Effect of quercetin on inhibiting gefitinib‑activated non‑small cell lung cancer‑induced cell pyroptosis in cardiomyocytes via modulating mitochondrial autophagy mediated by the SHP2/ROS/AMPK/XBP‑1/DJ‑1 signaling pathway

Zhang,Jie; Qi,Shanshan; Du,Yanyan; Dai,Honghong; Liu,Ninghua

doi:10.3892/or.2025.8890

Effect of quercetin on inhibiting gefitinib‑activated non‑small cell lung cancer‑induced cell pyroptosis in cardiomyocytes via modulating mitochondrial autophagy mediated by the SHP2/ROS/AMPK/XBP‑1/DJ‑1 signaling pathway

Authors:
- Jie Zhang
- Shanshan Qi
- Yanyan Du
- Honghong Dai
- Ninghua Liu
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Affiliations: Traditional Chinese Medicine Department, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China, Department of Oncology, Shijiazhuang Hospital of Traditional Chinese Medicine, Shijiazhuang, Hebei 050000, P.R. China, Clinical Laboratory Department, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China, Gynecology and Oncology Department, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China, Functional Department, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
Published online on: March 31, 2025 https://doi.org/10.3892/or.2025.8890
Article Number: 57
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

It has been reported that treatment of patients with non‑small cell lung cancer (NSCLC) with gefitinib increases the risk of QT interval prolongation. Therefore, the present study aimed to investigate whether quercetin could delay gefitinib‑induced cardiomyocyte apoptosis and its underlying mechanism. A total of 32 nude mice were divided into the sham, NSCLC, NSCLC + gefitinib and NSCLC + gefitinib + quercetin groups. Cardiac fibrosis in mouse heart tissues was assessed by Masson's trichrome staining. Additionally, immunohistochemical staining was performed to detect the expression levels of Src homology‑2 domain‑containing protein tyrosine phosphatase (SHP2), X‑box binding protein 1 (XBP‑1), phosphorylated (p)‑stimulator of interferon genes (STING) and Nod‑like receptor protein 3. Bioinformatics analysis was carried auto to predict the association between quercetin and the SHP2/reactive oxygen species (ROS) axis. Furthermore, the effects of adenosine triphosphate (ATP) + gefitinib, SHP2 silencing and H₂O₂ on ROS levels, as well as on the p‑AMP‑activated protein kinase (AMPK)/XBP‑1/Parkinsonism associated deglycase (DJ‑1) axis, mitochondrial autophagy and apoptosis were assessed via detecting the expression levels of the corresponding proteins in cardiomyocytes by western blot analysis. JC‑1 immunofluorescence was performed to evaluate mitochondrial membrane damage. The results showed that NSCLC could not significantly affect cardiac function. In addition, compared with NSCLC alone, ventricular fibrosis was exacerbated in the NSCLC + gefitinib group. However, treatment with quercetin inhibited gefitinib‑induced ventricular fibrosis, activated the gefitinib‑suppressed SHP2 protein expression and downregulated the gefitinib‑induced XBP‑1 and p‑STING expression. Furthermore, the bioinformatics analysis results predicted that quercetin could interact with SHP2/ROS. The in vitro experiments demonstrated that the expression levels of the ROS‑related proteins, namely NADPH oxidase 4 and XBP‑1/DJ‑1, and those of the mitochondrial autophagy‑ and apoptosis‑related proteins were enhanced, while those of p‑AMPK, were reduced in cardiomyocytes of the NSCLC + ATP + gefitinib group. However, cell treatment with quercetin inhibited ROS production and the expression levels of XBP‑1/DJ‑1 and apoptosis‑related proteins activated by NSCLC + ATP + gefitinib. By contrast, quercetin activated the expression levels of mitochondrial autophagy‑related proteins and those of p‑AMPK. Furthermore, SHP2 silencing and cell treatment with H₂O₂ could separately inhibit the NSCLC + ATP + gefitinib‑induced expression of mitochondrial autophagy‑related proteins and p‑AMPK, while they could promote ROS production and upregulate XBP‑1/DJ‑1 and apoptosis‑related proteins. In summary, the results of the current study revealed a promising therapeutic approach for addressing cardiac issues caused by gefitinib treatment in patients with NSCLC. Therefore, quercetin could inhibit the gefitinib‑induced NSCLC‑mediated cardiomyocyte apoptosis via regulating the SHP2/ROS/AMPK/XBP‑1/DJ‑1 signaling pathway through mitochondrial autophagy.

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1	Pan Z, Wang K, Wang X, Jia Z, Yang Y, Duan Y, Huang L, Wu ZX, Zhang JY and Ding X: Cholesterol promotes EGFR-TKIs resistance in NSCLC by inducing EGFR/Src/Erk/SP1 signaling-mediated ERRα re-expression. Mol Cancer. 21:772022. View Article : Google Scholar : PubMed/NCBI
2	Cheng C, Wang S, Dong J, Zhang S, Yu D and Wang Z: Effects of targeted lung cancer drugs on cardiomyocytes studied by atomic force microscopy. Anal Methods. 15:4077–4084. 2023. View Article : Google Scholar : PubMed/NCBI
3	Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, et al: Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 376:629–640. 2017. View Article : Google Scholar : PubMed/NCBI
4	Thein KZ, Swarup S, Ball S, Quirch M, Vorakunthada Y, Htwe KK, D'Cunha N, Hardwicke F, Awasthi S and Tijani L: 1388P Incidence of cardiac toxicities in patients with advanced non-small cell lung cancer treated with osimertinib: A combined analysis of two phase III randomized controlled trials. Ann Oncol. 29:viii5002018. View Article : Google Scholar
5	Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, et al: Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 378:113–125. 2018. View Article : Google Scholar : PubMed/NCBI
6	Wang M, Chen X, Yu F, Zhang L, Zhang Y and Chang W: The targeting of noncoding RNAs by quercetin in cancer prevention and therapy. Oxid Med Cell Longev. 2022:43306812022.PubMed/NCBI
7	Güran M, Şanlıtürk G, Kerküklü NR, Altundağ EM and Süha Yalçın A: Combined effects of quercetin and curcumin on anti-inflammatory and antimicrobial parameters in vitro. Eur J Pharmacol. 859:1724862019. View Article : Google Scholar : PubMed/NCBI
8	Ersoz M, Erdemir A, Derman S, Arasoglu T and Mansuroglu B: Quercetin-loaded nanoparticles enhance cytotoxicity and antioxidant activity on C6 glioma cells. Pharm Dev Technol. 25:757–766. 2020. View Article : Google Scholar : PubMed/NCBI
9	Sul OJ and Ra SW: Quercetin Prevents LPS-induced oxidative stress and inflammation by modulating NOX2/ROS/NF-kB in lung epithelial cells. Molecules. 26:69492021. View Article : Google Scholar : PubMed/NCBI
10	Lan CY, Chen SY, Kuo CW, Lu CC and Yen GC: Quercetin facilitates cell death and chemosensitivity through RAGE/PI3K/AKT/mTOR axis in human pancreatic cancer cells. J Food Drug Anal. 27:887–896. 2019. View Article : Google Scholar : PubMed/NCBI
11	Hasan AAS, Kalinina EV, Tatarskiy VV, Volodina YL, Petrova АS, Novichkova MD, Zhdanov DD and Shtil AA: Suppression of the antioxidant system and PI3K/Akt/mTOR signaling pathway in cisplatin-resistant cancer cells by quercetin. Bull Exp Biol Med. 173:760–764. 2022. View Article : Google Scholar : PubMed/NCBI
12	Li X, Zhou N, Wang J, Liu Z, Wang X, Zhang Q, Liu Q, Gao L and Wang R: Quercetin suppresses breast cancer stem cells (CD44(+)/CD24(−)) by inhibiting the PI3K/Akt/mTOR-signaling pathway. Life Sci. 196:56–62. 2018. View Article : Google Scholar : PubMed/NCBI
13	Zhou Y, Suo W, Zhang X, Lv J, Liu Z and Liu R: Roles and mechanisms of quercetin on cardiac arrhythmia: A review. Biomed Pharmacother. 153:1134472022. View Article : Google Scholar : PubMed/NCBI
14	Wang L, Tan A, An X, Xia Y and Xie Y: Quercetin dihydrate inhibition of cardiac fibrosis induced by angiotensin II in vivo and in vitro. Biomed Pharmacother. 127:1102052020. View Article : Google Scholar : PubMed/NCBI
15	Huang KY, Wang TH, Chen CC, Leu YL, Li HJ, Jhong CL and Chen CY: Growth suppression in lung cancer cells harboring EGFR-C797S mutation by quercetin. Biomolecules. 11:12712021. View Article : Google Scholar : PubMed/NCBI
16	Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, Wilson CJ, Lehár J, Kryukov GV, Sonkin D, et al: The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 483:603–607. 2012. View Article : Google Scholar : PubMed/NCBI
17	Heliste J, Jokilammi A, Vaparanta K, Paatero I and Elenius K: Combined genetic and chemical screens indicate protective potential for EGFR inhibition to cardiomyocytes under hypoxia. Sci Rep. 11:166612021. View Article : Google Scholar : PubMed/NCBI
18	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
19	Sunasee R, Araoye E, Pyram D, Hemraz UD, Boluk Y and Ckless K: Cellulose nanocrystal cationic derivative induces NLRP3 inflammasome-dependent IL-1β secretion associated with mitochondrial ROS production. Biochem Biophys Rep. 4:1–9. 2015.PubMed/NCBI
20	Greenhalgh J, Boland A, Bates V, Vecchio F, Dundar Y, Chaplin M and Green JA: First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer. Cochrane Database Syst Rev. 3:CD0103832021.PubMed/NCBI
21	Hou X, Li M, Wu G, Feng W, Su J, Jiang H, Jiang G, Chen J, Zhang B, You Z, et al: Gefitinib plus chemotherapy vs gefitinib alone in untreated EGFR-mutant non-small cell lung cancer in patients with brain metastases: The GAP BRAIN open-label, randomized, multicenter, phase 3 study. JAMA Netw Open. 6:e22550502023. View Article : Google Scholar : PubMed/NCBI
22	Wilkaniec A, Cieślik M, Murawska E, Babiec L, Gąssowska-Dobrowolska M, Pałasz E, Jęśko H and Adamczyk A: P2X7 receptor is involved in mitochondrial dysfunction induced by extracellular alpha synuclein in neuroblastoma SH-SY5Y cells. Int J Mol Sci. 21:39592020. View Article : Google Scholar : PubMed/NCBI
23	Hong Y, Zhou X, Li Q, Chen J, Wei Y, Long C, Shen L, Zheng X, Li D, Wang X, et al: X-box binding protein 1 caused an imbalance in pyroptosis and mitophagy in immature rats with di-(2-ethylhexyl) phthalate-induced testis toxicity. Genes Dis. 11:935–951. 2024. View Article : Google Scholar : PubMed/NCBI
24	Imberechts D, Kinnart I, Wauters F, Terbeek J, Manders L, Wierda K, Eggermont K, Madeiro RF, Sue C, Verfaillie C and Vandenberghe W: DJ-1 is an essential downstream mediator in PINK1/parkin-dependent mitophagy. Brain. 145:4368–4384. 2022. View Article : Google Scholar : PubMed/NCBI
25	Xu M, Hang H, Huang M, Li J, Xu D, Jiao J, Wang F, Wu H, Sun X, Gu J, et al: DJ-1 deficiency in hepatocytes improves liver ischemia-reperfusion injury by enhancing mitophagy. Cell Mol Gastroenterol Hepatol. 12:567–584. 2021. View Article : Google Scholar : PubMed/NCBI
26	Zhu G, Xie J, Kong W, Xie J, Li Y, Du L, Zheng Q, Sun L, Guan M, Li H, et al: Phase separation of disease-associated SHP2 mutants underlies MAPK hyperactivation. Cell. 183:490–502.e18. 2020. View Article : Google Scholar : PubMed/NCBI
27	Li Y, Chen H, Xie X, Yang B, Wang X, Zhang J, Qiao T, Guan J, Qiu Y, Huang YX, et al: PINK1-mediated mitophagy promotes oxidative phosphorylation and redox homeostasis to induce drug-tolerant persister cancer cells. Cancer Res. 83:398–413. 2023. View Article : Google Scholar : PubMed/NCBI
28	Liu H, Ho PW, Leung CT, Pang SY, Chang EES, Choi ZY, Kung MH, Ramsden DB and Ho SL: Aberrant mitochondrial morphology and function associated with impaired mitophagy and DNM1L-MAPK/ERK signaling are found in aged mutant Parkinsonian LRRK2^R1441G mice. Autophagy. 17:3196–3220. 2021. View Article : Google Scholar : PubMed/NCBI
29	Luo T, Jia X, Feng WD, Wang JY, Xie F, Kong LD, Wang XJ, Lian R, Liu X, Chu YJ, et al: Bergapten inhibits NLRP3 inflammasome activation and pyroptosis via promoting mitophagy. Acta Pharmacol Sin. 44:1867–1878. 2023. View Article : Google Scholar : PubMed/NCBI
30	Liu Z, Wang M, Wang X, Bu Q, Wang Q, Su W, Li L, Zhou H and Lu L: XBP1 deficiency promotes hepatocyte pyroptosis by impairing mitophagy to activate mtDNA-cGAS-STING signaling in macrophages during acute liver injury. Redox Biol. 52:1023052022. View Article : Google Scholar : PubMed/NCBI
31	Di Petrillo A, Orrù G, Fais A and Fantini MC: Quercetin and its derivates as antiviral potentials: A comprehensive review. Phytother Res. 36:266–278. 2022. View Article : Google Scholar : PubMed/NCBI
32	Reyes-Farias M and Carrasco-Pozo C: The anti-cancer effect of quercetin: Molecular implications in cancer metabolism. Int J Mol Sci. 20:31772019. View Article : Google Scholar : PubMed/NCBI
33	Wang B, Zhang W, Zhou X, Liu M, Hou X, Cheng Z and Chen D: Development of dual-targeted nano-dandelion based on an oligomeric hyaluronic acid polymer targeting tumor-associated macrophages for combination therapy of non-small cell lung cancer. Drug Deliv. 26:1265–1279. 2019. View Article : Google Scholar : PubMed/NCBI
34	Tang SM, Deng XT, Zhou J, Li QP, Ge XX and Miao L: Pharmacological basis and new insights of quercetin action in respect to its anti-cancer effects. Biomed Pharmacother. 121:1096042020. View Article : Google Scholar : PubMed/NCBI