Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Oncology Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1021-335X Online ISSN: 1791-2431
Journal Cover
October-2018 Volume 40 Issue 4

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
October-2018 Volume 40 Issue 4

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

Inhibition of cFLIP overcomes acquired resistance to sorafenib via reducing ER stress‑related autophagy in hepatocellular carcinoma

  • Authors:
    • Dong Liu
    • Yifu Fan
    • Jun Li
    • Binbin Cheng
    • Wanfu Lin
    • Xiaoyan Li
    • Juan Du
    • Changquan Ling
  • View Affiliations / Copyright

    Affiliations: Department of Chinese Medicine, Changhai Hospital, The Second Military Medical University, Shanghai 200433, P.R. China, Department of Chinese Medicine, Changhai Hospital, The Second Military Medical University, Shanghai 200433, P.R. China, Department of Chinese Medicine, Lanzhou General Hospital, Lanzhou, Gansu 730050, P.R. China
  • Pages: 2206-2214
    |
    Published online on: July 27, 2018
       https://doi.org/10.3892/or.2018.6606
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Treatment with sorafenib remains the first‑line therapy for patients with advanced stage hepatocellular carcinoma (HCC), however, it has limited effect due to the acquired resistance of HCC. Elucidating the potential mechanism can assist in developing promising strategies to overcome this resistance. In the present study, a sorafenib‑refractory HCC cell was established from the Huh7 parental cell line, which was resistant to sorafenib mediated‑cytotoxicity in vitro. The cell inhibition rate and apoptosis of cells were determined by MTT assay and flow cytometry, respectively. Electronic microscopy was used to detect autophagy in cells. The expression levels of endoplasmic reticulum stress (ERS)‑related protein, apoptosis‑related protein and cFLIP were examined by western blot analysis. Co‑immunoprecipitation was used to examine the ubiquitination of cFLIP. It was found that sustained exposure to sorafenib activated ERS in the HCC cells. The ERS inhibitor partly increased sorafenib‑induced cell death in these cells. In addition, ERS‑induced autophagy was important in resistance to sorafenib, as inhibiting autophagy led to the resistant HCC cells becoming more sensitive to sorafenib. However, ERS‑induced apoptosis did not differ between sorafenib‑sensitive HCC cells and sorafenib‑refractory HCC cells. The knockdown of cFLIP reversed the acquired sorafenib resistance by activating caspase‑8 and inhibiting activated ERS in the sorafenib‑resistant HCC cells. Mechanistically, a sustained increased in cFLIP was found to be dependent on USP2‑induced deubiquitination. In conclusion, cFLIP was identified as a potential target for overcoming the acquired sorafenib resistance in HCC. These effects occurred partially through reducing ERS‑related autophagy in HCC.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

View References

1 

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI

2 

Zhu AX: Systemic treatment of hepatocellular carcinoma: Dawn of a new era? Ann Surg Oncol. 17:1247–1256. 2010. View Article : Google Scholar : PubMed/NCBI

3 

Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, De Oliveira AC, Santoro A, Raoul JL, Forner A, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 359:378–390. 2008. View Article : Google Scholar : PubMed/NCBI

4 

Zhai B and Sun XY: Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma. World J Hepatol. 5:345–352. 2013. View Article : Google Scholar : PubMed/NCBI

5 

Hennessy BT, Smith DL, Ram PT, Lu Y and Mills GB: Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 4:988–1004. 2005. View Article : Google Scholar : PubMed/NCBI

6 

Micheau O: Cellular FLICE-inhibitory protein: An attractive therapeutic target? Expert Opin Ther Targets. 7:559–573. 2003. View Article : Google Scholar : PubMed/NCBI

7 

Poukkula M, Kaunisto A, Denessiouk K, Katajamäki T, Johnson MS, Sistonen L and Eriksson JE: Rapid turnover of c-FLIPshort is determined by its unique C-terminal tail. J Biol Chem. 280:27345–27355. 2005. View Article : Google Scholar : PubMed/NCBI

8 

Ueffing N, Singh KK, Christians A, Thorns C, Feller AC, Nagl F, Fend F, Heikaus S, Marx A, Zotz RB, et al: A single nucleotide polymorphism determines protein isoform production of the human c-FLIP protein. Blood. 114:572–579. 2009. View Article : Google Scholar : PubMed/NCBI

9 

Chaudhary PM, Eby MT, Jasmin A, Kumar A, Liu L and Hood L: Activation of the NF-kappaB pathway by caspase 8 and its homologs. Oncogene. 19:4451–4460. 2000. View Article : Google Scholar : PubMed/NCBI

10 

Iyer AK, Azad N, Talbot S, Stehlik C, Lu B, Wang L and Rojanasakul Y: Antioxidant c-FLIP inhibits Fas ligand-induced NF-kappaB activation in a phosphatidylinositol 3-kinase/Akt-dependent manner. J Immunol. 187:3256–3266. 2011. View Article : Google Scholar : PubMed/NCBI

11 

Quintavalle C, Incoronato M, Puca L, Zanca C, Romano G, Garofalo M, Iaboni M, Croce CM and Condorelli G: c-FLIPL enhances anti-apoptotic Akt functions by modulation of Gsk3beta activity. Cell Death Differ. 24:11342017. View Article : Google Scholar : PubMed/NCBI

12 

Ding WX and Yin XM: Sorting, recognition and activation of the misfolded protein degradation pathways through macroautophagy and the proteasome. Autophagy. 4:141–150. 2008. View Article : Google Scholar : PubMed/NCBI

13 

Fujita E, Kouroku Y, Isoai A, Kumagai H, Misutani A, Matsuda C, Hayashi YK and Momoi T: Two endoplasmic reticulum-associated degradation (ERAD) systems for the novel variant of the mutant dysferlin: Ubiquitin/proteasome ERAD(I) and autophagy/lysosome ERAD(II). Hum Mol Genet. 16:618–629. 2007. View Article : Google Scholar : PubMed/NCBI

14 

Shi YH, Ding ZB, Zhou J, Hui B, Shi GM, Ke AW, Wang XY, Dai Z, Peng YF, Gu CY, et al: Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis. Autophagy. 7:1159–1172. 2011. View Article : Google Scholar : PubMed/NCBI

15 

Zhai B, Hu F, Jiang X, Zhao D, Liu B, Pan S, Dong X, Tan G and Wei Z: Inhibition of Akt reverses the acquired resistance to sorafenib by switching protective autophagy to autophagic cell death in hepatocellular carcinoma. Mol Cancer Ther. 13:1589–1598. 2014. View Article : Google Scholar : PubMed/NCBI

16 

Du J, Wu J, Fu X, Tse AK, Li T, Su T and Yu ZL: Icariside II overcomes TRAIL resistance of melanoma cells through ROS-mediated downregulation of STAT3/cFLIP signaling. Oncotarget. 7:52218–52229. 2016. View Article : Google Scholar : PubMed/NCBI

17 

Salim K, Fenton T, Bacha J, Urien-Rodriguez H, Bonnert T, Skynner HA, Watts E, Kerby J, Heald A, Beer M, et al: Oligomerization of G-protein-coupled receptors shown by selective co-immunoprecipitation. J Biol Chem. 277:15482–15485. 2002. View Article : Google Scholar : PubMed/NCBI

18 

Krammer PH: CD95's deadly mission in the immune system. Nature. 407:789–795. 2000. View Article : Google Scholar : PubMed/NCBI

19 

Ciechanover A and Schwartz AL: The ubiquitin system: Pathogenesis of human diseases and drug targeting. Biochim Biophys Acta. 1695:3–17. 2004. View Article : Google Scholar : PubMed/NCBI

20 

Haimerl F, Erhardt A, Sass G and Tiegs G: Down-regulation of the de-ubiquitinating enzyme ubiquitin-specific protease 2 contributes to tumor necrosis factor-alpha-induced hepatocyte survival. J Biol Chem. 284:495–504. 2009. View Article : Google Scholar : PubMed/NCBI

21 

Berasain C: Hepatocellular carcinoma and sorafenib: Too many resistance mechanisms? Gut. 62:1674–1675. 2013. View Article : Google Scholar : PubMed/NCBI

22 

Jiang CC, Yang F, Thorne RF, Zhu BK, Hersey P and Zhang XD: Human melanoma cells under endoplasmic reticulum stress acquire resistance to microtubule-targeting drugs through XBP-1-mediated activation of Akt. Neoplasia. 11:436–447. 2009. View Article : Google Scholar : PubMed/NCBI

23 

Fan L, Sun G, Ma T, Zhong F, Lei Y, Li X and Wei W: Melatonin reverses tunicamycin-induced endoplasmic reticulum stress in human hepatocellular carcinoma cells and improves cytotoxic response to doxorubicin by increasing CHOP and decreasing survivin. J Pineal Res. 55:184–194. 2013. View Article : Google Scholar : PubMed/NCBI

24 

Fan L, Song B, Sun G, Ma T, Zhong F and Wei W: Endoplasmic reticulum stress-induced resistance to doxorubicin is reversed by paeonol treatment in human hepatocellular carcinoma cells. PloS One. 8:e626272013. View Article : Google Scholar : PubMed/NCBI

25 

Kato H and Nishitoh H: Stress responses from the endoplasmic reticulum in cancer. Front Oncol. 5:932015. View Article : Google Scholar : PubMed/NCBI

26 

Hu F, Han J, Zhai B, Ming X, Zhuang L, Liu Y, Pan S and Liu T: Blocking autophagy enhances the apoptosis effect of bufalin on human hepatocellular carcinoma cells through endoplasmic reticulum stress and JNK activation. Apoptosis. 19:210–223. 2014. View Article : Google Scholar : PubMed/NCBI

27 

Wang WA, Groenendyk J and Michalak M: Endoplasmic reticulum stress associated responses in cancer. Biochim Biophys Acta. 1843:2143–2149. 2014. View Article : Google Scholar : PubMed/NCBI

28 

Micheau O, Lens S, Gaide O, Alevizopoulos K and Tschopp J: NF-kappaB signals induce the expression of c-FLIP. Mol Cell Biol. 21:5299–5305. 2001. View Article : Google Scholar : PubMed/NCBI

29 

Song JH, Tse MC, Bellail A, Phuphanich S, Khuri F, Kneteman NM and Hao C: Lipid rafts and nonrafts mediate tumor necrosis factor related apoptosis-inducing ligand induced apoptotic and nonapoptotic signals in non small cell lung carcinoma cells. Cancer Res. 67:6946–6955. 2007. View Article : Google Scholar : PubMed/NCBI

30 

Chang L, Kamata H, Solinas G, Luo JL, Maeda S, Venuprasad K, Liu YC and Karin M: The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover. Cell. 124:601–613. 2006. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Liu D, Fan Y, Li J, Cheng B, Lin W, Li X, Du J and Ling C: Inhibition of cFLIP overcomes acquired resistance to sorafenib via reducing ER stress‑related autophagy in hepatocellular carcinoma . Oncol Rep 40: 2206-2214, 2018.
APA
Liu, D., Fan, Y., Li, J., Cheng, B., Lin, W., Li, X. ... Ling, C. (2018). Inhibition of cFLIP overcomes acquired resistance to sorafenib via reducing ER stress‑related autophagy in hepatocellular carcinoma . Oncology Reports, 40, 2206-2214. https://doi.org/10.3892/or.2018.6606
MLA
Liu, D., Fan, Y., Li, J., Cheng, B., Lin, W., Li, X., Du, J., Ling, C."Inhibition of cFLIP overcomes acquired resistance to sorafenib via reducing ER stress‑related autophagy in hepatocellular carcinoma ". Oncology Reports 40.4 (2018): 2206-2214.
Chicago
Liu, D., Fan, Y., Li, J., Cheng, B., Lin, W., Li, X., Du, J., Ling, C."Inhibition of cFLIP overcomes acquired resistance to sorafenib via reducing ER stress‑related autophagy in hepatocellular carcinoma ". Oncology Reports 40, no. 4 (2018): 2206-2214. https://doi.org/10.3892/or.2018.6606
Copy and paste a formatted citation
x
Spandidos Publications style
Liu D, Fan Y, Li J, Cheng B, Lin W, Li X, Du J and Ling C: Inhibition of cFLIP overcomes acquired resistance to sorafenib via reducing ER stress‑related autophagy in hepatocellular carcinoma . Oncol Rep 40: 2206-2214, 2018.
APA
Liu, D., Fan, Y., Li, J., Cheng, B., Lin, W., Li, X. ... Ling, C. (2018). Inhibition of cFLIP overcomes acquired resistance to sorafenib via reducing ER stress‑related autophagy in hepatocellular carcinoma . Oncology Reports, 40, 2206-2214. https://doi.org/10.3892/or.2018.6606
MLA
Liu, D., Fan, Y., Li, J., Cheng, B., Lin, W., Li, X., Du, J., Ling, C."Inhibition of cFLIP overcomes acquired resistance to sorafenib via reducing ER stress‑related autophagy in hepatocellular carcinoma ". Oncology Reports 40.4 (2018): 2206-2214.
Chicago
Liu, D., Fan, Y., Li, J., Cheng, B., Lin, W., Li, X., Du, J., Ling, C."Inhibition of cFLIP overcomes acquired resistance to sorafenib via reducing ER stress‑related autophagy in hepatocellular carcinoma ". Oncology Reports 40, no. 4 (2018): 2206-2214. https://doi.org/10.3892/or.2018.6606
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team