Objective  To investigate the effect and underlying mechanism of fork-head box protein 1 (FOXP1) on the viability and apoptosis of cisplatin (DDP) resistant cervical cancer cells.

Methods  Construction of FOXP1 interference DDP-resistant cervical cancer cell models using siRNA. Cell viability was assessed using CCK-8 assay, apoptosis was measured by flow cytometry, autophagy levels were detected via LC3 immunofluorescence, and changes in autophagy-related proteins and Wnt/β-catenin signaling pathway components were analyzed by Western blot. Functional rescue experiments were performed using the autophagy activator rapamycin (RAPA) or the Wnt pathway activator SKL2001 in FOXP1-silenced HeLa/DDP cells.

Results  Compared to normal cervical cancer cells, FOXP1 was highly expressed in DDP-resistant HeLa/DDP and SiHa/DDP cells. Inhibition of FOXP1 significantly reduced the cellular activity of HeLa/DDP and SiHa/DDP, elevated the sensitivity of cells to DDP, and promoted apoptosis. Additionally, FOXP1 silencing downregulated LC3-II and Beclin-1 protein expression while upregulating LC3-I and p62, indicating suppressed autophagy and Wnt/β-catenin signaling activation. These effects were partially reversed by RAPA or SKL2001 treatment.

Conclusion  FOXP1 can elevate autophagy to reduce the sensitivity of cervical cancer DDP-resistant cell lines HeLa/DDP and SiHa/DDP to DDP by activating the Wnt/β-catenin signalling pathway.

1.Buskwofie A, David-West G, Clare CA. A review of cervical cancer: incidence and disparities[J]. J Natl Med Assoc, 2020, 112(2): 229-232. DOI: 10.1016/j.jnma.2020.03.002.

2.戴琼芳，罗欢，程岚，等. 宫颈癌患者性健康管理的最佳证据总结[J]. 数理医药学杂志, 2024, 37(8): 619-629. [Dai QF, Luo H, Cheng L, et al. Sexual health management in cervical cancer patients: best evidence summary[J]. Journal of Mathematical Medicine, 2024, 37(8): 619-629.] DOI: 10.12173/j.issn.1004-4337.202404109.

3.Makovec T. Cisplatin and beyond: molecular mechanisms of action and drug resistance development in cancer chemotherapy[J]. Radiol Oncol, 2019, 53(2): 148-158. DOI: 10.2478/raon-2019-0018.

4.Co M, Anderson AG, Konopka G. FOXP transcription factors in vertebrate brain development, function, and disorders[J]. Wiley Interdiscip Rev Dev Biol, 2020, 9(5): e375. DOI: 10.1002/wdev.375.

5.Kim JH, Hwang J, Jung JH, et al. Molecular networks of FOXP family: dual biologic functions, interplay with other molecules and clinical implications in cancer progression[J]. Mol Cancer, 2019, 18(1): 180. DOI: 10.1186/s12943-019-1110-3.

6.Hu Z, Cai M, Zhang Y, et al. miR-29c-3p inhibits autophagy and cisplatin resistance in ovarian cancer by regulating FOXP1/ATG14 pathway[J]. Cell Cycle, 2020, 19(2): 193-206. DOI: 10.1080/15384101.2019.1704537.

7.Xia X, Li Z, Li Y, et al. LncRNA XIST promotes carboplatin resistance of ovarian cancer through activating autophagy via targeting miR-506-3p/FOXP1 axis[J]. J Gynecol Oncol, 2022, 33(6): e81. DOI: 10.3802/jgo.2022.33.e81.

8.Levavasseur F, Oussous S, Zubaidan T, et al. FOXP1 regulates oxidative stress, SIRT1 expression, and resistance to chemotherapies in acute myeloid leukemia cells[J]. Blood Adv, 2023, 7(13): 3265-3275. DOI: 10.1182/bloodadvances. 2022008585.

9.Yang Q, Jiang W, Li L, et al. Forkhead box protein P1 is a useful marker for the diagnosis of mucinous minimal deviation adenocarcinoma of uterine cervix[J]. Ann Diagn Pathol, 2014, 18(4): 232-237. DOI: 10.1016/j.anndiagpath.2014.04.003.

10.Cheng L, Shi X, Huo D, et al. MiR-449b-5p regulates cell proliferation, migration and radioresistance in cervical cancer by interacting with the transcription suppressor FOXP1[J]. Eur J Pharmacol, 2019, 856: 172399. DOI: 10.1016/j.ejphar.2019. 05.028.

11.Nussinov R, Tsai CJ, Jang H. Anticancer drug resistance: an update and perspective[J]. Drug Resist Updat, 2021, 59: 100796. DOI: 10.1016/j.drup.2021.100796.

12.姚梦圆, 温敏, 黄正元, 等. 丁苯酞调节PI3K/Akt/CREB信号通路对顺铂诱导的PC12细胞炎症和凋亡的影响 [J]. 药学前沿, 2025, 29(5): 721-729. [Yao MY, Wen  M, Huang  ZY, et al. The effect of butylphthalein regulating the PI3K/Akt/CREB signaling pathway on cisplatin-induced inflammation and apoptosis in PC12 cells[J]. Frontiers in Pharmaceutical Sciences, 2025, 29(5): 721-729.] DOI: 10.12173/j.issn.2097-4922. 202502073.

13.张玉清, 邢惠海, 刘立秋, 等. miR-196b调控PI3K/Akt通路对宫颈癌细胞顺铂耐药的影响研究[J]. 中国免疫学杂志, 2021, 37(23): 2865-2870. [Zhang YQ, Xing HH, Liu LQ, et al. Effect of miR-196b on cisplatin resistance of cervical cancer cells by regulating PI3K/Akt pathway[J]. Chinese Journal of Immunology, 2021, 37(23): 2865-2870.] DOI: 10.3969/j.issn.1000-484X.2021.23.010.

14.Li H, Han X, Yang S, et al. FOXP1 drives osteosarcoma development by repressing P21 and RB transcription downstream of P53[J]. Oncogene, 2021, 40(15): 2785-2802. DOI: 10.1038/s41388-021-01742-4.

15.Panigrahi SK, Broustas CG, Cuiper PQ, et al. FOXP1 and NDRG1 act differentially as downstream effectors of RAD9-mediated prostate cancer cell functions[J]. Cell Signal, 2021, 86: 110091. DOI: 10.1016/j.cellsig.2021.110091.

16.Hu Z, Zhu L, Gao J, et al. Expression of FOXP1 in epithelial ovarian cancer (EOC) and its correlation with chemotherapy resistance and prognosis[J]. Tumour Biol, 2015, 36(9): 7269-7275. DOI: 10.1007/s13277-015-3383-5.

17.He J, Yang Z, Wu Z, et al. Expression of FOXP1 and FOXO3a in extrahepatic cholangiocarcinoma and the implications in clinicopathological significance and prognosis[J]. Onco Targets Ther, 2019, 12: 2955-2965. DOI: 10.2147/OTT.S197001.

18.Chen Z, Wang T, Li C, et al. FOXP1-GINS1 axis promotes DLBCL proliferation and directs doxorubicin resistance[J]. J Cancer, 2023, 14(12): 2289-2300. DOI: 10.7150/jca.85906.

19.Wang B, Li D, Filkowski J, et al. A dual role of miR-22 modulated by RelA/p65 in resensitizing fulvestrant-resistant breast cancer cells to fulvestrant by targeting FOXP1 and HDAC4 and constitutive acetylation of p53 at Lys382[J]. Oncogenesis, 2018, 7(7): 54. DOI: 10.1038/s41389-018-0063-5.

20.Klionsky DJ, Petroni G, Amaravadi RK, et al. Autophagy in major human diseases[J]. EMBO J, 2021, 40(19): e108863. DOI: 10.15252/embj.2021108863.

21.Debnath J, Gammoh N, Ryan KM. Autophagy and autophagy-related pathways in cancer[J]. Nat Rev Mol Cell Biol, 2023, 24(8): 560-575. DOI: 10.1038/s41580-023-00585-z.

22.Zamame Ramirez JA, Romagnoli GG, Kaneno R. Inhibiting autophagy to prevent drug resistance and improve anti-tumor therapy[J]. Life Sci, 2021, 265: 118745. DOI: 10.1016/j.lfs.2020.118745.

23.Peng X, Gong F, Chen Y, et al. Autophagy promotes paclitaxel resistance of cervical cancer cells: involvement of Warburg effect activated hypoxia-induced factor 1-alpha-mediated signaling[J]. Cell Death Dis, 2014, 5(8): e1367. DOI: 10.1038/cddis.2014.297.

24.Huang H, Han Q, Zheng H, et al. MAP4K4 mediates the SOX6-induced autophagy and reduces the chemosensitivity of cervical cancer[J]. Cell Death Dis, 2021, 13(1): 13. DOI: 10.1038/s41419-021-04474-1.

25.Levine B, Kroemer G. Biological functions of autophagy genes: a disease perspective[J]. Cell, 2019, 176(1-2): 11-42. DOI: 10.1016/j.cell.2018.09.048.

26.Xu HD, Qin ZH. Beclin 1, Bcl-2 and autophagy[J]. Adv Exp Med Biol, 2019, 1206: 109-126. DOI: 10.1007/978-981-15-0602-4_5.

27.Turco E, Savova A, Gere F, et al. Reconstitution defines the roles of p62, NBR1 and TAX1BP1 in ubiquitin condensate formation and autophagy initiation[J]. Nat Commun, 2021, 12(1): 5212. DOI: 10.1038/s41467-021-25572-w.

28.Walker MP, Stopford CM, Cederlund M, et al. FOXP1 potentiates Wnt/beta-catenin signaling in diffuse large B cell lymphoma[J]. Sci Signal, 2015, 8(362): ra12. DOI: 10.1126/scisignal.2005654.

29.Zhang Y, Wang X. Targeting the Wnt/beta-catenin signaling pathway in cancer[J]. J Hematol Oncol, 2020, 13(1): 165. DOI: 10.1186/s13045-020-00990-3.

30.Zhou C, Yi C, Yi Y, et al. LncRNA PVT1 promotes gemcitabine resistance of pancreatic cancer via activating Wnt/beta-catenin and autophagy pathway through modulating the miR-619-5p/Pygo2 and miR-619-5p/ATG14 axes[J]. Mol Cancer, 2020, 19(1): 118. DOI: 10.1186/s12943-020-01237-y.

31.Wu Q, Ma J, Wei J, et al. lncRNA SNHG11 promotes gastric cancer progression by activating the wnt/beta-catenin pathway and oncogenic autophagy[J]. Mol Ther, 2021, 29(3): 1258-1278. DOI: 10.1016/j.ymthe.2020.10.011.

32.张月阳, 刘青松, 邓琳, 等. 宫颈癌细胞自噬与Wnt/β-catenin信号通路关系的研究进展[J]. 现代肿瘤医学, 2022, 30(14): 2639-2642. [Zhang YY, Liu QS, Deng L, et al. Review of the relationship between autophagy and Wnt/β-catenin signal pathway in cervical cancer[J]. Journal of Modern Oncology, 2022, 30(14): 2639-2642.] DOI: 10.3969/j.issn.1672-4992.2022.14.034.

33.Chi C, Hou W, Zhang Y, et al. PDHB-AS suppresses cervical cancer progression and cisplatin resistance via inhibition on Wnt/beta-catenin pathway[J]. Cell Death Dis, 2023, 14(2): 90. DOI: 10.1038/s41419-022-05547-5.

34.Wang T, Liu Z, Shi F, et al. Pin1 modulates chemo-resistance by up-regulating FoxM1 and the involvements of Wnt/beta-catenin signaling pathway in cervical cancer[J]. Mol Cell Biochem, 2016, 413(1-2): 179-187. DOI: 10.1007/s11010-015-2651-4.