Effects of Forkhead box O1 on lipopolysaccharide‑induced mitochondrial dysfunction in human cervical squamous carcinoma SiHa cells

Wang,Huizhi; Ma,Zhi; Gao,Fanshu; Jiang,Wei; Li,Yang; Li,Shuping

doi:10.3892/ol.2021.13109

Effects of Forkhead box O1 on lipopolysaccharide‑induced mitochondrial dysfunction in human cervical squamous carcinoma SiHa cells

Authors:
- Huizhi Wang
- Zhi Ma
- Fanshu Gao
- Wei Jiang
- Yang Li
- Shuping Li
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang 157000, P.R. China, Department of Pediatric Surgery, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang 157000, P.R. China
Published online on: October 22, 2021 https://doi.org/10.3892/ol.2021.13109
Article Number: 848
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Persistent infection and chronic inflammation play important roles in the development of cervical squamous cell carcinoma. Forkhead box O1 (FOXO1) is a notable regulator of mitochondrial metabolism, which is involved in the occurrence and development of tumors. The present study explored the effects of FOXO1 in human cervical squamous carcinoma SiHa cells. The expression of FOXO1 was examined using reverse transcription‑quantitative PCR, western blotting and immunohistochemical staining. SiHa cell migration and proliferation were detected using Transwell and 3H‑TdR assays. Mitochondrial functions were assessed based on reactive oxygen species (ROS) generation and changes in the mitochondrial membrane potential (ΔΨm). The present study revealed that lipopolysaccharide (LPS) stimulation significantly inhibited the expression of FOXO1 in cervical squamous carcinoma SiHa cells; while silencing FOXO1 resulted in the accumulation of mitochondrial ROS, a decrease in the ΔΨm and abnormal morphology of mitochondria. Accordingly, enhancing FOXO1 expression or treatment with metformin, which protects mitochondrial function, reversed LPS‑induced mitochondrial dysfunction, cell pyroptosis, migration and proliferation of cervical squamous carcinoma SiHa cells. Overall, the current study indicated that treatment with FOXO1 could potentially be used as therapeutic strategy to prevent LPS‑induced cervical squamous cell carcinoma‑related dysfunction in a mitochondria‑dependent manner.

View Figures

View References

1	Arbyn M, Weiderpass E, Bruni L, de Sanjosé S, Saraiya M, Ferlay J and Bray F: Estimates of incidence and mortality of cervical cancer in 2018: A worldwide analysis. Lancet Glob Health. 8:e191–e203. 2020. View Article : Google Scholar : PubMed/NCBI
2	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2020. CA Cancer J Clin. 70:7–30. 2020. View Article : Google Scholar : PubMed/NCBI
3	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global Cancer Statistics 2020: GLOBOCAN Estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI
4	Di J, Rutherford S and Chu C: Review of the cervical cancer burden and population-based cervical cancer screening in China. Asian Pac J Cancer Prev. 16:7401–7407. 2015. View Article : Google Scholar : PubMed/NCBI
5	Wen X, Liu S and Cui M: Effect of BRCA1 on the concurrent chemoradiotherapy resistance of cervical squamous cell carcinoma based on transcriptome sequencing analysis. BioMed Res Int. 2020:35984172020. View Article : Google Scholar : PubMed/NCBI
6	Fang J, Zhang H and Jin S: Epigenetics and cervical cancer: From pathogenesis to therapy. Tumour Biol. 35:5083–5093. 2014. View Article : Google Scholar : PubMed/NCBI
7	Takekuma M, Kasamatsu Y, Kado N, Kuji S, Tanaka A, Takahashi N, Abe M and Hirashima Y: The issues regarding postoperative adjuvant therapy and prognostic risk factors for patients with stage I–II cervical cancer: A review. J Obstet Gynaecol Res. 43:617–626. 2017. View Article : Google Scholar : PubMed/NCBI
8	Tewari AK, Stockert JA, Yadav SS, Yadav KK and Khan I: Inflammation and prostate cancer. Adv Exp Med Biol. 1095:41–65. 2018. View Article : Google Scholar : PubMed/NCBI
9	Sadri Nahand J, Moghoofei M, Salmaninejad A, Bahmanpour Z, Karimzadeh M, Nasiri M, Mirzaei HR, Pourhanifeh MH, Bokharaei-Salim F, Mirzaei H, et al: Pathogenic role of exosomes and microRNAs in HPV-mediated inflammation and cervical cancer: A review. Int J Cancer. 146:305–320. 2020. View Article : Google Scholar : PubMed/NCBI
10	Xie X, Yang M, Ding Y and Chen J: Microbial infection, inflammation and epithelial ovarian cancer. Oncol Lett. 14:1911–1919. 2017. View Article : Google Scholar : PubMed/NCBI
11	Katoh M: Multi layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/β catenin signaling activation (Review). Int J Mol Med. 42:713–725. 2018.PubMed/NCBI
12	Monkkonen T and Debnath J: Inflammatory signaling cascades and autophagy in cancer. Autophagy. 14:190–198. 2018. View Article : Google Scholar : PubMed/NCBI
13	Liu X, Zhao W, Wang W, Lin S and Yang L: Puerarin suppresses LPS-induced breast cancer cell migration, invasion and adhesion by blockage NF-kappaB and Erk pathway. Biomed Pharmacother. 92:429–436. 2017. View Article : Google Scholar : PubMed/NCBI
14	You L, Cui H, Zhao F, Sun H, Zhong H, Zhou G and Chen X: Inhibition of HMGB1/RAGE axis suppressed the lipopolysaccharide (LPS)-induced vicious transformation of cervical epithelial cells. Bioengineered. 12:4995–5003. 2021. View Article : Google Scholar : PubMed/NCBI
15	Winograd R, Simeone DM and Bar-Sagi D: A novel target for combination immunotherapy in pancreatic cancer: IL-1β mediates immunosuppression in the tumour microenvironment. Br J Cancer. 124:1754–1756. 2021. View Article : Google Scholar : PubMed/NCBI
16	Zhang B, Gui LS, Zhao XL, Zhu LL and Li QW: FOXO1 is a tumor suppressor in cervical cancer. Genet Mol Res. 14:6605–6616. 2015. View Article : Google Scholar : PubMed/NCBI
17	Goto T and Takano M: Transcriptional role of FOXO1 in drug resistance through antioxidant defense systems. Adv Exp Med Biol. 665:171–179. 2009. View Article : Google Scholar : PubMed/NCBI
18	He A, Ji R, Shao J, He C, Jin M and Xu Y: TLR4-MyD88-TRAF6-TAK1 complex-mediated NF-κB activation contribute to the anti-inflammatory effect of V8 in LPS-induced human cervical cancer SiHa cells. Inflammation. 39:172–181. 2016. View Article : Google Scholar : PubMed/NCBI
19	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
20	Gao LJ, Gu PQ, Fan WM, Liu Z, Qiu F, Peng YZ and Guo XR: The role of gC1qR in regulating survival of human papillomavirus 16 oncogene-transfected cervical cancer cells. Int J Oncol. 39:1265–1272. 2011.PubMed/NCBI
21	Tyszka-Czochara M, Bukowska-Strakova K and Majka M: Metformin and caffeic acid regulate metabolic reprogramming in human cervical carcinoma SiHa/HTB-35 cells and augment anticancer activity of Cisplatin via cell cycle regulation. Food Chem Toxicol. 106:260–272. 2017. View Article : Google Scholar : PubMed/NCBI
22	Liu XH, Wu LM, Wang JL, Dong XH, Zhang SC, Li XH, Xu H, Liu DB, Li ZH, Liu ZM, et al: Long non-coding RNA RP11-490M8.1 inhibits lipopolysaccharide-induced pyroptosis of human umbilical vein endothelial cells via the TLR4/NF-κB pathway. Immunobiology. 226:1521332021. View Article : Google Scholar : PubMed/NCBI
23	Safe S, Nair V and Karki K: Metformin-induced anticancer activities: Recent insights. Biol Chem. 399:321–335. 2018. View Article : Google Scholar : PubMed/NCBI
24	Nguyen TLL, Huynh DTN, Jin Y, Jeon H and Heo KS: Protective effects of ginsenoside-Rg2 and -Rh1 on liver function through inhibiting TAK1 and STAT3-mediated inflammatory activity and Nrf2/ARE-mediated antioxidant signaling pathway. Arch Pharm Res. 44:241–252. 2021. View Article : Google Scholar : PubMed/NCBI
25	Liu LM, Liang DY, Ye CG, Tu WJ and Zhu T: The UII/UT system mediates upregulation of proinflammatory cytokines through p38 MAPK and NF-κB pathways in LPS-stimulated Kupffer cells. PLoS One. 10:e01213832015. View Article : Google Scholar : PubMed/NCBI
26	Shen JQ, Zhang ZX, Shen CF and Liao JZ: Anticarcinogenic effect of Umbelliferone in human prostate carcinoma: An in vitro study. J BUON. 22:94–101. 2017.PubMed/NCBI
27	Veena VK, Popavath RN, Kennedy K and Sakthivel N: In vitro antiproliferative, pro-apoptotic, antimetastatic and anti-inflammatory potential of 2,4-diacetylphloroglucinol (DAPG) by Pseudomonas aeruginosa strain FP10. Apoptosis. 20:1281–1295. 2015. View Article : Google Scholar : PubMed/NCBI
28	Zhang M, Dong W, Li Z, Xiao Z, Xie Z, Ye Z, Liu S, Li R, Chen Y, Zhang L, et al: Effect of forkhead box O1 in renal tubular epithelial cells on endotoxin-induced acute kidney injury. Am J Physiol Renal Physiol. 320:F262–F272. 2021. View Article : Google Scholar : PubMed/NCBI
29	Moloney JN and Cotter TG: ROS signalling in the biology of cancer. Semin Cell Dev Biol. 80:50–64. 2018. View Article : Google Scholar : PubMed/NCBI
30	Poillet-Perez L, Despouy G, Delage-Mourroux R and Boyer-Guittaut M: Interplay between ROS and autophagy in cancer cells, from tumor initiation to cancer therapy. Redox Biol. 4:184–192. 2015. View Article : Google Scholar : PubMed/NCBI
31	Yang JB, Zhao ZB, Liu QZ, Hu TD, Long J, Yan K and Lian ZX: FoxO1 is a regulator of MHC-II expression and anti-tumor effect of tumor-associated macrophages. Oncogene. 37:1192–1204. 2018. View Article : Google Scholar : PubMed/NCBI
32	Essers MA, de Vries-Smits LM, Barker N, Polderman PE, Burgering BM and Korswagen HC: Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science. 308:1181–1184. 2005. View Article : Google Scholar : PubMed/NCBI
33	Haj-Mirzaian A, Ramezanzadeh K, Tafazolimoghadam A, Kazemi K, Nikbakhsh R, Nikbakhsh R, Amini-Khoei H, Afshari K, Haddadi NS, Shakiba S, et al: Protective effect of minocycline on LPS-induced mitochondrial dysfunction and decreased seizure threshold through nitric oxide pathway. Eur J Pharmacol. 858:1724462019. View Article : Google Scholar : PubMed/NCBI
34	Mihaly SR, Ninomiya-Tsuji J and Morioka S: TAK1 control of cell death. Cell Death Differ. 21:1667–1676. 2014. View Article : Google Scholar : PubMed/NCBI
35	Liu X, Cui Y, Li M, Xu H, Zuo J, Fang F and Chang Y: Cobalt protoporphyrin induces HO-1 expression mediated partially by FOXO1 and reduces mitochondria-derived reactive oxygen species production. PLoS One. 8:e805212013. View Article : Google Scholar : PubMed/NCBI
36	Li DX, Wang CN, Wang Y, Ye CL, Jiang L, Zhu XY and Liu YJ: NLRP3 inflammasome-dependent pyroptosis and apoptosis in hippocampus neurons mediates depressive-like behavior in diabetic mice. Behav Brain Res. 391:1126842020. View Article : Google Scholar : PubMed/NCBI
37	Shi C, Wang Q, Rao Z, Shi Y, Wei S, Wang H, Lu X, Wang P, Lu L, Zhou H, et al: Diabetes induces hepatocyte pyroptosis by promoting oxidative stress-mediated NLRP3 inflammasome activation during liver ischaemia and reperfusion injury. Ann Transl Med. 8:7392020. View Article : Google Scholar : PubMed/NCBI
38	Oh S, Yang J, Park C, Son K and Byun K: Dieckol attenuated glucocorticoid-induced muscle atrophy by decreasing NLRP3 inflammasome and pyroptosis. Int J Mol Sci. 22:80572021. View Article : Google Scholar : PubMed/NCBI
39	Yang H, Fang Z, Qu X, Zhang X and Wang Y: Procyanidin compound (PC) suppresses lipopolysaccharide-induced cervical cancer cell proliferation through blocking the TLR4/NF-κB pathway. Cancer Manag Res. 12:497–509. 2020. View Article : Google Scholar : PubMed/NCBI
40	Singh BK, Sinha RA, Zhou J, Tripathi M, Ohba K, Wang ME, Astapova I, Ghosh S, Hollenberg AN, Gauthier K, et al: Hepatic FOXO1 target genes are co-regulated by thyroid hormone via RICTOR protein deacetylation and MTORC2-AKT protein inhibition. J Biol Chem. 291:198–214. 2016. View Article : Google Scholar : PubMed/NCBI
41	Zhang N, Qiu J, Zheng T, Zhang X, Hua K and Zhang Y: Goserelin promotes the apoptosis of epithelial ovarian cancer cells by upregulating forkhead box O1 through the PI3K/AKT signaling pathway. Oncol Rep. 39:1034–1042. 2018.PubMed/NCBI
42	Prasad SB, Yadav SS, Das M, Govardhan HB, Pandey LK, Singh S, Pradhan S and Narayan G: Down regulation of FOXO1 promotes cell proliferation in cervical cancer. J Cancer. 5:655–662. 2014. View Article : Google Scholar : PubMed/NCBI
43	Zou J, Hong L, Luo C, Li Z, Zhu Y, Huang T, Zhang Y, Yuan H, Hu Y, Wen T, et al: Metformin inhibits estrogen-dependent endometrial cancer cell growth by activating the AMPK-FOXO1 signal pathway. Cancer Sci. 107:1806–1817. 2016. View Article : Google Scholar : PubMed/NCBI