Suppressed epithelial‑mesenchymal transition and cancer stem cell properties mediate the anti‑cancer effects of ethyl pyruvate via regulation of the AKT/nuclear factor‑κB pathway in prostate cancer cells

Huang,Bin; Lv,Dao‑Jun; Wang,Chong; Shu,Fang‑Peng; Gong,Zhi‑Cheng; Xie,Tao; Yu,Yu‑Zhong; Song,Xian‑Lu; Xie,Jia‑Jia; Li,Sen; Liu,Ya‑Meng; Qi,Huan; Zhao,Shan‑Chao

doi:10.3892/ol.2018.8958

Suppressed epithelial‑mesenchymal transition and cancer stem cell properties mediate the anti‑cancer effects of ethyl pyruvate via regulation of the AKT/nuclear factor‑κB pathway in prostate cancer cells

Authors:
- Bin Huang
- Dao‑Jun Lv
- Chong Wang
- Fang‑Peng Shu
- Zhi‑Cheng Gong
- Tao Xie
- Yu‑Zhong Yu
- Xian‑Lu Song
- Jia‑Jia Xie
- Sen Li
- Ya‑Meng Liu
- Huan Qi
- Shan‑Chao Zhao
View Affiliations

Affiliations: Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, Department of Radiation Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Guangdong 510095, P.R. China, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
Published online on: June 12, 2018 https://doi.org/10.3892/ol.2018.8958
Pages: 2271-2278
Copyright: © Huang 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

Castration‑resistant prostate cancer (CRPC) is a leading cause of mortality among cases of prostate cancer (PCa). Current treatment options for CRPC are limited. Ethyl pyruvate (EP), a lipophilic derivative of pyruvic acid, has been reported to have antitumor activities. In the present study, the efficacy of EP against PCa was investigated using two human PCa cell lines and a mouse xenograft tumor model. PC3 and CWR22RV1 cells were treated with EP, and cytotoxicity was evaluated via Cell Counting Kit‑8 and colony formation assays, while cell cycle distribution was assessed by flow cytometry. Changes in cell migration and invasion caused by EP treatment were also evaluated with Transwell and wound healing assays, and changes in the expression of intracellular signaling pathway components were detected by western blotting. EP treatment reduced cell viability, induced G1 arrest, and activated the intrinsic apoptosis pathway. Additionally, the in vivo experiments revealed that EP administration markedly inhibited tumor growth. EP also reversed epithelial‑mesenchymal transition and suppressed cancer stem cell properties in part through negative regulation of AKT/nuclear factor‑κB signaling. These results indicate that EP has anticancer activity in vitro and in vivo, and is therefore a promising therapeutic agent for the treatment of PCa.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2018. CA Cancer J Clin. 68:7–30. 2018. View Article : Google Scholar : PubMed/NCBI
2	Shafi AA, Yen AE and Weigel NL: Androgen receptors in hormone-dependent and castration-resistant prostate cancer. Pharmacol Ther. 140:223–238. 2013. View Article : Google Scholar : PubMed/NCBI
3	Loriot Y, Bianchini D, Ileana E, Sandhu S, Patrikidou A, Pezaro C, Albiges L, Attard G, Fizazi K, De Bono JS and Massard C: Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100). Ann Oncol. 24:1807–1812. 2013. View Article : Google Scholar : PubMed/NCBI
4	Schrader AJ, Boegemann M, Ohlmann CH, Schnoeller TJ, Krabbe LM, Hajili T, Jentzmik F, Stoeckle M, Schrader M, Herrmann E and Cronauer MV: Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. Eur Urol. 65:30–36. 2014. View Article : Google Scholar : PubMed/NCBI
5	Chaffer CL, Juan San BP, Lim E and Weinberg RA: Emt, cell plasticity and metastasis. Cancer Metastasis Rev. 35:645–654. 2016. View Article : Google Scholar : PubMed/NCBI
6	Wang D, Plukker J and Coppes RP: Cancer stem cells with increased metastatic potential as a therapeutic target for esophageal cancer. Semin Cancer Biol. 44:60–66. 2017. View Article : Google Scholar : PubMed/NCBI
7	Lamouille S, Xu J and Derynck R: Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 15:178–196. 2014. View Article : Google Scholar : PubMed/NCBI
8	Jaworska D, Król W and Szliszka E: Prostate cancer stem cells: Research advances. Int J Mol Sci. 16:27433–27449. 2015. View Article : Google Scholar : PubMed/NCBI
9	Bitting RL, Schaeffer D, Somarelli JA, Garcia-Blanco MA and Armstrong AJ: The role of epithelial plasticity in prostate cancer dissemination and treatment resistance. Cancer Metastasis Rev. 33:441–468. 2014. View Article : Google Scholar : PubMed/NCBI
10	Chen X, Li Q, Liu X, Liu C, Liu R, Rycaj K, Zhang D, Liu B, Jeter C, Calhoun-Davis T, et al: Defining a population of stem-like human prostate cancer cells that can generate and propagate castration-resistant prostate cancer. Clin Cancer Res. 22:4505–4516. 2016. View Article : Google Scholar : PubMed/NCBI
11	Chen W, Lian J, Ye JJ, Mo QF, Qin J, Hong GL, Chen LW, Zhi SC, Zhao GJ and Lu ZQ: Ethyl pyruvate reverses development of Pseudomonas aeruginosa pneumonia during sepsis-induced immunosuppression. Int Immunopharmacol. 52:61–69. 2017. View Article : Google Scholar : PubMed/NCBI
12	Fink MP: Ethyl pyruvate: A novel anti-inflammatory agent. J Intern Med. 261:349–362. 2007. View Article : Google Scholar : PubMed/NCBI
13	Pellegrini L, Xue J, Larson D, Pastorino S, Jube S, Forest KH, Saad-Jube ZS, Napolitano A, Pagano I, Negi VS, et al: HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma. Oncotarget. 8:22649–22661. 2017. View Article : Google Scholar : PubMed/NCBI
14	Birkenmeier G, Hemdan NY, Kurz S, Bigl M, Pieroh P, Debebe T, Buchold M, Thieme R, Wichmann G and Dehghani F: Ethyl pyruvate combats human leukemia cells but spares normal blood cells. PLoS One. 11:e01615712016. View Article : Google Scholar : PubMed/NCBI
15	Liang X, Chavez AR, Schapiro NE, Loughran P, Thorne SH, Amoscato AA, Zeh HJ, Beer-Stolz D, Lotze MT and de Vera ME: Ethyl pyruvate administration inhibits hepatic tumor growth. J Leukoc Biol. 86:599–607. 2009. View Article : Google Scholar : PubMed/NCBI
16	Li ML, Wang XF, Tan ZJ, Dong P, Gu J, Lu JH, Wu XS, Zhang L, Ding QC, Wu WG, et al: Ethyl pyruvate administration suppresses growth and invasion of gallbladder cancer cells via downregulation of HMGB1-RAGE axis. Int J Immunopathol Pharmacol. 25:955–965. 2012. View Article : Google Scholar : PubMed/NCBI
17	Park SY, Yi EY, Jung M, Lee YM and Kim YJ: Ethyl pyruvate, an anti-inflammatory agent, inhibits tumor angiogenesis through inhibition of the NF-κB signaling pathway. Cancer Lett. 303:150–154. 2011. View Article : Google Scholar : PubMed/NCBI
18	Cheng P, Dai W, Wang F, Lu J, Shen M, Chen K, Li J, Zhang Y, Wang C, Yang J, et al: Ethyl pyruvate inhibits proliferation and induces apoptosis of hepatocellular carcinoma via regulation of the HMGB1-RAGE and AKT pathways. Biochem Biophys Res Commun. 443:1162–1168. 2014. View Article : Google Scholar : PubMed/NCBI
19	Lv D, Wu H, Xing R, Shu F, Lei B, Lei C, Zhou X, Wan B, Yang Y, Zhong L, et al: HnRNP-L mediates bladder cancer progression by inhibiting apoptotic signaling and enhancing MAPK signaling pathways. Oncotarget. 8:13586–13599. 2017.PubMed/NCBI
20	Zhong D, Zhang HJ, Jiang YD, Wu P, Qi H, Cai C, Zheng SB and Dang Q: Saikosaponin-d: A potential chemotherapeutics in castration resistant prostate cancer by suppressing cancer metastases and cancer stem cell phenotypes. Biochem Biophys Res Commun. 474:722–729. 2016. View Article : Google Scholar : PubMed/NCBI
21	Ye X and Weinberg RA: Epithelial-mesenchymal plasticity: A central regulator of cancer progression. Trends Cell Biol. 25:675–686. 2015. View Article : Google Scholar : PubMed/NCBI
22	Karlsson MC, Gonzalez SF, Welin J and Fuxe J: Epithelial-mesenchymal transition in cancer metastasis through the lymphatic system. Mol Oncol. 11:781–791. 2017. View Article : Google Scholar : PubMed/NCBI
23	Lessard L, Karakiewicz PI, Bellon-Gagnon P, Alam-Fahmy M, Ismail HA, Mes-Masson AM and Saad F: Nuclear localization of nuclear factor-kappaB p65 in primary prostate tumors is highly predictive of pelvic lymph node metastases. Clin Cancer Res. 12:5741–5745. 2006. View Article : Google Scholar : PubMed/NCBI
24	Ismail HA, Lessard L, Mes-Masson AM and Saad F: Expression of NF-kappaB in prostate cancer lymph node metastases. Prostate. 58:308–313. 2004. View Article : Google Scholar : PubMed/NCBI
25	Min C, Eddy SF, Sherr DH and Sonenshein GE: NF-kappaB and epithelial to mesenchymal transition of cancer. J Cell Biochem. 104:733–744. 2008. View Article : Google Scholar : PubMed/NCBI
26	Rajasekhar VK, Studer L, Gerald W, Socci ND and Scher HI: Tumour-initiating stem-like cells in human prostate cancer exhibit increased NF-κB signalling. Nat Commun. 2:1622011. View Article : Google Scholar : PubMed/NCBI
27	Nakazawa M and Kyprianou N: Epithelial-mesenchymal-transition regulators in prostate cancer: Androgens and beyond. J Steroid Biochem Mol Biol. 166:84–90. 2017. View Article : Google Scholar : PubMed/NCBI
28	Li P, Yang R and Gao WQ: Contributions of epithelial-mesenchymal transition and cancer stem cells to the development of castration resistance of prostate cancer. Mol Cancer. 13:552014. View Article : Google Scholar : PubMed/NCBI
29	Sun Y, Wang BE, Leong KG, Yue P, Li L, Jhunjhunwala S, Chen D, Seo K, Modrusan Z, Gao WQ, et al: Androgen deprivation causes epithelial-mesenchymal transition in the prostate: Implications for androgen-deprivation therapy. Cancer Res. 72:527–536. 2012. View Article : Google Scholar : PubMed/NCBI
30	Figiel S, Vasseur C, Bruyere F, Rozet F, Maheo K and Fromont G: Clinical significance of epithelial-mesenchymal transition markers in prostate cancer. Hum Pathol. 61:26–32. 2017. View Article : Google Scholar : PubMed/NCBI
31	Shiota M, Yokomizo A, Tada Y, Inokuchi J, Kashiwagi E, Masubuchi D, Eto M, Uchiumi T and Naito S: Castration resistance of prostate cancer cells caused by castration-induced oxidative stress through Twist1 and androgen receptor overexpression. Oncogene. 29:237–250. 2010. View Article : Google Scholar : PubMed/NCBI
32	Wu K, Gore C, Yang L, Fazli L, Gleave M, Pong RC, Xiao G, Zhang L, Yun EJ, Tseng SF, et al: Slug, a unique androgen-regulated transcription factor, coordinates androgen receptor to facilitate castration resistance in prostate cancer. Mol Endocrinol. 26:1496–1507. 2012. View Article : Google Scholar : PubMed/NCBI
33	Ni J, Cozzi P, Hao J, Duan W, Graham P, Kearsley J and Li Y: Cancer stem cells in prostate cancer chemoresistance. Curr Cancer Drug Targets. 14:225–240. 2014. View Article : Google Scholar : PubMed/NCBI
34	Yun EJ, Zhou J, Lin CJ, Hernandez E, Fazli L, Gleave M and Hsieh JT: Targeting cancer stem cells in castration-resistant prostate cancer. Clin Cancer Res. 22:670–679. 2016. View Article : Google Scholar : PubMed/NCBI
35	Wang X, Kruithof-de Julio M, Economides KD, Walker D, Yu H, Halili MV, Hu YP, Price SM, Abate-Shen C and Shen MM: A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature. 461:495–500. 2009. View Article : Google Scholar : PubMed/NCBI
36	Jeter CR, Liu B, Liu X, Chen X, Liu C, Calhoun-Davis T, Repass J, Zaehres H, Shen JJ and Tang DG: NANOG promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation. Oncogene. 30:3833–3845. 2011. View Article : Google Scholar : PubMed/NCBI
37	Jeter CR, Badeaux M, Choy G, Chandra D, Patrawala L, Liu C, Calhoun-Davis T, Zaehres H, Daley GQ and Tang DG: Functional evidence that the self-renewal gene NANOG regulates human tumor development. Stem Cells. 27:993–1005. 2009. View Article : Google Scholar : PubMed/NCBI
38	Rybak AP and Tang D: SOX2 plays a critical role in EGFR-mediated self-renewal of human prostate cancer stem-like cells. Cell Signal. 25:2734–2742. 2013. View Article : Google Scholar : PubMed/NCBI
39	Kregel S, Kiriluk KJ, Rosen AM, Cai Y, Reyes EE, Otto KB, Tom W, Paner GP, Szmulewitz RZ and Griend Vander DJ: Sox2 is an androgen receptor-repressed gene that promotes castration-resistant prostate cancer. PLoS One. 8:e537012013. View Article : Google Scholar : PubMed/NCBI
40	Taniguchi K and Karin M: NF-κB, inflammation, immunity and cancer: Coming of age. Nat Rev Immunol. 18:309–324. 2018. View Article : Google Scholar : PubMed/NCBI
41	Kotiyal S and Bhattacharya S: Breast cancer stem cells, emt and therapeutic targets. Biochem Biophys Res Commun. 453:112–116. 2014. View Article : Google Scholar : PubMed/NCBI
42	Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM and Donner DB: NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature. 401:82–85. 1999. View Article : Google Scholar : PubMed/NCBI
43	Han Y, Englert JA, Yang R, Delude RL and Fink MP: Ethyl pyruvate inhibits nuclear factor-kappaB-dependent signaling by directly targeting p65. J Pharmacol Exp Ther. 312:1097–1105. 2005. View Article : Google Scholar : PubMed/NCBI
44	Lee SO, Lou W, Nadiminty N, Lin X and Gao AC: Requirement for NF-(kappa)B in interleukin-4-induced androgen receptor activation in prostate cancer cells. Prostate. 64:160–167. 2005. View Article : Google Scholar : PubMed/NCBI
45	Penning TM: Mechanisms of drug resistance that target the androgen axis in castration resistant prostate cancer (CRPC). J Steroid Biochem Mol Biol. 153:105–113. 2015. View Article : Google Scholar : PubMed/NCBI
46	Bennett-Guerrero E, Swaminathan M, Grigore AM, Roach GW, Aberle LG, Johnston JM and Fink MP: A phase II multicenter double-blind placebo-controlled study of ethyl pyruvate in high-risk patients undergoing cardiac surgery with cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 23:324–329. 2009. View Article : Google Scholar : PubMed/NCBI