ATPase inhibitory factor 1 inhibition improves the antitumor of YC‑1 against hepatocellular carcinoma

Ding,Xuemei; Kong,Jian; Xu,Wenlei; Dong,Shuying; Du,Yingrui; Yao,Changyu; Gao,Jun; Ke,Shan; Wang,Shaohong; Sun,Wenbing

doi:10.3892/ol.2018.9266

ATPase inhibitory factor 1 inhibition improves the antitumor of YC‑1 against hepatocellular carcinoma

Authors:
- Xuemei Ding
- Jian Kong
- Wenlei Xu
- Shuying Dong
- Yingrui Du
- Changyu Yao
- Jun Gao
- Shan Ke
- Shaohong Wang
- Wenbing Sun
View Affiliations

Affiliations: Department of Hepatobiliary Surgery, Beijing Chao‑yang Hospital, Capital Medical University, Beijing 100043, P.R. China
Published online on: August 3, 2018 https://doi.org/10.3892/ol.2018.9266
Pages: 5230-5236
Copyright: © Ding 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

YC‑1 is a synthetic compound, which serves as a hypoxia‑inducible factor 1‑α inhibitor or sensitizer to enhance the effect of chemotherapy. Previous studies have revealed the anti‑cancer effects of YC‑1 in various types of cancer, including hepatocellular carcinoma (HCC). ATPase inhibitory factor 1 (IF1) is upregulated in a number of human carcinomas and regulates mitochondrial bioenergetics and structure. However, whether IF1 is involved in the antitumor effects of YC‑1 against HCC remains unclear. The present study examined the function of IF1 in HCC and its potential role in YC‑1 effects within HCC cells. MTT, colony formation and Transwell assays revealed that IF1 overexpression promoted proliferation, colony formation and invasion of HCC cells, while IF1 downregulation had the opposite effects. Overexpression of IF1 reversed the inhibitory effects of YC‑1 on Huh7 cell growth and invasion activities, while downregulation of IF1 increased the sensitivity of HCCLM3 cells to YC‑1. YC‑1 treatment of HCCLM3 and Huh7 cells reduced the levels of phosphorylated (p‑) signal transducer and activator of transcription 3 (STAT3) and IF1, and increased the expression of E‑cadherin. IF1 knockdown resulted in decreased p‑STAT3 levels and increased E‑cadherin expression, while IF1 overexpression increased p‑STAT3 levels and reduced the expression of E‑cadherin. The present study demonstrated that the inhibition of IF1 improves the antitumor effects of YC‑1 in HCC cells. These findings support the clinical strategy of combining YC‑1 and an IF1 inhibitor for the treatment of HCC.

View Figures

View References

1	Forner A, Llovet JM and Bruix J: Hepatocellular carcinoma. Lancet. 379:1245–1255. 2012. View Article : Google Scholar : PubMed/NCBI
2	Xu XL, Liu XD, Liang M and Luo BM: Radiofrequency ablation versus hepatic resection for small hepatocellular carcinoma: Systematic review of randomized controlled trials with meta-analysis and trial sequential analysis. Radiology. 287:461–472. 2018. View Article : Google Scholar : PubMed/NCBI
3	Niu L, Liu L, Yang S, Ren J, Lai PBS and Chen GG: New insights into sorafenib resistance in hepatocellular carcinoma: Responsible mechanisms and promising strategies. Biochim Biophys Acta. 1868:564–570. 2017.PubMed/NCBI
4	Bruix J, Cheng AL, Meinhardt G, Nakajima K, De Sanctis Y and Llovet J: Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: Analysis of two phase III studies. J Hepatol. 67:999–1008. 2017. View Article : Google Scholar : PubMed/NCBI
5	Chun YS, Yeo EJ and Park JW: Versatile pharmacological actions of YC-1: Anti-platelet to anticancer. Cancer Lett. 207:1–7. 2004. View Article : Google Scholar : PubMed/NCBI
6	Yeo EJ, Ryu JH, Chun YS, Cho YS, Jang IJ, Cho H, Kim J, Kim MS and Park JW: YC-1 induces S cell cycle arrest and apoptosis by activating checkpoint kinases. Cancer Res. 66:6345–6352. 2006. View Article : Google Scholar : PubMed/NCBI
7	Lau CK, Yang ZF, Lam CT, Tam KH, Poon RT and Fan ST: Suppression of hypoxia inducible factor-1alpha (HIF-1alpha) by YC-1 is dependent on murine double minute 2 (Mdm2). Biochem Biophys Res Commun. 348:1443–1448. 2006. View Article : Google Scholar : PubMed/NCBI
8	Lau CK, Yang ZF, Lam SP, Lam CT, Ngai P, Tam KH, Poon RT and Fan ST: Inhibition of Stat3 activity by YC-1 enhances chemo-sensitivity in hepatocellular carcinoma. Cancer Biol Ther. 6:1900–1907. 2007. View Article : Google Scholar : PubMed/NCBI
9	Kong J, Kong F, Gao J, Zhang Q, Dong S, Gu F, Ke S, Pan B, Shen Q, Sun H, et al: YC-1 enhances the anti-tumor activity of sorafenib through inhibition of signal transducer and activator of transcription 3 (STAT3) in hepatocellular carcinoma. Mol Cancer. 13:72014. View Article : Google Scholar : PubMed/NCBI
10	García-Bermúdez J and Cuezva JM: The ATPase inhibitory factor 1 (IF1): A master regulator of energy metabolism and of cell survival. Biochim Biophys Acta. 1857:1167–1182. 2016. View Article : Google Scholar : PubMed/NCBI
11	Garcia-Ledo L, Nuevo-Tapioles C, Cuevas-Martin C, Martínez-Reyes I, Soldevilla B, González-Llorente L and Cuezva JM: Overexpression of the ATPase inhibitory factor 1 favors a non-metastatic phenotype in breast cancer. Front Oncol. 7:692017. View Article : Google Scholar : PubMed/NCBI
12	Faccenda D, Nakamura J, Gorini G, Dhoot GK, Piacentini M, Yoshida M and Campanella M: Control of mitochondrial remodeling by the ATPase inhibitory factor 1 unveils a pro-survival relay via OPA1. Cell Rep. 18:1869–1883. 2017. View Article : Google Scholar : PubMed/NCBI
13	Gao YX, Chen L, Hu XG, Wu HB, Cui YH, Zhang X, Wang Y, Liu XD and Bian XW: ATPase inhibitory factor 1 expression is an independent prognostic factor in non-small cell lung cancer. Am J Cancer Res. 6:1141–1148. 2016.PubMed/NCBI
14	Yin T, Lu L, Xiong Z, Wei S and Cui D: ATPase inhibitory factor 1 is a prognostic marker and contributes to proliferation and invasion of human gastric cancer cells. Biomed Pharmacother. 70:90–96. 2015. View Article : Google Scholar : PubMed/NCBI
15	Wei S, Fukuhara H, Kawada C, Kurabayashi A, Furihata M, Ogura S, Inoue K and Shuin T: Silencing of ATPase inhibitory factor 1 inhibits cell growth via cell cycle arrest in bladder cancer. Pathobiology. 82:224–232. 2015. View Article : Google Scholar : PubMed/NCBI
16	Song R, Song H, Liang Y, Yin D, Zhang H, Zheng T, Wang J, Lu Z, Song X, Pei T, et al: Reciprocal activation between ATPase inhibitory factor 1 and NF-κB drives hepatocellular carcinoma angiogenesis and metastasis. Hepatology. 60:1659–1673. 2014. View Article : Google Scholar : PubMed/NCBI
17	Huang LJ, Chuang IC, Dong HP and Yang RC: Hypoxia-inducible factor 1α regulates the expression of the mitochondrial ATPase inhibitor protein (IF1) in rat liver. Shock. 36:90–96. 2011. View Article : Google Scholar : PubMed/NCBI
18	Wu J, Shan Q, Li P, Wu Y, Xie J and Wang X: ATPase inhibitory factor 1 is a potential prognostic marker for the migration and invasion of glioma. Oncol Lett. 10:2075–2080. 2015. 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	Santacatterina F, Sánchez-Cenizo L, Formentini L, Mobasher MA, Casas E, Rueda CB, Martínez-Reyes I, Núñez de Arenas C, García-Bermúdez J, Zapata JM, et al: Down-regulation of oxidative phosphorylation in the liver by expression of the ATPase inhibitory factor 1 induces a tumor-promoter metabolic state. Oncotarget. 7:490–508. 2016. View Article : Google Scholar : PubMed/NCBI
21	Sánchez-Aragó M, Formentini L, Martinez-Reyes I, García-Bermudez J, Santacatterina F, Sánchez-Cenizo L, Willers IM, Aldea M, Nájera L, Juarránz A, et al: Expression, regulation and clinical relevance of the ATPase inhibitory factor 1 in human cancers. Oncogenesis. 2:e462013. View Article : Google Scholar : PubMed/NCBI
22	Sánchez-Cenizo L, Formentini L, Aldea M, Ortega AD, García-Huerta P, Sánchez-Aragó M and Cuezva JM: Up-regulation of the ATPase inhibitory factor 1 (IF1) of the mitochondrial H+-ATP synthase in human tumors mediates the metabolic shift of cancer cells to a Warburg phenotype. J Biol Chem. 285:25308–25313. 2010. View Article : Google Scholar : PubMed/NCBI
23	Kong J, Kong J, Pan B, Ke S, Dong S, Li X, Zhou A, Zheng L and Sun WB: Insufficient radiofrequency ablation promotes angiogenesis of residual hepatocellular carcinoma via HIF-1α/VEGFA. PLoS One. 7:e372662012. View Article : Google Scholar : PubMed/NCBI
24	Wang SW, Pan SL, Guh JH, Chen HL, Huang DM, Chang YL, Kuo SC, Lee FY and Teng CM: YC-1 [3-(5′-Hydroxymethyl-2′-furyl)-1-benzyl Indazole] exhibits a novel antiproliferative effect and arrests the cell cycle in G0-G1 in human hepatocellular carcinoma cells. J Pharmacol Exp Ther. 312:917–925. 2005. View Article : Google Scholar : PubMed/NCBI
25	Lee CS, Kwak SW, Kim YJ, Lee SA, Park ES, Myung SC, Kim W, Lee MS and Lee JJ: Guanylate cyclase activator YC-1 potentiates apoptotic effect of licochalcone A on human epithelial ovarian carcinoma cells via activation of death receptor and mitochondrial pathways. Eur J Pharmacol. 683:54–62. 2012. View Article : Google Scholar : PubMed/NCBI
26	Huynh J, Etemadi N, Hollande F, Ernst M and Buchert M: The JAK/STAT3 axis: A comprehensive drug target for solid malignancies. Semin Cancer Biol. 45:13–22. 2017. View Article : Google Scholar : PubMed/NCBI
27	Bixel K, Saini U, Kumar Bid H, Fowler J, Riley M, Wanner R, Deepa Priya Dorayappan K, Rajendran S, Konishi I, Matsumura N, et al: Targeting STAT3 by HO3867 induces apoptosis in ovarian clear cell carcinoma. Int J Cancer. 141:1856–1866. 2017. View Article : Google Scholar : PubMed/NCBI
28	Khan MW, Saadalla A, Ewida AH, Al-Katranji K, Al-Saoudi G, Giaccone ZT, Gounari F, Zhang M, Frank DA and Khazaie K: The STAT3 inhibitor pyrimethamine displays anti-cancer and immune stimulatory effects in murine models of breast cancer. Cancer Immunol Immunother. 67:13–23. 2018. View Article : Google Scholar : PubMed/NCBI
29	Zeng R, Tang Y, Zhou H, Liu Y, Huang J, Li L, Liu W, Feng Y, Zhou Y, Chen T, et al: STAT3 mediates multidrug resistance of Burkitt lymphoma cells by promoting antioxidant feedback. Biochem Biophys Res Commun. 488:182–188. 2017. View Article : Google Scholar : PubMed/NCBI
30	Gao P, Niu N, Wei T, Tozawa H, Chen X, Zhang C, Zhang J, Wada Y, Kapron CM and Liu J: The roles of signal transducer and activator of transcription factor 3 in tumor angiogenesis. Oncotarget. 8:69139–69161. 2017.PubMed/NCBI
31	Kim BH, Yi EH and Ye SK: Signal transducer and activator of transcription 3 as a therapeutic target for cancer and the tumor microenvironment. Arch Pharm Res. 39:1085–1099. 2016. View Article : Google Scholar : PubMed/NCBI