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 Letters
Join Editorial Board Propose a Special Issue
Print ISSN: 1792-1074 Online ISSN: 1792-1082
Journal Cover
2014-March Volume 7 Issue 3

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
2014-March Volume 7 Issue 3

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

Knockdown of glucose‑regulated protein 78 abrogates chemoresistance of hypopharyngeal carcinoma cells to cisplatin induced by unfolded protein in response to severe hypoxia

  • Authors:
    • Lihong Pi
    • Xiaoming Li
    • Qi Song
    • Yupeng Shen
    • Xiuying Lu
    • Bin Di
  • View Affiliations / Copyright

    Affiliations: Department of Otorhinolaryngology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China, Department of Otolaryngology Head and Neck Surgery, Bethune International Peace Hospital, Shijiazhuang, Hebei 050082, P.R. China
  • Pages: 685-692
    |
    Published online on: December 11, 2013
       https://doi.org/10.3892/ol.2013.1753
  • 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

Hypoxia renders tumor cells with reduced sensitivity and increased resistance to chemotherapeutic agents. One of the possible mechanisms underlying this unfavorable status is activation of the unfolded protein response (UPR) under hypoxic conditions, due to the upregulation of glucose‑regulated protein 78 (GRP78) expression. GRP78, an endoplasmic reticulum chaperone protein and a key regulator of the UPR, has been reported to be overexpressed in various types of cancer. However, the role of GRP78 in regulating the cell growth and apoptosis of hypopharyngeal carcinoma cells, with regard to the severity of hypoxia, remains unclear. Therefore, the aim of the present study was to investigate whether, and under what circumstances, GRP78 is associated with hypoxia‑induced chemoresistance in hypopharyngeal carcinoma. For this purpose, cells from the FaDu human hypopharyngeal carcinoma cell line were cultured under normoxic and hypoxic conditions for different time periods. No significant changes in GRP78 and C/EBP homology protein (CHOP) protein expression levels were revealed under moderately hypoxic conditions (oxygen concentration, 1%), but these levels were changed over time under severely hypoxic conditions (oxygen concentration, <0.02%). This indicated that severe hypoxia, rather than moderate hypoxia, leads to UPR activation in hypopharyngeal carcinoma cells. Knockdown of GRP78 with short hairpin RNA inhibited cell proliferation and promoted apoptosis under severely hypoxic conditions, even with cisplatin treatment, indicating that GRP78 confers FaDu cells resistant to chemotherapy in response to severe hypoxia. Furthermore, knockdown of GRP78 resulted in a significant increase in CHOP and Bax expression levels and a decrease in Bcl‑2 expression levels with simultaneous increase in the levels of apoptosis under severely hypoxic conditions. It was concluded that severe hypoxia leads to UPR activation and elevation of GRP78 expression, promoting cell survival and inducing chemoresistance. Silencing of GRP78 may block the pro‑survival arm of UPR, simultaneously promoting proapoptotic signaling through induction of CHOP. Downregulation of GRP78 may be a promising strategy for overcoming the resistance of hypopharyngeal cancer to chemotherapy.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

View References

1 

Chien CY, Su CY, Hwang CF, Chuang HC, Hsiao YC, Wu SL and Huang CC: Clinicopathologic significance of CD105 expression in squamous cell carcinoma of the hypopharynx. Head Neck. 28:441–446. 2006. View Article : Google Scholar : PubMed/NCBI

2 

Brown JM and Wilson WR: Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer. 4:437–447. 2004. View Article : Google Scholar

3 

Wouters BG and Koritzinsky M: Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer. 8:851–864. 2008. View Article : Google Scholar : PubMed/NCBI

4 

Ghosh R, Lipson KL, Sargent KE, Mercurio AM, Hunt JS, Ron D and Urano F: Transcriptional regulation of VEGF-A by the unfolded protein response pathway. PLoS ONE. 5:e95752010. View Article : Google Scholar : PubMed/NCBI

5 

Rzymski T, Milani M, Pike L, et al: Regulation of autophagy by ATF4 in response to severe hypoxia. Oncogene. 29:4424–4435. 2010. View Article : Google Scholar : PubMed/NCBI

6 

Koumenis C and Wouters BG: ‘Translating’ tumor hypoxia: unfolded protein response (UPR)-dependent and UPR-independent pathways. Mol Cancer Res. 4:423–436. 2006.

7 

Rutkowski DT and Kaufman RJ: A trip to the ER: coping with stress. Trends Cell Bio. 14:20–28. 2004. View Article : Google Scholar : PubMed/NCBI

8 

Grkovic S, O’Reilly VC, Han S, Hong M, Baxter RC and Firth SM: IGFBP-3 binds GRP78, stimulates autophagy and promotes the survival of breast cancer cells exposed to adverse microenvironments. Oncogene. 32:2412–2420. 2012. View Article : Google Scholar : PubMed/NCBI

9 

Kandala PK and Srivastava SK: Regulation of macroautophagy in ovarian cancer cells in vitro and in vivo by controlling glucose regulatory protein 78 and AMPK. Oncotarget. 3:435–449. 2012.PubMed/NCBI

10 

de Ridder G, Ray R, Misra UK and Pizzo SV: Modulation of the unfolded protein response by GRP78 in prostate cancer. Methods Enzymol. 489:245–257. 2011.PubMed/NCBI

11 

Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T and Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 58:71–96. 2008. View Article : Google Scholar

12 

Sun Q, Li X, Lu X and Di B: Cancer stem cells may be mostly maintained by fluctuating hypoxia. Med Hypotheses. 76:471–473. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Huang LW, Lin CY, Lee CC, Liu TZ and Jeng CJ: Overexpression of GRP78 is associated with malignant transformation in epithelial ovarian tumors. Appl Immunohistochem Mol Morphol. 20:381–385. 2012. View Article : Google Scholar : PubMed/NCBI

14 

Kuroda K, Horiguchi A, Asano T, et al: Glucose-regulated protein 78 positivity as a predictor of poor survival in patients with renal cell carcinoma. Urol Int. 87:450–456. 2011. View Article : Google Scholar : PubMed/NCBI

15 

Koumenis C, Bi M, Ye J, Feldman D and Koong AC: Hypoxia and the unfolded protein response. Methods Enzymol. 435:275–293. 2007. View Article : Google Scholar : PubMed/NCBI

16 

Krivoruchko A and Storey KB: Activation of the unfolded protein response during anoxia exposure in the turtle Trachemys scripta elegans. Mol Cell Biochem. 374:91–103. 2013. View Article : Google Scholar : PubMed/NCBI

17 

Pyrko P, Schönthal AH, Hofman FM, Chen TC and Lee AS: The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas. Cancer Res. 67:9809–9816. 2007. View Article : Google Scholar

18 

Healy SJ, Gorman AM, Mousavi-Shafaei P, Gupta S and Samali A: Targeting the endoplasmic reticulum-stress response as an anticancer strategy. Eur J Pharmacol. 625:234–246. 2009. View Article : Google Scholar : PubMed/NCBI

19 

Fu Y, Li J and Lee AS: GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis. Cancer Res. 67:3734–3740. 2007. View Article : Google Scholar

20 

Zhou H, Zhang Y, Fu Y, Chan L and Lee AS: Novel mechanism of anti-apoptotic function of 78-kDa glucose-regulated protein (GRP78): endocrine resistance factor in breast cancer, through release of B-cell lymphoma 2 (BCL-2) from BCL-2-interacting killer (BIK). J Biol Chem. 286:25687–25696. 2011. View Article : Google Scholar

21 

McCullough KD, Martindale JL, Klotz LO, Aw TY and Holbrook NJ: Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol. 21:1249–1259. 2001. View Article : Google Scholar

22 

Dong D, Ni M, Li J, et al: Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development. Cancer Res. 68:498–505. 2008. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Pi L, Li X, Song Q, Shen Y, Lu X and Di B: Knockdown of glucose‑regulated protein 78 abrogates chemoresistance of hypopharyngeal carcinoma cells to cisplatin induced by unfolded protein in response to severe hypoxia. Oncol Lett 7: 685-692, 2014.
APA
Pi, L., Li, X., Song, Q., Shen, Y., Lu, X., & Di, B. (2014). Knockdown of glucose‑regulated protein 78 abrogates chemoresistance of hypopharyngeal carcinoma cells to cisplatin induced by unfolded protein in response to severe hypoxia. Oncology Letters, 7, 685-692. https://doi.org/10.3892/ol.2013.1753
MLA
Pi, L., Li, X., Song, Q., Shen, Y., Lu, X., Di, B."Knockdown of glucose‑regulated protein 78 abrogates chemoresistance of hypopharyngeal carcinoma cells to cisplatin induced by unfolded protein in response to severe hypoxia". Oncology Letters 7.3 (2014): 685-692.
Chicago
Pi, L., Li, X., Song, Q., Shen, Y., Lu, X., Di, B."Knockdown of glucose‑regulated protein 78 abrogates chemoresistance of hypopharyngeal carcinoma cells to cisplatin induced by unfolded protein in response to severe hypoxia". Oncology Letters 7, no. 3 (2014): 685-692. https://doi.org/10.3892/ol.2013.1753
Copy and paste a formatted citation
x
Spandidos Publications style
Pi L, Li X, Song Q, Shen Y, Lu X and Di B: Knockdown of glucose‑regulated protein 78 abrogates chemoresistance of hypopharyngeal carcinoma cells to cisplatin induced by unfolded protein in response to severe hypoxia. Oncol Lett 7: 685-692, 2014.
APA
Pi, L., Li, X., Song, Q., Shen, Y., Lu, X., & Di, B. (2014). Knockdown of glucose‑regulated protein 78 abrogates chemoresistance of hypopharyngeal carcinoma cells to cisplatin induced by unfolded protein in response to severe hypoxia. Oncology Letters, 7, 685-692. https://doi.org/10.3892/ol.2013.1753
MLA
Pi, L., Li, X., Song, Q., Shen, Y., Lu, X., Di, B."Knockdown of glucose‑regulated protein 78 abrogates chemoresistance of hypopharyngeal carcinoma cells to cisplatin induced by unfolded protein in response to severe hypoxia". Oncology Letters 7.3 (2014): 685-692.
Chicago
Pi, L., Li, X., Song, Q., Shen, Y., Lu, X., Di, B."Knockdown of glucose‑regulated protein 78 abrogates chemoresistance of hypopharyngeal carcinoma cells to cisplatin induced by unfolded protein in response to severe hypoxia". Oncology Letters 7, no. 3 (2014): 685-692. https://doi.org/10.3892/ol.2013.1753
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