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
June-2015 Volume 33 Issue 6

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
June-2015 Volume 33 Issue 6

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

RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1/XBP1 axis

  • Authors:
    • Ti Zhou
    • Xing Lv
    • Xin Guo
    • Bai Ruan
    • Dong Liu
    • Rui Ding
    • Yuan Gao
    • Jie Ding
    • Kefeng Dou
    • Yong Chen
  • View Affiliations / Copyright

    Affiliations: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China, Department of Pharmacy, Xi'an Central Hospital, Xi'an, Shaanxi 710032, P.R. China
  • Pages: 3006-3014
    |
    Published online on: April 21, 2015
       https://doi.org/10.3892/or.2015.3920
  • 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

Sorafenib is one of the preferred drugs for the treatment of advanced primary hepatocellular carcinoma (HCC). However, its side-effects and acquired resistance limit its use. The unfolded protein response (UPR) induced by chemotherapeutics has been demonstrated to be required for tumor cells to maintain malignancy and therapy resistance. Activation of the IRE1/XBP1 pathway during the UPR is important for tumor survival under pathophysiological conditions. In the present study, we found that the UPR was activated and RACK1 was overexpressed in three human HCC cell lines and in HCC samples. Activation of the IRE1/XBP1 signaling pathway plays a protective role when HCC cells encounter endoplasmic reticulum (ER) stress due to in vitro sorafenib treatment. We then found that the interaction between IRE1 and RACK1 was essential for the activation of IRE1 signaling in sorafenib-treated cells. Exogenous overexpression of RACK1 enhanced the phosphorylation level of IRE1 and increased XBP1 mRNA splicing activity, which protected the HCC cells from sorafenib-induced apoptosis. However, the re-expression of RACK1 led HCC cells to regain susceptibility to sorafenib-induced apoptosis. Taken together, the present study suggests that the RACK1/IRE1 complex may contribute to activation of the UPR in HCC cells. Targeting RACK1 in combination with sorafenib administration is a potential strategy for clinical trials of advanced HCC treatment.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

View References

1 

Ferlay J; ISME: GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. http://globocan.iarc.fr/Default.aspx. IARC CancerBase; 2013

2 

Flores A and Marrero JA: Emerging trends in hepatocellular carcinoma: Focus on diagnosis and therapeutics. Clin Med Insights Oncol. 8:71–76. 2014.PubMed/NCBI

3 

Peck-Radosavljevic M: Drug therapy for advanced-stage liver cancer. Liver Cancer. 3:125–131. 2014. View Article : Google Scholar : PubMed/NCBI

4 

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

5 

Gauthier A and Ho M: Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update. Hepatol Res. 43:147–154. 2013. View Article : Google Scholar :

6 

Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, et al: BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 64:7099–7109. 2004. View Article : Google Scholar : PubMed/NCBI

7 

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

8 

Rahmani M, Davis EM, Bauer C, Dent P and Grant S: Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation. J Biol Chem. 280:35217–35227. 2005. View Article : Google Scholar : PubMed/NCBI

9 

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

10 

Li X, Zhang K and Li Z: Unfolded protein response in cancer: The physician’s perspective. J Hematol Oncol. 4:82011. View Article : Google Scholar

11 

Vandewynckel YP, Laukens D, Geerts A, Bogaerts E, Paridaens A, Verhelst X, Janssens S, Heindryckx F and Van Vlierberghe H: The paradox of the unfolded protein response in cancer. Anticancer Res. 33:4683–4694. 2013.PubMed/NCBI

12 

Zhang XD, Hersey P, Tay KH, Tseng H, Jiang CC and Dong L: Adaptation to ER stress as a mechanism of resistance of melanoma to treatment. Current Management of Malignant Melanoma. Cao M: InTech, Rijeka; Croatia: 2011

13 

Suh DH, Kim MK, Kim HS, Chung HH and Song YS: Unfolded protein response to autophagy as a promising druggable target for anticancer therapy. Ann NY Acad Sci. 1271:20–32. 2012. View Article : Google Scholar : PubMed/NCBI

14 

Gardner BM and Walter P: Unfolded proteins are Ire1-activating ligands that directly induce the unfolded protein response. Science. 333:1891–1894. 2011. View Article : Google Scholar : PubMed/NCBI

15 

Schröder M and Kaufman RJ: ER stress and the unfolded protein response. Mutat Res. 569:29–63. 2005. View Article : Google Scholar

16 

Han D, Lerner AG, Vande Walle L, Upton JP, Xu W, Hagen A, Backes BJ, Oakes SA and Papa FR: IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell. 138:562–575. 2009. View Article : Google Scholar : PubMed/NCBI

17 

Hassler J, Cao SS and Kaufman RJ: IRE1, a double-edged sword in pre-miRNA slicing and cell death. Dev Cell. 23:921–923. 2012. View Article : Google Scholar : PubMed/NCBI

18 

Tirosh B, Iwakoshi NN, Glimcher LH and Ploegh HL: Rapid turnover of unspliced Xbp-1 as a factor that modulates the unfolded protein response. J Biol Chem. 281:5852–5860. 2006. View Article : Google Scholar

19 

Yoshida H, Matsui T, Yamamoto A, Okada T and Mori K: XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 107:881–891. 2001. View Article : Google Scholar

20 

Maurel M, Chevet E, Tavernier J and Gerlo S: Getting RIDD of RNA: IRE1 in cell fate regulation. Trends Biochem Sci. 39:245–254. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Chitnis N, Pytel D and Diehl JA: UPR-inducible miRNAs contribute to stressful situations. Trends Biochem Sci. 38:447–452. 2013. View Article : Google Scholar : PubMed/NCBI

22 

Lin JH, Li H, Yasumura D, Cohen HR, Zhang C, Panning B, Shokat KM, Lavail MM and Walter P: IRE1 signaling affects cell fate during the unfolded protein response. Science. 318:944–949. 2007. View Article : Google Scholar : PubMed/NCBI

23 

Ron D, Chen CH, Caldwell J, Jamieson L, Orr E and Mochly-Rosen D: Cloning of an intracellular receptor for protein kinase C: A homolog of the beta subunit of G proteins. Proc Natl Acad Sci USA. 91:839–843. 1994. View Article : Google Scholar : PubMed/NCBI

24 

Adams DR, Ron D and Kiely PA: RACK1, A multifaceted scaffolding protein: Structure and function. Cell Commun Signal. 9:222011. View Article : Google Scholar : PubMed/NCBI

25 

Ma J, Wu R, Zhang Q, Wu JB, Lou J, Zheng Z, Ding JQ and Yuan Z: DJ-1 interacts with RACK1 and protects neurons from oxidative-stress-induced apoptosis. Biochem J. 462:489–497. 2014. View Article : Google Scholar : PubMed/NCBI

26 

McCahill A, Warwicker J, Bolger GB, Houslay MD and Yarwood SJ: The RACK1 scaffold protein: A dynamic cog in cell response mechanisms. Mol Pharmacol. 62:1261–1273. 2002. View Article : Google Scholar : PubMed/NCBI

27 

Wu J, Meng J, Du Y, Huang Y, Jin Y, Zhang J, Wang B, Zhang Y, Sun M and Tang J: RACK1 promotes the proliferation, migration and invasion capacity of mouse hepatocellular carcinoma cell line in vitro probably by PI3K/Rac1 signaling pathway. Biomed Pharmacother. 67:313–319. 2013. View Article : Google Scholar : PubMed/NCBI

28 

Cao XX, Xu JD, Liu XL, Xu JW, Wang WJ, Li QQ, Chen Q, Xu ZD and Liu XP: RACK1: A superior independent predictor for poor clinical outcome in breast cancer. Int J Cancer. 127:1172–1179. 2010. View Article : Google Scholar

29 

Ruan Y, Sun L, Hao Y, Wang L, Xu J, Zhang W, Xie J, Guo L, Zhou L, Yun X, et al: Ribosomal RACK1 promotes chemoresistance and growth in human hepatocellular carcinoma. J Clin Invest. 122:2554–2566. 2012. View Article : Google Scholar : PubMed/NCBI

30 

Arimoto K, Fukuda H, Imajoh-Ohmi S, Saito H and Takekawa M: Formation of stress granules inhibits apoptosis by suppressing stress-responsive MAPK pathways. Nat Cell Biol. 10:1324–1332. 2008. View Article : Google Scholar : PubMed/NCBI

31 

Qiu Y, Mao T, Zhang Y, Shao M, You J, Ding Q, Chen Y, Wu D, Xie D, Lin X, et al: A crucial role for RACK1 in the regulation of glucose-stimulated IRE1alpha activation in pancreatic beta cells. Sci Signal. 3:ra72010. View Article : Google Scholar : PubMed/NCBI

32 

Liver Cancer Study Group of Japan: The General Rules for the Clinical and Pathological Study of Primary Liver Cancer. 2nd English edition. Kanehara & Co, Ltd; Tokyo: pp. 13–14. 2003

33 

Rojas R, Segovia C, Trombert AN, Santander J and Manque P: The effect of tunicamycin on the glucose uptake, growth, and cellular adhesion in the protozoan parasite Crithidia fasciculata. Curr Microbiol. 69:541–548. 2014. View Article : Google Scholar : PubMed/NCBI

34 

Chen Y and Brandizzi F: IRE1: ER stress sensor and cell fate executor. Trends Cell Biol. 23:547–555. 2013. View Article : Google Scholar : PubMed/NCBI

35 

Li X, Zhang K and Li Z: Unfolded protein response in cancer: The physician’s perspective. J Hematol Oncol. 4:82011. View Article : Google Scholar

36 

Fujimoto T, Onda M, Nagai H, Nagahata T, Ogawa K and Emi M: Upregulation and overexpression of human X-box binding protein 1 (hXBP-1) gene in primary breast cancers. Breast Cancer. 10:301–306. 2003. View Article : Google Scholar : PubMed/NCBI

37 

Shuda M, Kondoh N, Imazeki N, Tanaka K, Okada T, Mori K, Hada A, Arai M, Wakatsuki T, Matsubara O, et al: Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: A possible involvement of the ER stress pathway in hepatocarcinogenesis. J Hepatol. 38:605–614. 2003. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Zhou T, Lv X, Guo X, Ruan B, Liu D, Ding R, Gao Y, Ding J, Dou K, Chen Y, Chen Y, et al: RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1/XBP1 axis. Oncol Rep 33: 3006-3014, 2015.
APA
Zhou, T., Lv, X., Guo, X., Ruan, B., Liu, D., Ding, R. ... Chen, Y. (2015). RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1/XBP1 axis. Oncology Reports, 33, 3006-3014. https://doi.org/10.3892/or.2015.3920
MLA
Zhou, T., Lv, X., Guo, X., Ruan, B., Liu, D., Ding, R., Gao, Y., Ding, J., Dou, K., Chen, Y."RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1/XBP1 axis". Oncology Reports 33.6 (2015): 3006-3014.
Chicago
Zhou, T., Lv, X., Guo, X., Ruan, B., Liu, D., Ding, R., Gao, Y., Ding, J., Dou, K., Chen, Y."RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1/XBP1 axis". Oncology Reports 33, no. 6 (2015): 3006-3014. https://doi.org/10.3892/or.2015.3920
Copy and paste a formatted citation
x
Spandidos Publications style
Zhou T, Lv X, Guo X, Ruan B, Liu D, Ding R, Gao Y, Ding J, Dou K, Chen Y, Chen Y, et al: RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1/XBP1 axis. Oncol Rep 33: 3006-3014, 2015.
APA
Zhou, T., Lv, X., Guo, X., Ruan, B., Liu, D., Ding, R. ... Chen, Y. (2015). RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1/XBP1 axis. Oncology Reports, 33, 3006-3014. https://doi.org/10.3892/or.2015.3920
MLA
Zhou, T., Lv, X., Guo, X., Ruan, B., Liu, D., Ding, R., Gao, Y., Ding, J., Dou, K., Chen, Y."RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1/XBP1 axis". Oncology Reports 33.6 (2015): 3006-3014.
Chicago
Zhou, T., Lv, X., Guo, X., Ruan, B., Liu, D., Ding, R., Gao, Y., Ding, J., Dou, K., Chen, Y."RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1/XBP1 axis". Oncology Reports 33, no. 6 (2015): 3006-3014. https://doi.org/10.3892/or.2015.3920
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