Ginkgolic acid inhibits the growth of renal cell carcinoma cells via inactivation of the EGFR signaling pathway

Zhu,Chao; Na,Na; Sheng,Haibo; Feng,Bing; Wang,Hao; Zhu,Ping; Zhang,Wei; Zhang,Meina; Deng,Zhen

doi:10.3892/etm.2020.8570

Ginkgolic acid inhibits the growth of renal cell carcinoma cells via inactivation of the EGFR signaling pathway

Authors:
- Chao Zhu
- Na Na
- Haibo Sheng
- Bing Feng
- Hao Wang
- Ping Zhu
- Wei Zhang
- Meina Zhang
- Zhen Deng
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Affiliations: Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China, Department of Outpatients, 900th Hospital of The Joint Logistics Support Force (People's Liberation Army), Fuzhou, Fujian 350000, P.R. China, Department of Urology, Airforce Medical Center (People's Liberation Army), Beijing 100142, P.R. China, Department of Pathology, 971st Navy Hospital of PLA, Qingdao, Shandong 266071, P.R. China, Department of Urology, 900th Hospital of The Joint Logistics Support Force (People's Liberation Army), Fuzhou, Fujian 350000, P.R. China
Published online on: February 27, 2020 https://doi.org/10.3892/etm.2020.8570
Pages: 2949-2956
Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Renal cell carcinoma (RCC) is one of the most common urological malignancies occurring in adult human kidneys worldwide. Recent research on antitumor drugs has focused on plant extracts, a class of compounds that play critical roles in cancer treatment. The present study aimed to investigate the potential antitumor effect of ginkgolic acid (GA) in RCC. Transwell invasion assay, cell counting kit‑8 assay and flow cytometry were used to measure cell migration, cell viability and apoptosis, respectively. A network pharmacology approach was applied to identify pathway information, combining molecular docking techniques to screen for key target information. In the present study, GA inhibited the viability and proliferation of RCC cells (786‑O and A498), both in vitro and in vivo, via G1 arrest. GA also reduced RCC cell invasion and migration. In addition, the epidermal growth factor receptor (EGFR) was identified as a critical target protein of GA, which significantly inactivated EGFR signaling in RCC (P<0.05). Collectively, the present study provided evidence that GA exerts its anticancer function by directly targeting the EGFR signaling pathway, revealing the potential of GA therapy for RCC.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2017. CA Cancer J Clin. 67:7–30. 2017.PubMed/NCBI View Article : Google Scholar
2	Cindolo L, Patard JJ, Chiodini P, Schips L, Ficarra V, Tostain J, de La Taille A, Altieri V, Lobel B, Zigeuner RE, et al: Comparison of predictive accuracy of four prognostic models for nonmetastatic renal cell carcinoma after nephrectomy: A multicenter European study. Cancer. 104:1362–1371. 2005.PubMed/NCBI View Article : Google Scholar
3	Patil S, Ishill N, Deluca J and Motzer RJ: Stage migration and increasing proportion of favorable-prognosis metastatic renal cell carcinoma patients: Implications for clinical trial design and interpretation. Cancer. 116:347–354. 2010.PubMed/NCBI View Article : Google Scholar
4	Redova M, Svoboda M and Slaby O: MicroRNAs and their target gene networks in renal cell carcinoma. Biochem Biophys Res Commun. 405:153–156. 2011.PubMed/NCBI View Article : Google Scholar
5	Mangolini A, Bonon A, Volinia S, Lanza G, Gambari R, Pinton P, Russo GR, Del Senno L, Dell'Atti L and Aguiari G: Differential expression of microRNA501-5p affects the aggressiveness of clear cell renal carcinoma. FEBS Open Bio. 4:952–965. 2014.PubMed/NCBI View Article : Google Scholar
6	van Beek TA and Wintermans MS: Preparative isolation and dual column high-performance liquid chromatography of ginkgolic acids from Ginkgo biloba. J Chromatogr A. 930:109–117. 2001.PubMed/NCBI View Article : Google Scholar
7	Major RT: The ginkgo, the most ancient living tree. The resistance of Ginkgo biloba L. to pests accounts in part for the longevity of this species. Science. 157:1270–1273. 1967.PubMed/NCBI View Article : Google Scholar
8	Siegers CP: Cytotoxicity of alkylphenols from Ginkgo biloba. Phytomedicine. 6:281–283. 1999.PubMed/NCBI View Article : Google Scholar
9	Hecker H, Johannisson R, Koch E and Siegers CP: In vitro evaluation of the cytotoxic potential of alkylphenols from Ginkgo biloba L. Toxicology. 177:167–177. 2002.PubMed/NCBI View Article : Google Scholar
10	Zhou C, Li X, Du W, Feng Y, Kong X, Li Y, Xiao L and Zhang P: Antitumor effects of ginkgolic acid in human cancer cell occur via cell cycle arrest and decrease the Bcl-2/Bax ratio to induce apoptosis. Chemotherapy. 56:393–402. 2010.PubMed/NCBI View Article : Google Scholar
11	Lü JM, Yan S, Jamaluddin S, Weakley SM, Liang Z, Siwak EB, Yao Q and Chen C: Ginkgolic acid inhibits HIV protease activity and HIV infection in vitro. Med Sci Monit. 18:BR293–BR298. 2012.PubMed/NCBI View Article : Google Scholar
12	Li H, Meng X, Zhang D, Xu X, Li S and Li Y: Ginkgolic acid suppresses the invasion of HepG2 cells via downregulation of HGF/cMet signaling. Oncol Rep. 41:369–376. 2019.PubMed/NCBI View Article : Google Scholar
13	Qiao L, Zheng J, Jin X, Wei G, Wang G, Sun X and Li X: Ginkgolic acid inhibits the invasiveness of colon cancer cells through AMPK activation. Oncol Lett. 14:5831–5838. 2017.PubMed/NCBI View Article : Google Scholar
14	Hamdoun S and Efferth T: Ginkgolic acids inhibit migration in breast cancer cells by inhibition of NEMO sumoylation and NF-κB activity. Oncotarget. 8:35103–35115. 2017.PubMed/NCBI View Article : Google Scholar
15	Baek SH, Ko JH, Lee JH, Kim C, Lee H, Nam D, Lee J, Lee SG, Yang WM, Um JY, et al: Ginkgolic acid inhibits invasion and migration and TGF-β-induced EMT of lung cancer cells through PI3K/Akt/mTOR inactivation. J Cell Physiol. 232:346–354. 2017.PubMed/NCBI View Article : Google Scholar
16	Ye HZ, Zheng CS, Xu XJ, Wu MX and Liu XX: Potential synergistic and multitarget effect of herbal pair Chuanxiong Rhizome-Paeonia Albifora Pall on osteoarthritis disease: A computational pharmacology approach. Chin J Integr Med. 17:698–703. 2011.PubMed/NCBI View Article : Google Scholar
17	Xenarios I, Salwínski L, Duan XJ, Higney P, Kim SM and Eisenberg D: DIP, the database of interacting proteins: A research tool for studying cellular networks of protein interactions. Nucleic Acids Res. 30:303–305. 2002.PubMed/NCBI View Article : Google Scholar
18	Xu R and Wunsch DC II: Clustering algorithms in biomedical research: A review. IEEE Rev Biomed Eng. 3:120–154. 2010.PubMed/NCBI View Article : Google Scholar
19	Ramadan E, Naef A and Ahmed M: Protein complexes predictions within protein interaction networks using genetic algorithms. BMC Bioinformatics. 17:(Suppl 7): S269. 2016.PubMed/NCBI View Article : Google Scholar
20	Wang D, Zhu C, Zhang Y, Zheng Y, Ma F, Su L and Shao G: MicroRNA-30e-3p inhibits cell invasion and migration in clear cell renal cell carcinoma by targeting Snail1. Oncol Lett. 13:2053–2058. 2017.PubMed/NCBI View Article : Google Scholar
21	Renal cell cancer treatment (PDQ(R)): Patient version, in PDQ cancer information summaries. 2002: Bethesda (MD).
22	Shingarev R and Jaimes EA: Renal cell carcinoma: New insights and challenges for a clinician scientist. Am J Physiol Renal Physiol. 313:F145–F154. 2017.PubMed/NCBI View Article : Google Scholar
23	Wang C, Ren Q, Chen XT, Song ZQ, Ning ZC, Gan JH, Ma XL, Liang DR, Guan DG, Liu ZL and Lu AP: System pharmacology-based strategy to decode the synergistic mechanism of Zhi-zhu Wan for functional dyspepsia. Front Pharmacol. 9(841)2018.PubMed/NCBI View Article : Google Scholar
24	Zhang J, Li Y, Chen X, Pan Y, Zhang S and Wang Y: Systems pharmacology dissection of multi-scale mechanisms of action for herbal medicines in stroke treatment and prevention. PLoS One. 9(e102506)2014.PubMed/NCBI View Article : Google Scholar
25	Ma J, Duan W, Han S, Lei J, Xu Q, Chen X, Jiang Z, Nan L, Li J, Chen K, et al: Ginkgolic acid suppresses the development of pancreatic cancer by inhibiting pathways driving lipogenesis. Oncotarget. 6:20993–21003. 2015.PubMed/NCBI View Article : Google Scholar
26	Liu Y, Yang B, Zhang L, Cong X, Liu Z, Hu Y, Zhang J and Hu H: Ginkgolic acid induces interplay between apoptosis and autophagy regulated by ROS generation in colon cancer. Biochem Biophys Res Commun. 498:246–253. 2018.PubMed/NCBI View Article : Google Scholar
27	Zhou CC, Du W, Wen Z, Li JY and Zhang P: Effects of natural plant ginkgolic acids on the apoptosis of human Hep-2 cancer cells. Sichuan Da Xue Xue Bao Yi Xue Ban. 40:459–461. 2009.PubMed/NCBI(In Chinese).
28	Yuan H, Ma Q, Cui H, Liu G, Zhao X, Li W and Piao G: How can synergism of traditional medicines benefit from network pharmacology? Molecules. 22(E1135)2017.PubMed/NCBI View Article : Google Scholar
29	Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, et al: A human protein-protein interaction network: A resource for annotating the proteome. Cell. 122:957–968. 2005.PubMed/NCBI View Article : Google Scholar
30	Boezio B, Audouze K, Ducrot P and Taboureau O: Network-based approaches in pharmacology. Mol Inform. 36:2017.PubMed/NCBI View Article : Google Scholar
31	Harris RC, Chung E and Coffey RJ: EGF receptor ligands. Exp Cell Res. 284:2–13. 2003.PubMed/NCBI View Article : Google Scholar
32	Freed DM, Bessman NJ, Kiyatkin A, Salazar-Cavazos E, Byrne PO, Moore JO, Valley CC, Ferguson KM, Leahy DJ, Lidke DS and Lemmon MA: EGFR ligands differentially stabilize receptor dimers to specify signaling kinetics. Cell. 171:683–695.e18. 2017.PubMed/NCBI View Article : Google Scholar
33	Sigismund S, Avanzato D and Lanzetti L: Emerging functions of the EGFR in cancer. Mol Oncol. 12:3–20. 2018.PubMed/NCBI View Article : Google Scholar
34	Wang Z: ErbB receptors and cancer. Methods Mol Biol. 1652:3–35. 2017.PubMed/NCBI View Article : Google Scholar
35	Liu Q, Yu S, Zhao W, Qin S, Chu Q and Wu K: EGFR-TKIs resistance via EGFR-independent signaling pathways. Mol Cancer. 17(53)2018.PubMed/NCBI View Article : Google Scholar
36	Cosmai L, Gallieni M and Porta C: Renal toxicity of anticancer agents targeting HER2 and EGFR. J Nephrol. 28:647–657. 2015.PubMed/NCBI View Article : Google Scholar
37	Liu F, Shangli Z and Hu Z: CAV2 promotes the growth of renal cell carcinoma through the EGFR/PI3K/Akt pathway. Onco Targets Ther. 11:6209–6216. 2018.PubMed/NCBI View Article : Google Scholar
38	Liu L, Miao L, Liu Y, Qi A, Xie P, Chen J and Zhu H: S100A11 regulates renal carcinoma cell proliferation, invasion, and migration via the EGFR/Akt signaling pathway and E-cadherin. Tumour Biol. 39(1010428317705337)2017.PubMed/NCBI View Article : Google Scholar
39	Feng ZH, Fang Y, Zhao LY, Lu J, Wang YQ, Chen ZH, Huang Y, Wei JH, Liang YP, Cen JJ, et al: RIN1 promotes renal cell carcinoma malignancy by activating EGFR signaling through Rab25. Cancer Sci. 108:1620–1627. 2017.PubMed/NCBI View Article : Google Scholar
40	Chen F, Deng J, Liu X, Li W and Zheng J: HCRP-1 regulates cell migration and invasion via EGFR-ERK mediated up-regulation of MMP-2 with prognostic significance in human renal cell carcinoma. Sci Rep. 5(13470)2015.PubMed/NCBI View Article : Google Scholar
41	Liang L, Li L, Zeng J, Gao Y, Chen YL, Wang ZQ, Wang XY, Chang LS and He D: Inhibitory effect of silibinin on EGFR signal-induced renal cell carcinoma progression via suppression of the EGFR/MMP-9 signaling pathway. Oncol Rep. 28:999–1005. 2012.PubMed/NCBI View Article : Google Scholar