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BMC Cancer
Published in: BMC Cancer 1/2023

Open Access 01-12-2023 | Metastasis | Research

Atovaquone inhibits colorectal cancer metastasis by regulating PDGFRβ/NF-κB signaling pathway

Authors: Bin Liu, Xin Zheng, Jiajun Li, Peng Yao, Peng Guo, Wei Liu, Gaoping Zhao

Published in: BMC Cancer | Issue 1/2023

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Abstract

Background

Colorectal cancer is a common malignant tumour. Invasive growth and distant metastasis are the main characteristics of its malignant biological behaviour, and they are also the primary factors leading to death in colon cancer patients. Atovaquone is an antimalarial drug, and its anticancer effect has recently been demonstrated in several cancer models in vitro and in vivo, but it has not been examined in the treatment of colorectal cancer.

Methods

To elucidate the effect of atovaquone on colorectal cancer. We used RNA transcriptome sequencing, RT‒PCR and Western blot experiments to examine the expression of NF-κB (p-P65), EMT-related proteins and related inflammatory factors (IL1B, IL6, CCL20, CCL2, CXCL8, CXCL6, IL6ST, FAS, IL10 and IL1A). The effect of atovaquone on colorectal cancer metastasis was validated using an animal model of lung metastases. We further used transcriptome sequencing, the GCBI bioinformatics database and the STRING database to predict relevant target proteins. Furthermore, pathological sections were collected from relevant cases for immunohistochemical verification.

Results

This study showed that atovaquone could inhibit colorectal cancer metastasis and invasion in vivo and in vitro, inhibit the expression of E-cadherin protein, and promote the protein expression of N-cadherin, vimentin, ZEB1, Snail and Slug. Atovaquone could inhibit EMT by inhibiting NF-κB (p-P65) and related inflammatory factors. Further bioinformatics analysis and verification showed that PDGFRβ was one of the targets of atovaquone.

Conclusion

In summary, atovaquone can inhibit the expression of NF-κB (p-P65) and related inflammatory factors by inhibiting the protein expression of p-PDGFRβ, thereby inhibiting colorectal cancer metastasis. Atovaquone may be a promising drug for the treatment of colorectal cancer metastasis.
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Literature
1.
Terzić J, Grivennikov S, Karin E, Karin M. Inflammation and colon Cancer. Gastroenterology. 2010;138(6):2101–2114e2105.CrossRefPubMed
2.
Van Cutsem E, Nordlinger B, Cervantes A. Advanced Colorectal cancer: ESMO Clinical Practice guidelines for treatment. Ann Oncol. 2010;21(Suppl 5):v93–97.CrossRefPubMed
3.
Madden RM, Pui CH, Hughes WT, Flynn PM, Leung W. Prophylaxis of Pneumocystis carinii Pneumonia with atovaquone in children with Leukemia. Cancer. 2007;109(8):1654–8.CrossRefPubMed
4.
Stickles AM, Smilkstein MJ, Morrisey JM, Li Y, Forquer IP, Kelly JX, Pou S, Winter RW, Nilsen A, Vaidya AB, et al. Atovaquone and ELQ-300 combination therapy as a Novel Dual-Site Cytochrome bc1 inhibition strategy for Malaria. Antimicrob Agents Chemother. 2016;60(8):4853–9.CrossRefPubMedPubMedCentral
5.
Lv Z, Yan X, Lu L, Su C, He Y. Atovaquone enhances doxorubicin’s efficacy via inhibiting mitochondrial respiration and STAT3 in aggressive thyroid cancer. J Bioenerg Biomembr. 2018;50(4):263–70.CrossRefPubMed
6.
Zhou J, Duan L, Chen H, Ren X, Zhang Z, Zhou F, Liu J, Pei D, Ding K. Atovaquone derivatives as potent cytotoxic and apoptosis inducing agents. Bioorg Med Chem Lett. 2009;19(17):5091–4.CrossRefPubMed
7.
Ke F, Yu J, Chen W, Si X, Li X, Yang F, Liao Y, Zuo Z. The anti-malarial atovaquone selectively increases chemosensitivity in retinoblastoma via mitochondrial dysfunction-dependent oxidative damage and Akt/AMPK/mTOR inhibition. Biochem Biophys Res Commun. 2018;504(2):374–9.CrossRefPubMed
8.
Takabe H, Warnken ZN. A repurposed drug for Brain Cancer: enhanced atovaquone amorphous solid dispersion by combining a spontaneously emulsifying component with a polymer carrier. Pharmaceutics 2018, 10(2).
9.
Tian S, Chen H, Tan W. Targeting mitochondrial respiration as a therapeutic strategy for Cervical cancer. Biochem Biophys Res Commun. 2018;499(4):1019–24.CrossRefPubMed
10.
Chaffer CL, Thompson EW, Williams ED. Mesenchymal to epithelial transition in development and Disease. Cells Tissues Organs. 2007;185(1–3):7–19.CrossRefPubMed
11.
Inácio Pinto N, Carnier J, Oyama LM, Otoch JP, Alcântara PS, Tokeshi F, Nascimento CM. Cancer as a Proinflammatory Environment: Metastasis and Cachexia. Mediators Inflamm 2015, 2015:791060.
12.
Candido J, Hagemann T. Cancer-related inflammation. J Clin Immunol. 2013;33(Suppl 1):79–84.CrossRef
13.
Benelli R, Lorusso G, Albini A, Noonan DM. Cytokines and chemokines as regulators of angiogenesis in health and Disease. Curr Pharm Des. 2006;12(24):3101–15.CrossRefPubMed
14.
St John MA. Inflammatory mediators drive Metastasis and drug resistance in head and neck squamous cell carcinoma. Laryngoscope. 2015;125(Suppl 3):1–11.
15.
Ho EA, Piquette-Miller M. Regulation of multidrug resistance by pro-inflammatory cytokines. Curr Cancer Drug Targets. 2006;6(4):295–311.CrossRefPubMed
16.
17.
Zhou J, Zheng S, Liu T, Liu Q, Chen Y, Tan D, Ma R, Lu X. IL-1β from M2 macrophages promotes migration and invasion of ESCC cells enhancing epithelial-mesenchymal transition and activating NF-κB signaling pathway. 2018, 119(8):7040–52.
18.
Perez-Yepez EA, Ayala-Sumuano JT, Lezama R, Meza I. A novel β-catenin signaling pathway activated by IL-1β leads to the onset of epithelial-mesenchymal transition in Breast cancer cells. Cancer Lett. 2014;354(1):164–71.CrossRefPubMed
19.
Wang L, Tang C, Cao H, Li K, Pang X, Zhong L, Dang W, Tang H, Huang Y, Wei L, et al. Activation of IL-8 via PI3K/Akt-dependent pathway is involved in leptin-mediated epithelial-mesenchymal transition in human Breast cancer cells. Cancer Biol Ther. 2015;16(8):1220–30.CrossRefPubMedPubMedCentral
20.
Shang GS, Liu L, Qin YW. IL-6 and TNF-α promote Metastasis of Lung cancer by inducing epithelial-mesenchymal transition. Oncol Lett. 2017;13(6):4657–60.CrossRefPubMedPubMedCentral
21.
Yu L, Mu Y, Sa N, Wang H, Xu W. Tumor necrosis factor α induces epithelial-mesenchymal transition and promotes Metastasis via NF-κB signaling pathway-mediated TWIST expression in hypopharyngeal cancer. Oncol Rep. 2014;31(1):321–7.CrossRefPubMed
22.
Kibble M, Saarinen N, Tang J, Wennerberg K, Mäkelä S, Aittokallio T. Network pharmacology applications to map the unexplored target space and therapeutic potential of natural products. Nat Prod Rep. 2015;32(8):1249–66.CrossRefPubMed
23.
Luo TT, Lu Y, Yan SK, Xiao X, Rong XL, Guo J. Network Pharmacology in Research of Chinese Medicine Formula: methodology, application and prospective. Chin J Integr Med. 2020;26(1):72–80.CrossRefPubMed
24.
Paulsson J, Ehnman M, Östman A. PDGF receptors in Tumor biology: prognostic and predictive potential. Future Oncol. 2014;10(9):1695–708.CrossRefPubMed
25.
Ostman A, Heldin CH. PDGF receptors as targets in Tumor treatment. Adv Cancer Res. 2007;97:247–74.CrossRefPubMed
26.
Chang KK, Yoon C, Yi BC, Tap WD, Simon MC, Yoon SS. Platelet-derived growth factor receptor-α and -β promote cancer stem cell phenotypes in sarcomas. Oncogenesis. 2018;7(6):47.CrossRefPubMedPubMedCentral
27.
Valderrama-Treviño AI, Barrera-Mera B, Ceballos-Villalva JC, Montalvo-Javé EE. Hepatic Metastasis from Colorectal Cancer. Euroasian J hepato-gastroenterology. 2017;7(2):166–75.CrossRef
28.
Gao X, Liu X, Shan W, Liu Q, Wang C, Zheng J, Yao H, Tang R, Zheng J. Anti-malarial atovaquone exhibits anti-tumor effects by inducing DNA damage in hepatocellular carcinoma. Am J Cancer Res. 2018;8(9):1697–711.PubMedPubMedCentral
29.
Fiorillo M, Lamb R, Tanowitz HB, Mutti L, Krstic-Demonacos M, Cappello AR, Martinez-Outschoorn UE, Sotgia F, Lisanti MP. Repurposing atovaquone: targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells. Oncotarget. 2016;7(23):34084–99.CrossRefPubMedPubMedCentral
30.
31.
Lee JG, Ko MK, Kay EP. Endothelial mesenchymal transformation mediated by IL-1β-induced FGF-2 in corneal endothelial cells. Exp Eye Res. 2012;95(1):35–9.CrossRefPubMed
32.
Miao JW, Liu LJ, Huang J. Interleukin-6-induced epithelial-mesenchymal transition through signal transducer and activator of transcription 3 in human cervical carcinoma. Int J Oncol. 2014;45(1):165–76.CrossRefPubMed
33.
Lu H, Chen B, Hong W, Liang Y, Bai Y. Transforming growth factor-β1 stimulates hedgehog signaling to promote epithelial-mesenchymal transition after kidney injury. FEBS J. 2016;283(20):3771–90.CrossRefPubMed
34.
Techasen A, Namwat N, Loilome W, Bungkanjana P, Khuntikeo N, Puapairoj A, Jearanaikoon P, Saya H, Yongvanit P. Tumor necrosis factor-α (TNF-α) stimulates the epithelial-mesenchymal transition regulator snail in cholangiocarcinoma. Med Oncol (Northwood Lond Engl). 2012;29(5):3083–91.CrossRef
35.
Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the Tumor microenvironment. J Immunol Res. 2014;2014:149185.CrossRefPubMedPubMedCentral
36.
Pandi J, Arulprakasam A, Dhandapani R, Ramanathan S, Thangavelu S, Chinnappan J, Vidhya Rajalakshmi V, Alghamdi S, Shesha NT, Prasath S. Biomarkers for breast adenocarcinoma using in Silico approaches. Evid Based Complement Alternat Med. 2022;2022:7825272.CrossRefPubMedPubMedCentral
37.
Ajucarmelprecilla A, Pandi J, Dhandapani R, Ramanathan S, Chinnappan J, Paramasivam R, Thangavelu S, Mohammed Ghilan AK, Aljohani SAS, Oyouni AAA, Farasani A, Altayar MA, Althagafi HAE, Alzahrani OR, Durairaj K, Shrestha A. In Silico Identification of Hub Genes as Observing Biomarkers for Gastric Cancer Metastasis. Evid Based Complement Alternat Med 2022, 2022:6316158.
38.
Liu ZC, Wang HS, Zhang G, Liu H, Chen XH, Zhang F, Chen DY, Cai SH, Du J. AKT/GSK-3β regulates stability and transcription of snail which is crucial for bFGF-induced epithelial-mesenchymal transition of Prostate cancer cells. Biochim Biophys Acta. 2014;1840(10):3096–105.CrossRefPubMed
39.
Hu L, Lau SH, Tzang CH, Wen JM, Wang W, Xie D, Huang M, Wang Y, Wu MC, Huang JF, et al. Association of Vimentin overexpression and hepatocellular carcinoma Metastasis. Oncogene. 2004;23(1):298–302.CrossRefPubMed
40.
Nijkamp MM, Span PN, Hoogsteen IJ, van der Kogel AJ, Kaanders JH, Bussink J. Expression of E-cadherin and vimentin correlates with Metastasis formation in head and neck squamous cell carcinoma patients. Radiother Oncol. 2011;99(3):344–8.CrossRefPubMed
41.
Nieto MA. The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol. 2002;3(3):155–66.CrossRefPubMed
Metadata
Title
Atovaquone inhibits colorectal cancer metastasis by regulating PDGFRβ/NF-κB signaling pathway
Authors
Bin Liu
Xin Zheng
Jiajun Li
Peng Yao
Peng Guo
Wei Liu
Gaoping Zhao
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2023
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-023-11585-9

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