BAY 87‑2243 sensitizes hepatocellular carcinoma Hep3B cells to histone deacetylase inhibitors treatment via GSK‑3β activation

Li,Yang‑Ling; Rao,Ming‑Jun; Zhang,Ning‑Yu; Wu,Lin‑Wen; Lin,Neng‑Ming; Zhang,Chong

doi:10.3892/etm.2019.7500

BAY 87‑2243 sensitizes hepatocellular carcinoma Hep3B cells to histone deacetylase inhibitors treatment via GSK‑3β activation

Authors:
- Yang‑Ling Li
- Ming‑Jun Rao
- Ning‑Yu Zhang
- Lin‑Wen Wu
- Neng‑Ming Lin
- Chong Zhang
View Affiliations

Affiliations: Department of Clinical Pharmacology, Hangzhou First People's Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, P.R. China, School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang 310015, P.R. China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China
Published online on: April 18, 2019 https://doi.org/10.3892/etm.2019.7500
Pages: 4547-4553
Copyright: © Li 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

Hepatocellular carcinoma (HCC) is associated with some of the highest cancer‑associated mortality rates. Histone deacetylase (HDAC) inhibitors anti‑HCC activities have been shown to promote Snail‑induced metastasis. In the present study, it was shown that BAY 87‑2243, a hypoxia‑inducible transcription factor‑1α inhibitor, could enhance the anti‑HCC effects of HDAC inhibitors, including trichostatin A and vorinostat. In addition, BAY 87‑2243 plus HDAC inhibitors exhibited synergistic cytotoxicity and induced significant cell death in Hep3B cells. Additionally, BAY 87‑2243 combined with HDAC inhibitors‑treated Hep3B cells formed fewer and smaller colonies as compared with either the control or single agent‑treated cells. Furthermore, glycogen synthase kinase‑3β might be involved in the enhanced cell death induced by BAY 87‑2243 plus HDAC inhibitors. The present data also indicated that BAY 87‑2243 combined with HDAC inhibitors could suppress the migration of Hep3B cells, and BAY 87‑2243 could reverse the HDAC inhibitor‑induced Snail activation in Hep3B cells. In conclusion, BAY 87‑2243 combined with HDAC inhibitors might be an attractive chemotherapy strategy for HCC therapy.

View Figures

View References

1	Geng Y, Michowski W, Chick JM, Wang YE, Jecrois ME, Sweeney KE, Liu L, Han RC, Ke N, Zagozdzon A, et al: Kinase-independent function of E-type cyclins in liver cancer. Proc Natl Acad Sci USA. 115:1015–1020. 2018. View Article : Google Scholar : PubMed/NCBI
2	Fu M, Shi W, Li Z and Liu H: Activation of mPTP-dependent mitochondrial apoptosis pathway by a novel pan HDAC inhibitor resminostat in hepatocellular carcinoma cells. Biochem Biophys Res Commun. 477:527–533. 2016. View Article : Google Scholar : PubMed/NCBI
3	Yang J, Jin X, Yan Y, Shao Y, Pan Y, Roberts LR, Zhang J, Huang H and Jiang J: Inhibiting histone deacetylases suppresses glucose metabolism and hepatocellular carcinoma growth by restoring FBP1 expression. Sci Rep. 7:438642017. View Article : Google Scholar : PubMed/NCBI
4	Chen T, Gu C, Xue C, Yang T, Zhong Y, Liu S, Nie Y and Yang H: LncRNA-uc002mbe.2 interacting with hnRNPA2B1 Mediates AKT deactivation and p21 Up-regulation induced by trichostatin in liver cancer cells. Front Pharmacol. 8:6692017. View Article : Google Scholar : PubMed/NCBI
5	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
6	Zhang J and Zhong Q: Histone deacetylase inhibitors and cell death. Cell Mol Life Sci. 71:3885–3901. 2014. View Article : Google Scholar : PubMed/NCBI
7	Yuan H, Li AJ, Ma SL, Cui LJ, Wu B, Yin L and Wu MC: Inhibition of autophagy signi fi cantly enhances combination therapy with sorafenib and HDAC inhibitors for human hepatoma cells. World J Gastroenterol. 20:4953–4962. 2014. View Article : Google Scholar : PubMed/NCBI
8	Yoon CY, Park MJ, Lee JS, Lee SC, Oh JJ, Park H, Chung CW, Abdullajanov MM, Jeong SJ, Hong SK, et al: The histone deacetylase inhibitor trichostatin A synergistically resensitizes a cisplatin resistant human bladder cancer cell line. J Urol. 185:1102–1111. 2011. View Article : Google Scholar : PubMed/NCBI
9	Li YL, Zhang NY, Hu X, Chen JL, Rao MJ, Wu LW, Li QY, Zhang B, Yan W and Zhang C: Evodiamine induces apoptosis and promotes hepatocellular carcinoma cell death induced by vorinostat via downregulating HIF-1α under hypoxia. Biochem Biophys Res Commun. 498:481–486. 2018. View Article : Google Scholar : PubMed/NCBI
10	Huang GW, Yang LY and Lu WQ: Expression of hypoxia-inducible factor 1alpha and vascular endothelial growth factor in hepatocellular carcinoma: Impact on neovascularization and survival. World J Gastroenterol. 11:1705–1708. 2005. View Article : Google Scholar : PubMed/NCBI
11	Ellinghaus P, Heisler I, Unterschemmann K, Haerter M, Beck H, Greschat S, Ehrmann A, Summer H, Flamme I, Oehme F, et al: BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I. Cancer Med. 2:611–624. 2013.PubMed/NCBI
12	Schöckel L, Glasauer A, Basit F, Bitschar K, Truong H, Erdmann G, Algire C, Hägebarth A, Willems PH, Kopitz C, et al: Targeting mitochondrial complex I using BAY 87-2243 reduces melanoma tumor growth. Cancer Metab. 3:112015. View Article : Google Scholar : PubMed/NCBI
13	Basit F, van Oppen LM, Schöckel L, Bossenbroek HM, van Emst-de Vries SE, Hermeling JC, Grefte S, Kopitz C, Heroult M, Hgm Willems P and Koopman WJ: Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells. Cell Death Dis. 8:e27162017. View Article : Google Scholar : PubMed/NCBI
14	Helbig L, Koi L, Brüchner K, Gurtner K, Hess-Stumpp H, Unterschemmann K, Baumann M, Zips D and Yaromina A: BAY 87-2243, a novel inhibitor of hypoxia-induced gene activation, improves local tumor control after fractionated irradiation in a schedule-dependent manner in head and neck human xenografts. Radiat Oncol. 9:2072014. View Article : Google Scholar : PubMed/NCBI
15	Häcker G: The morphology of apoptosis. Cell Tissue Res. 301:5–17. 2000. View Article : Google Scholar : PubMed/NCBI
16	Lan Y, Han J, Wang Y, Wang J, Yang G, Li K, Song R, Zheng T, Liang Y, Pan S, et al: STK17B promotes carcinogenesis and metastasis via AKT/GSK-3β/Snail signaling in hepatocellular carcinoma. Cell Death Dis. 9:2362018. View Article : Google Scholar : PubMed/NCBI
17	Liu L, Dai Y, Chen J, Zeng T, Li Y, Chen L, Zhu YH, Li J, Li Y, Ma S, et al: Maelstrom promotes hepatocellular carcinoma metastasis by inducing epithelial-mesenchymal transition by way of Akt/GSK-3β/Snail signaling. Hepatology. 59:531–543. 2014. View Article : Google Scholar : PubMed/NCBI
18	Peinado H, Portillo F and Cano A: Switching on-off Snail: LOXL2 versus GSK3beta. Cell Cycle. 4:1749–1752. 2005. View Article : Google Scholar : PubMed/NCBI
19	Cassim S, Raymond VA, Dehbidi-Assadzadeh L, Lapierre P and Bilodeau M: Metabolic reprogramming enables hepatocarcinoma cells to efficiently adapt and survive to a nutrient-restricted microenvironment. Cell Cycle. 17:903–916. 2018. View Article : Google Scholar : PubMed/NCBI
20	Amann T, Maegdefrau U, Hartmann A, Agaimy A, Marienhagen J, Weiss TS, Stoeltzing O, Warnecke C, Schölmerich J, Oefner PJ, et al: GLUT1 expression is increased in hepatocellular carcinoma and promotes tumorigenesis. Am J Pathol. 174:1544–1552. 2009. View Article : Google Scholar : PubMed/NCBI
21	Kitajima Y and Miyazaki K: The critical impact of HIF-1a on gastric cancer biology. Cancers (Basel). 5:15–26. 2013. View Article : Google Scholar : PubMed/NCBI
22	Hall JL, Chatham JC, Eldar-Finkelman H and Gibbons GH: Upregulation of glucose metabolism during intimal lesion formation is coupled to the inhibition of vascular smooth muscle cell apoptosis. Role of GSK3beta. Diabetes. 50:1171–1179. 2001. View Article : Google Scholar : PubMed/NCBI
23	Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M and Hung MC: Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol. 6:931–940. 2004. View Article : Google Scholar : PubMed/NCBI
24	Liu KY, Wang LT and Hsu SH: Modification of epigenetic histone acetylation in hepatocellular carcinoma. Cancers (Basel). 10(pii): E82018. View Article : Google Scholar : PubMed/NCBI
25	Lin KT, Wang YW, Chen CT, Ho CM, Su WH and Jou YS: HDAC inhibitors augmented cell migration and metastasis through induction of PKCs leading to identification of low toxicity modalities for combination cancer therapy. Clin Cancer Res. 18:4691–4701. 2012. View Article : Google Scholar : PubMed/NCBI
26	Xu W, Liu H, Liu ZG, Wang HS, Zhang F, Wang H, Zhang J, Chen JJ, Huang HJ, Tan Y, et al: Histone deacetylase inhibitors upregulate Snail via Smad2/3 phosphorylation and stabilization of Snail to promote metastasis of hepatoma cells. Cancer Lett. 420:1–13. 2018. View Article : Google Scholar : PubMed/NCBI