B1, a novel HDAC inhibitor, induces apoptosis through the regulation of STAT3 and NF-κB

Cheng,Meng-Hsuan; Wong,Yun-Hong; Chang,Chia-Ming; Yang,Chun-Chien; Chen,Shih-Hua; Yuan,Chun-Lung; Kuo,Hsiao-Mei; Yang,Chun-Yuh; Chiu,Hui-Fen

doi:10.3892/ijmm.2017.2946

B1, a novel HDAC inhibitor, induces apoptosis through the regulation of STAT3 and NF-κB

Authors:
- Meng-Hsuan Cheng
- Yun-Hong Wong
- Chia-Ming Chang
- Chun-Chien Yang
- Shih-Hua Chen
- Chun-Lung Yuan
- Hsiao-Mei Kuo
- Chun-Yuh Yang
- Hui-Fen Chiu
View Affiliations

Affiliations: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan, R.O.C., Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, R.O.C., Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, R.O.C., Department of Chemistry, Republic of China Military Academy, Fengshan, Kaohsiung 83059, Taiwan, R.O.C., Department of Neuroscience, Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan, R.O.C., Faculty of Public Health, College of Health Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, R.O.C.
Published online on: April 7, 2017 https://doi.org/10.3892/ijmm.2017.2946
Pages: 1137-1148
Copyright: © Cheng 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

We previously demonstrated that B1 induced significant cytotoxic effects, cell cycle G1 arrest and apoptosis in human lung cancer A549 cells through the inhibition of DNA topoisomerase II activity. In the present study, we focused on the histone deacetylase (HDAC) modulation of B1 in A549 cells. HDACs, important enzymes affecting epigenetic regulation, play a crucial role in human carcinogenesis. Our findings showed that B1 could suppress the growth of A549 cells in vitro through the inhibition of HDAC activity. Additionally, B1 caused disruption of the mitochondrial membrane potential and induced DNA double-strand breaks (DSBs) in a dose- and time-dependent manner, which consequently led to cell apoptosis. We also observed that B1 inhibited cancer cell migration and angiogenesis-related signal expression, including vascular endothelial growth factor (VEGF) and pro-matrix metalloproteinases-2 and -9 (pro-MMP-2/9). Gelatin zymography suggested that B1 decreased pro-MMP-2 and pro-MMP-9 activity. Transcription factors, signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB), are vital players in the many steps of carcinogenesis. B1 showed significant dose-response inhibitory effects on cytoplasmic expression and nuclear translocation of both phosphorylated STAT3 (pSTAT3) and NF-κB. It has been well documented that reactivated telomerase confers cancer cells the ability to repair DNA. Real-time PCR results indicated that B1 inhibited STAT3 and NF-κB mRNA expression and telomerase activity. Taken together, our results demonstrated that B1 exerted significant inhibitory effects on HDAC, telomerase activities, oncogenic STAT3 and NF-κB expression. The inhibition of the intricate crosstalk between STAT3 and NF-κB may be a major factor in the molecular action mechanism of B1. The multiple targeting effects of B1 render it a potential new drug for lung cancer therapy.

View Figures

View References

1	Cheng MH, Yang YC, Wong YH, Chen TR, Lee CY, Yang CC, Chen SH, Yang IN, Yang YS, Huang HS, et al: B1, a novel topoisomerase II inhibitor, induces apoptosis and cell cycle G1 arrest in lung adenocarcinoma A549 cells. Anticancer Drugs. 23:191–199. 2012. View Article : Google Scholar
2	Cataldo VD, Gibbons DL, Pérez-Soler R and Quintás-Cardama A: Treatment of non-small-cell lung cancer with erlotinib or gefitinib. N Engl J Med. 364:947–955. 2011. View Article : Google Scholar : PubMed/NCBI
3	Pande V: Understanding the Complexity of Epigenetic Target Space. J Med Chem. 59:1299–1307. 2016. View Article : Google Scholar : PubMed/NCBI
4	Marks PA: Discovery and development of SAHA as an anticancer agent. Oncogene. 26:1351–1356. 2007. View Article : Google Scholar : PubMed/NCBI
5	Singh BN, Zhang G, Hwa YL, Li J, Dowdy SC and Jiang SW: Nonhistone protein acetylation as cancer therapy targets. Expert Rev Anticancer Ther. 10:935–954. 2010. View Article : Google Scholar : PubMed/NCBI
6	Duvic M: Histone deacetylase inhibitors for cutaneous T-cell lymphoma. Dermatol Clin. 33:757–764. 2015. View Article : Google Scholar : PubMed/NCBI
7	Xu L, Li S and Stohr BA: The role of telomere biology in cancer. Annu Rev Pathol. 8:49–78. 2013. View Article : Google Scholar
8	Sekaran V, Soares J and Jarstfer MB: Telomere maintenance as a target for drug discovery. J Med Chem. 57:521–538. 2014. View Article : Google Scholar
9	Thomas SJ, Snowden JA, Zeidler MP and Danson SJ: The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. Br J Cancer. 113:365–371. 2015. View Article : Google Scholar : PubMed/NCBI
10	Furtek SL, Backos DS, Matheson CJ and Reigan P: Strategies and approaches of targeting STAT3 for cancer treatment. ACS Chem Biol. 11:308–318. 2016. View Article : Google Scholar : PubMed/NCBI
11	Koliaraki V, Pasparakis M and Kollias G: IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer. J Exp Med. 212:2235–2251. 2015. View Article : Google Scholar : PubMed/NCBI
12	Li Y and Tergaonkar V: Noncanonical functions of telomerase: Implications in telomerase-targeted cancer therapies. Cancer Res. 74:1639–1644. 2014. View Article : Google Scholar : PubMed/NCBI
13	Hoesel B and Schmid JA: The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer. 12:862013. View Article : Google Scholar
14	Wang GW, Lv C, Shi ZR, Zeng RT, Dong XY, Zhang WD, Liu RH, Shan L and Shen YH: Abieslactone induces cell cycle arrest and apoptosis in human hepatocellular carcinomas through the mitochondrial pathway and the generation of reactive oxygen species. PLoS One. 9:e1151512014. View Article : Google Scholar : PubMed/NCBI
15	Correia C, Lee SH, Meng XW, Vincelette ND, Knorr KL, Ding H, Nowakowski GS, Dai H and Kaufmann SH: Emerging understanding of Bcl-2 biology: Implications for neoplastic progression and treatment. Biochim Biophys Acta. 1853:1658–1671. 2015. View Article : Google Scholar : PubMed/NCBI
16	Lunardi S, Muschel RJ and Brunner TB: The stromal compartments in pancreatic cancer: Are there any therapeutic targets? Cancer Lett. 343:147–155. 2014. View Article : Google Scholar
17	Grivennikov SI and Karin M: Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. 21:11–19. 2010. View Article : Google Scholar
18	Wang XH, Liu BR, Qu B, Xing H, Gao SL, Yin JM, Wang XF and Cheng YQ: Silencing STAT3 may inhibit cell growth through regulating signaling pathway, telomerase, cell cycle, apoptosis and angiogenesis in hepatocellular carcinoma: Potential uses for gene therapy. Neoplasma. 58:158–171. 2011. View Article : Google Scholar : PubMed/NCBI
19	Barneda-Zahonero B and Parra M: Histone deacetylases and cancer. Mol Oncol. 6:579–589. 2012. View Article : Google Scholar : PubMed/NCBI
20	Li Z and Zhu WG: Targeting histone deacetylases for cancer therapy: From molecular mechanisms to clinical implications. Int J Biol Sci. 10:757–770. 2014. View Article : Google Scholar : PubMed/NCBI
21	Bhaskara S and Hiebert SW: Role for histone deacetylase 3 in maintenance of genome stability. Cell Cycle. 10:727–728. 2011. View Article : Google Scholar : PubMed/NCBI
22	Helleday T, Petermann E, Lundin C, Hodgson B and Sharma RA: DNA repair pathways as targets for cancer therapy. Nat Rev Cancer. 8:193–204. 2008. View Article : Google Scholar : PubMed/NCBI
23	Bhaskara S, Knutson SK, Jiang G, Chandrasekharan MB, Wilson AJ, Zheng S, Yenamandra A, Locke K, Yuan JL, Bonine-Summers AR, et al: Hdac3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell. 18:436–447. 2010. View Article : Google Scholar : PubMed/NCBI
24	Danial NN: BAD: Undertaker by night, candyman by day. Oncogene. 27(Suppl 1): S53–S70. 2008. View Article : Google Scholar
25	Bolden JE, Shi W, Jankowski K, Kan CY, Cluse L, Martin BP, MacKenzie KL, Smyth GK and Johnstone RW: HDAC inhibitors induce tumor-cell-selective pro-apoptotic transcriptional responses. Cell Death Dis. 4:e5192013. View Article : Google Scholar : PubMed/NCBI
26	Gialeli C, Theocharis AD and Karamanos NK: Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 278:16–27. 2011. View Article : Google Scholar
27	Frankowski H, Gu YH, Heo JH, Milner R and Del Zoppo GJ: Use of gel zymography to examine matrix metalloproteinase (gelatinase) expression in brain tissue or in primary glial cultures. Methods Mol Biol. 814:221–233. 2012. View Article : Google Scholar
28	Leinonen T, Pirinen R, Bohm J, Johansson R and Kosma VM: Increased expression of matrix metalloproteinase-2 (MMP-2) predicts tumour recurrence and unfavourable outcome in non-small cell lung cancer. Histology and histopathology. 23:693–700. 2008.PubMed/NCBI
29	Lee H, Kim JS and Kim E: Fucoidan from seaweed Fucus vesiculosus inhibits migration and invasion of human lung cancer cell via PI3K-Akt-mTOR pathways. PLoS One. 7:e506242012. View Article : Google Scholar : PubMed/NCBI
30	Wang Z, Zhu S, Shen M, Liu J, Wang M, Li C, Wang Y, Deng A and Mei Q: STAT3 is involved in esophageal carcinogenesis through regulation of Oct-1. Carcinogenesis. 34:678–688. 2013. View Article : Google Scholar
31	Connelly L, Barham W, Onishko HM, Sherrill T, Chodosh LA, Blackwell TS and Yull FE: Inhibition of NF-kappa B activity in mammary epithelium increases tumor latency and decreases tumor burden. Oncogene. 30:1402–1412. 2011. View Article : Google Scholar
32	Haybaeck J, Zeller N, Wolf MJ, Weber A, Wagner U, Kurrer MO, Bremer J, Iezzi G, Graf R, Clavien PA, et al: A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell. 16:295–308. 2009. View Article : Google Scholar : PubMed/NCBI
33	Fan Y, Mao R and Yang J: NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell. 4:176–185. 2013. View Article : Google Scholar : PubMed/NCBI
34	West AC and Johnstone RW: New and emerging HDAC inhibitors for cancer treatment. J Clin Invest. 124:30–39. 2014. View Article : Google Scholar : PubMed/NCBI
35	Song X, Wang J, Zheng T, Song R, Liang Y, Bhatta N, Yin D, Pan S, Liu J, Jiang H, et al: LBH589 Inhibits proliferation and metastasis of hepatocellular carcinoma via inhibition of gankyrin/stat3/akt pathway. Mol Cancer. 12:1142013. View Article : Google Scholar : PubMed/NCBI
36	Lin TY, Fenger J, Murahari S, Bear MD, Kulp SK, Wang D, Chen CS, Kisseberth WC and London CA: AR-42, a novel HDAC inhibitor, exhibits biologic activity against malignant mast cell lines via down-regulation of constitutively activated Kit. Blood. 115:4217–4225. 2010. View Article : Google Scholar : PubMed/NCBI
37	Chien W, Lee DH, Zheng Y, Wuensche P, Alvarez R, Wen DL, Aribi AM, Thean SM, Doan NB, Said JW, et al: Growth inhibition of pancreatic cancer cells by histone deacetylase inhibitor belinostat through suppression of multiple pathways including HIF, NFκB, and mTOR signaling in vitro and in vivo. Mol Carcinog. 53:722–735. 2014. View Article : Google Scholar
38	He G and Karin M: NF-κB and STAT3 - key players in liver inflammation and cancer. Cell Res. 21:159–168. 2011. View Article : Google Scholar
39	Carpenter RL and Lo HW: STAT3 target genes relevant to human cancers. Cancers (Basel). 6:897–925. 2014. View Article : Google Scholar
40	Song L, Rawal B, Nemeth JA and Haura EB: JAK1 activates STAT3 activity in non-small-cell lung cancer cells and IL-6 neutralizing antibodies can suppress JAK1-STAT3 signaling. Mol Cancer Ther. 10:481–494. 2011. View Article : Google Scholar : PubMed/NCBI
41	Jeannot V, Busser B, Vanwonterghem L, Michallet S, Ferroudj S, Cokol M, Coll JL, Ozturk M and Hurbin A: Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma. Onco Targets Ther. 9:6843–6855. 2016. View Article : Google Scholar : PubMed/NCBI
42	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
43	Low KC and Tergaonkar V: Telomerase: Central regulator of all of the hallmarks of cancer. Trends Biochem Sci. 38:426–434. 2013. View Article : Google Scholar : PubMed/NCBI
44	Sharma V, Koul N, Joseph C, Dixit D, Ghosh S and Sen E: HDAC inhibitor, scriptaid, induces glioma cell apoptosis through JNK activation and inhibits telomerase activity. J Cell Mol Med. 14:2151–2161. 2010. View Article : Google Scholar
45	Li CT, Hsiao YM, Wu TC, Lin YW, Yeh KT and Ko JL: Vorinostat, SAHA, represses telomerase activity via epigenetic regulation of telomerase reverse transcriptase in non-small cell lung cancer cells. J Cell Biochem. 112:3044–3053. 2011. View Article : Google Scholar : PubMed/NCBI
46	Kim JS, Lee SC, Min HY, Park KH, Hyun SY, Kwon SJ, Choi SP, Kim WY, Lee HJ and Lee HY: Activation of insulin-like growth factor receptor signaling mediates resistance to histone deacetylase inhibitors. Cancer Lett. 361:197–206. 2015. View Article : Google Scholar : PubMed/NCBI
47	Lee SC, Min HY, Jung HJ, Park KH, Hyun SY, Cho J, Woo JK, Kwon SJ, Lee HJ, Johnson FM, et al: Essential role of insulin-like growth factor 2 in resistance to histone deacetylase inhibitors. Oncogene. 35:5515–5526. 2016. View Article : Google Scholar : PubMed/NCBI
48	Min HY, Lee SC, Woo JK, Jung HJ, Park KH, Jeong HM, Hyun SY, Cho J, Lee W, Park JE, et al: Essential role of DNA methyltransferase 1-mediated transcription of insulin-like growth factor 2 in resistance to histone deacetylase inhibitors. Clin Cancer Res. 23:1299–1311. 2017. View Article : Google Scholar
49	Ceccacci E and Minucci S: Inhibition of histone deacetylases in cancer therapy: Lessons from leukaemia. Br J Cancer. 114:605–611. 2016. View Article : Google Scholar : PubMed/NCBI
50	Chen JB, Chern TR, Wei TT, Chen CC, Lin JH and Fang JM: Design and synthesis of dual-action inhibitors targeting histone deacetylases and 3-hydroxy-3-methylglutaryl coenzyme A reductase for cancer treatment. J Med Chem. 56:3645–3655. 2013. View Article : Google Scholar : PubMed/NCBI