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Article

Regorafenib induces extrinsic and intrinsic apoptosis through inhibition of ERK/NF-κB activation in hepatocellular carcinoma cells

  • Authors:
    • Jai-Jen Tsai
    • Po-Jung Pan
    • Fei-Ting Hsu
  • View Affiliations / Copyright

    Affiliations: Division of Gastroenterology, Department of Medicine, National Yang-Ming University Hospital, Yilan 260, Taiwan, R.O.C., Cancer Medical Care Center, National Yang‑Ming University Hospital, Yilan 260, Taiwan, R.O.C., Department of Medical Imaging, Taipei Medical University Hospital, Taipei 110, Taiwan, R.O.C.
  • Pages: 1036-1044
    |
    Published online on: December 20, 2016
       https://doi.org/10.3892/or.2016.5328
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Abstract

The aim of the present study was to investigate the role of NF-κB inactivation in regorafenib-induced apoptosis in human hepatocellular carcinoma SK-HEP-1 cells. SK-HEP-1 cells were treated with different concentrations of the NF-κB inhibitor 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine (QNZ) or regorafenib for different periods. The effects of QNZ and regorafenib on cell viability, expression of NF-κB-modulated anti-apoptotic proteins and apoptotic pathways were analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, western blotting, DNA gel electrophoresis, flow cytometry and NF-κB reporter gene assay. Inhibitors of various kinases including AKT, c-Jun N-terminal kinase (JNK), P38 and extracellular signal-regulated kinase (ERK) were used to evaluate the mechanism of regorafenib-induced NF-κB inactivation. The results demonstrated that both QNZ and regorafenib significantly inhibited the expression of anti-apoptotic proteins and triggered extrinsic and intrinsic apoptosis. We also demonstrated that regorafenib inhibited NF-κB activation through ERK dephosphorylation. Taken all together, our findings indicate that regorafenib triggers extrinsic and intrinsic apoptosis through suppression of ERK/NF-κB activation in SK-HEP-1 cells.
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1 

Hassan M, Watari H, AbuAlmaaty A, Ohba Y and Sakuragi N: Apoptosis and molecular targeting therapy in cancer. Biomed Res Int. 2014:1508452014. View Article : Google Scholar : PubMed/NCBI

2 

Fulda S and Debatin KM: Apoptosis signaling in tumor therapy. Ann NY Acad Sci. 1028:150–156. 2004. View Article : Google Scholar : PubMed/NCBI

3 

Verheij M and Bartelink H: Radiation-induced apoptosis. Cell Tissue Res. 301:133–142. 2000. View Article : Google Scholar : PubMed/NCBI

4 

Pommier Y, Sordet O, Antony S, Hayward RL and Kohn KW: Apoptosis defects and chemotherapy resistance: Molecular interaction maps and networks. Oncogene. 23:2934–2949. 2004. View Article : Google Scholar : PubMed/NCBI

5 

Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, et al: Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: A phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 10:25–34. 2009. View Article : Google Scholar : PubMed/NCBI

6 

Du X, Bao G, He X, Zhao H, Yu F, Qiao Q, Lu J and Ma Q: Expression and biological significance of c-FLIP in human hepatocellular carcinomas. J Exp Clin Cancer Res. 28:24–31. 2009. View Article : Google Scholar : PubMed/NCBI

7 

Fleischer B, Schulze-Bergkamen H, Schuchmann M, Weber A, Biesterfeld S, Müller M, Krammer PH and Galle PR: Mcl-1 is an anti-apoptotic factor for human hepatocellular carcinoma. Int J Oncol. 28:25–32. 2006.PubMed/NCBI

8 

Augello C, Caruso L, Maggioni M, Donadon M, Montorsi M, Santambrogio R, Torzilli G, Vaira V, Pellegrini C, Roncalli M, et al: Inhibitors of apoptosis proteins (IAPs) expression and their prognostic significance in hepatocellular carcinoma. BMC Cancer. 9:125–134. 2009. View Article : Google Scholar : PubMed/NCBI

9 

Chen JH, Chen WL and Liu YC: Amentoflavone induces anti-angiogenic and anti-metastatic effects through suppression of NF-κB activation in MCF-7 cells. Anticancer Res. 35:6685–6693. 2015.PubMed/NCBI

10 

Baud V and Karin M: Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov. 8:33–40. 2009. View Article : Google Scholar : PubMed/NCBI

11 

Hsu FT, Liu YC, Chiang IT, Liu RS, Wang HE, Lin WJ and Hwang JJ: Sorafenib increases efficacy of vorinostat against human hepatocellular carcinoma through transduction inhibition of vorinostat-induced ERK/NF-κB signaling. Int J Oncol. 45:177–188. 2014.PubMed/NCBI

12 

Hsu FT, Liu YC, Liu TT and Hwang JJ: Curcumin sensitizes hepatocellular carcinoma cells to radiation via suppression of radiation-induced NF-κB activity. Biomed Res Int. 2015:3636712015. View Article : Google Scholar : PubMed/NCBI

13 

Jin Y, Chen J, Feng Z, Fan W, Wang Y, Li J and Tong D: The expression of Survivin and NF-κB associated with prognostically worse clinicopathologic variables in hepatocellular carcinoma. Tumour Biol. 35:9905–9910. 2014. View Article : Google Scholar : PubMed/NCBI

14 

Ravi S and Singal AK: Regorafenib: An evidence-based review of its potential in patients with advanced liver cancer. Core Evid. 9:81–87. 2014.PubMed/NCBI

15 

Tai WT, Chu PY, Shiau CW, Chen YL, Li YS, Hung MH, Chen LJ, Chen PL, Su JC, Lin PY, et al: STAT3 mediates regorafenib-induced apoptosis in hepatocellular carcinoma. Clin Cancer Res. 20:5768–5776. 2014. View Article : Google Scholar : PubMed/NCBI

16 

Ma CY, Ji WT, Chueh FS, Yang JS, Chen PY, Yu CC and Chung JG: Butein inhibits the migration and invasion of SK-HEP-1 human hepatocarcinoma cells through suppressing the ERK, JNK, p38, and uPA signaling multiple pathways. J Agric Food Chem. 59:9032–9038. 2011. View Article : Google Scholar : PubMed/NCBI

17 

Chiang IT, Liu YC, Wang WH, Hsu FT, Chen HW, Lin WJ, Chang WY and Hwang JJ: Sorafenib inhibits TPA-induced MMP-9 and VEGF expression via suppression of ERK/NF-κB pathway in hepatocellular carcinoma cells. In Vivo. 26:671–681. 2012.PubMed/NCBI

18 

Wang WH, Chiang IT, Ding K, Chung JG, Lin WJ, Lin SS and Hwang JJ: Curcumin-induced apoptosis in human hepatocellular carcinoma j5 cells: Critical role of Ca+2-dependent pathway. Evid Based Complement Alternat Med. 2012:5129072012. View Article : Google Scholar : PubMed/NCBI

19 

Huang SH, Wu LW, Huang AC, Yu CC, Lien JC, Huang YP, Yang JS, Yang JH, Hsiao YP, Wood WG, et al: Benzyl isothiocyanate (BITC) induces G2/M phase arrest and apoptosis in human melanoma A375.S2 cells through reactive oxygen species (ROS) and both mitochondria-dependent and death receptor-mediated multiple signaling pathways. J Agric Food Chem. 60:665–675. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Ting CY, Wang HE, Yu CC, Liu HC, Liu YC and Chiang IT: Curcumin triggers DNA damage and inhibits expression of DNA repair proteins in human lung cancer cells. Anticancer Res. 35:3867–3873. 2015.PubMed/NCBI

21 

Liu H, Yang J, Yuan Y, Xia Z, Chen M, Xie L, Ma X, Wang J, Ouyang S, Wu Q, et al: Regulation of Mcl-1 by constitutive activation of NF-κB contributes to cell viability in human esophageal squamous cell carcinoma cells. BMC Cancer. 14:98–110. 2014. View Article : Google Scholar : PubMed/NCBI

22 

Scott FL, Denault JB, Riedl SJ, Shin H, Renatus M and Salvesen GS: XIAP inhibits caspase-3 and −7 using two binding sites: Evolutionarily conserved mechanism of IAPs. EMBO J. 24:645–655. 2005. View Article : Google Scholar : PubMed/NCBI

23 

Elmore S: Apoptosis: A review of programmed cell death. Toxicol Pathol. 35:495–516. 2007. View Article : Google Scholar : PubMed/NCBI

24 

Perciavalle RM and Opferman JT: Delving deeper: MCL-1's contributions to normal and cancer biology. Trends Cell Biol. 23:22–29. 2013. View Article : Google Scholar : PubMed/NCBI

25 

Morciano G, Giorgi C, Balestra D, Marchi S, Perrone D, Pinotti M and Pinton P: Mcl-1 involvement in mitochondrial dynamics is associated with apoptotic cell death. Mol Biol Cell. 27:20–34. 2016. View Article : Google Scholar : PubMed/NCBI

26 

Chen D, Wei L, Yu J and Zhang L: Regorafenib inhibits colorectal tumor growth through PUMA-mediated apoptosis. Clin Cancer Res. 20:3472–3484. 2014. View Article : Google Scholar : PubMed/NCBI

27 

Schmitz KJ, Wohlschlaeger J, Lang H, Sotiropoulos GC, Malago M, Steveling K, Reis H, Cicinnati VR, Schmid KW and Baba HA: Activation of the ERK and AKT signalling pathway predicts poor prognosis in hepatocellular carcinoma and ERK activation in cancer tissue is associated with hepatitis C virus infection. J Hepatol. 48:83–90. 2008. View Article : Google Scholar : PubMed/NCBI

28 

Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M and Carter C: Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 66:11851–11858. 2006. View Article : Google Scholar : PubMed/NCBI

29 

Cheng JC, Chou CH, Kuo ML and Hsieh CY: Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-kappaB signal transduction pathway. Oncogene. 25:7009–7018. 2006. View Article : Google Scholar : PubMed/NCBI

30 

Woo MS, Jung SH, Kim SY, Hyun JW, Ko KH, Kim WK and Kim HS: Curcumin suppresses phorbol ester-induced matrix metalloproteinase-9 expression by inhibiting the PKC to MAPK signaling pathways in human astroglioma cells. Biochem Biophys Res Commun. 335:1017–1025. 2005. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Tsai J, Pan P and Hsu F: Regorafenib induces extrinsic and intrinsic apoptosis through inhibition of ERK/NF-κB activation in hepatocellular carcinoma cells. Oncol Rep 37: 1036-1044, 2017.
APA
Tsai, J., Pan, P., & Hsu, F. (2017). Regorafenib induces extrinsic and intrinsic apoptosis through inhibition of ERK/NF-κB activation in hepatocellular carcinoma cells. Oncology Reports, 37, 1036-1044. https://doi.org/10.3892/or.2016.5328
MLA
Tsai, J., Pan, P., Hsu, F."Regorafenib induces extrinsic and intrinsic apoptosis through inhibition of ERK/NF-κB activation in hepatocellular carcinoma cells". Oncology Reports 37.2 (2017): 1036-1044.
Chicago
Tsai, J., Pan, P., Hsu, F."Regorafenib induces extrinsic and intrinsic apoptosis through inhibition of ERK/NF-κB activation in hepatocellular carcinoma cells". Oncology Reports 37, no. 2 (2017): 1036-1044. https://doi.org/10.3892/or.2016.5328
Copy and paste a formatted citation
x
Spandidos Publications style
Tsai J, Pan P and Hsu F: Regorafenib induces extrinsic and intrinsic apoptosis through inhibition of ERK/NF-κB activation in hepatocellular carcinoma cells. Oncol Rep 37: 1036-1044, 2017.
APA
Tsai, J., Pan, P., & Hsu, F. (2017). Regorafenib induces extrinsic and intrinsic apoptosis through inhibition of ERK/NF-κB activation in hepatocellular carcinoma cells. Oncology Reports, 37, 1036-1044. https://doi.org/10.3892/or.2016.5328
MLA
Tsai, J., Pan, P., Hsu, F."Regorafenib induces extrinsic and intrinsic apoptosis through inhibition of ERK/NF-κB activation in hepatocellular carcinoma cells". Oncology Reports 37.2 (2017): 1036-1044.
Chicago
Tsai, J., Pan, P., Hsu, F."Regorafenib induces extrinsic and intrinsic apoptosis through inhibition of ERK/NF-κB activation in hepatocellular carcinoma cells". Oncology Reports 37, no. 2 (2017): 1036-1044. https://doi.org/10.3892/or.2016.5328
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