Targeting <i>PLA2G4A</i> promotes Erastin-induced ferroptosis in lung adenocarcinoma cells by inhibiting <i>SLC7A11</i> expression_West China Medical Journal

Authors：

NI Yinyun , YANG Ying ,  ZHANG Li

Laboratory of Molecular Phenotyping of Lung Cancer, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

ZHANG Li, Email: zhangli2809@wchscu.cn

Keywords：

PLA2G4A; SLC7A11; ferroptosis; Erastin

DOI：

10.7507/1002-0179.202404185

Video：

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Objective To investigate the regulatory role of PLA2G4A targeting in ferroptosis and its sensitizing effect on the ferroptosis inducer Erastin. Methods PLA2G4A expression in lung adenocarcinoma (LUAD) was assessed by analyzing data from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium databases, followed by immunohistochemical validation. PLA2G4A expression was knocked down in H1299 lung cancer cells using small interfering RNA. The correlation between PLA2G4A and ferroptosis marker genes was examined through gene correlation analysis and Western blotting. The regulatory relationship between PLA2G4A and ferrous ion (Fe²⁺) was analyzed using high-content fluorescence imaging. Cell proliferation after PLA2G4A inhibition and Erastin treatment was measured by CCK-8 assay. Flow cytometry and high-content fluorescence imaging were employed to evaluate the effects of PLA2G4A suppression combined with Erastin on intracellular Fe²⁺ and lipid peroxidation levels. Results Both mRNA (P<0.05) and protein (P<0.001) levels of PLA2G4A were significantly upregulated in LUAD tissues, and its high expression was associated with poor prognosis in LUAD patients (P<0.05). PLA2G4A expression was positively correlated with SLC7A11 expression (r=0.23, P<0.001). PLA2G4A knockdown suppressed SLC7A11 protein expression and increased cellular Fe²⁺ levels (P<0.01). Compared with the control group, PLA2G4A-silenced cells exhibited significantly reduced viability upon Erastin treatment (P<0.001). Furthermore, Erastin enhanced PLA2G4A targeting-induced Fe²⁺ accumulation and lipid peroxidation (P<0.001). Conclusion Targeting PLA2G4A induces ferroptosis in lung cancer cells by inhibiting SLC7A11 expression and enhances their sensitivity to Erastin.

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18.	Brown N, Morrow JD, Slaughter JC, et al. Restoration of on-time embryo implantation corrects the timing of parturition in cytosolic phospholipase A2 group IVA deficient mice. Biol Reprod, 2009, 81(6): 1131-1138.
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21.	Xu S, Tuo QZ, Meng J, et al. Thrombin induces ferroptosis in triple-negative breast cancer through the cPLA2α/ACSL4 signaling pathway. Transl Oncol, 2024, 39: 101817.

1. Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin, 2023, 73(1): 17-48.
2. Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature, 2018, 553(7689): 446-454.
3. Hirsch FR, Scagliotti GV, Mulshine JL, et al. Lung cancer: current therapies and new targeted treatments. Lancet, 2017, 389(10066): 299-311.
4. Murtuza A, Bulbul A, Shen JP, et al. Novel third-generation EGFR tyrosine kinase inhibitors and strategies to overcome therapeutic resistance in lung cancer. Cancer Res, 2019, 79(4): 689-698.
5. Kashima Y, Shibahara D, Suzuki A, et al. Single-cell analyses reveal diverse mechanisms of resistance to EGFR tyrosine kinase inhibitors in lung cancer. Cancer Res, 2021, 81(18): 4835-4848.
6. Spella M, Stathopoulos GT. Immune resistance in lung adenocarcinoma. Cancers (Basel), 2021, 13(3): 384-401.
7. Miao YD, Quan W, Dong X, et al. A bibliometric analysis of ferroptosis, necroptosis, pyroptosis, and cuproptosis in cancer from 2012 to 2022. Cell Death Discov, 2023, 9(1): 129-149.
8. Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell, 2012, 149(5): 1060-1072.
9. Koppula P, Zhuang L, Gan B. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy. Protein Cell, 2021, 12(8): 599-620.
10. Wang L, Liu Y, Du T, et al. ATF3 promotes erastin-induced ferroptosis by suppressing system Xc. Cell Death Differ, 2020, 27(2): 662-675.
11. Ma CS, Lv QM, Zhang KR, et al. NRF2-GPX4/SOD2 axis imparts resistance to EGFR-tyrosine kinase inhibitors in non-small-cell lung cancer cells. Acta Pharmacol Sin, 2021, 42(4): 613-623.
12. Lou JS, Zhao LP, Huang ZH, et al. Ginkgetin derived from Ginkgo biloba leaves enhances the therapeutic effect of cisplatin via ferroptosis-mediated disruption of the Nrf2/HO-1 axis in EGFR wild-type non-small-cell lung cancer. Phytomedicine, 2021, 80: 153370.
13. Peng Z, Chang Y, Fan J, et al. Phospholipase A2 superfamily in cancer. Cancer Lett, 2021, 497(1): 165-177.
14. Koundouros N, Karali E, Tripp A, et al. Metabolic fingerprinting links oncogenic PIK3CA with enhanced arachidonic acid-derived eicosanoids. Cell, 2020, 181(7): 1596-1611.
15. Lei G, Zhuang L, Gan B. Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer, 2022, 22(7): 381-396.
16. Mou Y, Wang J, Wu J, et al. Ferroptosis, a new form of cell death: opportunities and challenges in cancer. J Hematol Oncol, 2019, 12(1): 34-50.
17. Zhang X, Yu K, Ma L, et al. Endogenous glutamate determines ferroptosis sensitivity via ADCY10-dependent YAP suppression in lung adenocarcinoma. Theranostics, 2021, 11(12): 5650-5674.
18. Brown N, Morrow JD, Slaughter JC, et al. Restoration of on-time embryo implantation corrects the timing of parturition in cytosolic phospholipase A2 group IVA deficient mice. Biol Reprod, 2009, 81(6): 1131-1138.
19. Zhao R, Lv Y, Feng T, et al. ATF6α promotes prostate cancer progression by enhancing PLA2G4A-mediated arachidonic acid metabolism and protecting tumor cells against ferroptosis. Prostate, 2022, 82(5): 617-629.
20. Liao P, Wang W, Wang W, et al. CD8⁺ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4. Cancer Cell, 2022, 40(4): 365-378.
21. Xu S, Tuo QZ, Meng J, et al. Thrombin induces ferroptosis in triple-negative breast cancer through the cPLA2α/ACSL4 signaling pathway. Transl Oncol, 2024, 39: 101817.

West China Medical Journal

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