokine Growth Fac-tor Rev, 2022, 64：33-45. DOI: 10.1016/j.cytogfr.2022.01.006.

10.Viswanathan VS, Ryan MJ, Dhruv HD, et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway[J]. Nature, 2017, 547(7664): 453-457. DOI: 10.1038/nature23007.

11.Hangauer MJ, Viswanathan VS, Ryan MJ, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition[J]. Nature, 2017, 551(7679): 247-250. DOI: 10.1038/nature24297.

12.Loh CY, Chai JY, Tang TF, et al. The E-cadherin and N-cadherin switch in epithelial-to-mesenchymal transition: signaling, therapeutic implications, and challenges[J]. Cells, 2019, 8(10): 1118. DOI: 10.3390/cells8101118.

13.Liao P, Wang W, Wang W, et al. CD8+ T cells and fatty acids orchestrate tumor ferroptosis and im-munity via ACSL4[J]. Cancer Cell, 2022, 40(4): 365-378.e6. DOI: 10.1016/j.ccell.2022.02.003.

14.王娟, 韩旭, 赵宁, 等. 长链非编码RNA在非小细胞肺癌中的研究进展[J]. 医学新知. [Wang J, Han X, Zhao N, et al. The research progress into long non-coding RNA in non-small cell lung cancer[J]. New Medicine.] DOI: 10.12173/j.issn.1004-5511.202207025.

15.沈姗, 杨洁, 刘云霞. 安罗替尼治疗晚期非小细胞肺癌的快速卫生技术评估[J]. 医学新知, 2021, 31(5): 350-356. [Shen S, Yang J, Liu YX. Rapid health technology assessment of anlotinib in treatment of advanced non-small cell lung cancer[J]. New Medicine, 2021, 31(5): 350-356.] DOI: 10.12173/j.issn.1004-5511.202102017.

16.苏广全, 张旭东, 方萍萍. 信迪利单抗一线治疗晚期鳞状非小细胞肺癌的成本-效用分析[J].药物流行病学杂志, 2022, 31(11): 756-760. [Su GQ, Zhang XD, Fang PP, et al. Cost-utility analysis of first-line treatment of ad-vanced squamous non-small cell lung cancer with sintilimab[J]. Chinese Journal of Pharmacoepidemi-ology, 2022, 31(11): 756-760.] DOI: 10.19960/j.cnki.issn1005-0698.2022.11.007.

17.Mittal V. Epithelial mesenchymal transition in tumor metastasis[J]. Annu Rev Pathol, 2018, 13: 395-412. DOI: 10.1146/annurev-pathol-020117-043854.

18.Paolillo M, Schinelli S. Extracellular matrix alterations in metastatic processes[J]. Int J Mol Sci, 2019, 20(19): 4947. DOI: 10.3390/ijms20194947.

19.Khanbabaei H, Ebrahimi S, García-Rodríguez JL, et al. Non-coding RNAs and epithelial mesenchymal tran-sition in cancer: molecular mechanisms and clinical implications[J]. J Exp Clin Cancer Res, 2022, 41(1): 278. DOI: 10.1186/s13046-022-02488-x.

20.Xie S, Wu Z, Qi Y, et al. The metastasizing mechanisms of lung cancer: Recent advances and therapeu-tic challenges[J]. Biomed Pharmacother, 2021, 138: 111450. DOI: 10.1016/j.biopha.2021.111450.

21.Xie Y, Hou W, Song X, et al. Ferroptosis: process and function[J]. Cell Death Differ, 2016, 23(3): 369-379. DOI: 10.1038/cdd.2015.158.

22.Stockwell BR, Friedmann Angeli JP, Bayir H, et al. Ferroptosis: a regulated cell death nexus linking me-tabolism, redox biology, and disease[J]. Cell, 2017, 171(2): 273-285. DOI: 10.1016/j.cell.2017.09.021.

23.Yan HF, Zou T, Tuo QZ, et al. Ferroptosis: mechanisms and links with diseases[J]. Signal Transduct Target Ther, 2021, 6(1): 49. DOI: 10.1038/s41392-020-00428-9.

24.Yang WS, Kim KJ, Gaschler MM, et al. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis[J]. Proc Natl Acad Sci USA, 2016, 113(34): E4966-4975. DOI: 10.1073/pnas.1603244113.

25.Lee J, You JH, Kim MS, et al. Epigenetic reprogramming of epithelial-mesenchymal transition pro-motes ferroptosis of head and neck cancer[J]. Redox Biol, 2020, 37: 101697. DOI: 10.1016/j.redox.2020.101697.

26.Wang M, Li S, Wang Y, et al. Gambogenic acid induces ferroptosis in melanoma cells undergoing epi-thelial-to-mesenchymal transition[J]. Toxicol Appl Pharmacol, 2020, 401: 115110. DOI: 10.1016/j.taap.2020.115110.

27.Sato M, Matsumoto M, Saiki Y, et al. BACH1 promotes pancreatic cancer metastasis by repressing epithelial genes and enhancing epithelial-mesenchymal transition[J]. Cancer Res, 2020, 80(6): 1279-1292. DOI: 10.1158/0008-5472.

28.Wu J, Minikes AM, Gao M, et al. Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling[J]. Nature, 2019, 572(7769): 402-406. DOI: 10.1038/s41586-019-1426-6.

29.Chen P, Li X, Zhang R, et al. Combinative treatment of β-elemene and cetuximab is sensitive to KRAS mutant colorectal cancer cells by inducing ferroptosis and inhibiting epithelial-mesenchymal transfor-mation[J]. Theranostics, 2020, 10(11): 5107-5119. DOI: 10.7150/thno.44705.

30.Müller S, Sindikubwabo F, Cañeque T, et al. CD44 regulates epigenetic plasticity by mediating iron en-docytosis[J]. Nat Chem, 2020, 12(10): 929-938. DOI: 10.1038/s41557-020-0513-5.

31.Jorgovanovic D, Song M, Wang L, et al. Roles of IFN-γ in tumor progression and regression: a re-view[J]. Biomark  Res, 2020, 8: 49. DOI: 10.1186/s40364-020-00228-x.

32.Yarla NS, Bishayee A, Sethi G, et al. Targeting arachidonic acid pathway by natural products for cancer prevention and therapy[J]. Semin Cancer Biol, 2016, 40-41: 48-81. DOI: 10.1016/j.semcancer.2016.02.001.