Involvement of GRP78 in the Resistance of Ovarian Carcinoma Cells to Paclitaxel

  • Zhang, Li-Ying (Department of Obstetrics and Gynaecology, the Second Affiliated Hospital of Harbin Medical University) ;
  • Li, Pei-Ling (Department of Obstetrics and Gynaecology, the Second Affiliated Hospital of Harbin Medical University) ;
  • Xu, Aili (Department of Obstetrics and Gynaecology, the Second Affiliated Hospital of Harbin Medical University) ;
  • Zhang, Xin-Chen (Department of General Surgery, the Second Affiliated Hospital of Harbin Medical University)
  • Published : 2015.04.29


Background: Glucose regulated protein 78 (GRP78) is a type of molecular chaperone. It is a possible candidate protein that contributes to development of drug resistance. We first examined the involvement of GRP78 in chemotherapy-resistance in human ovarian cancer cell. Materials and Methods: The expression of GRP78 mRNA and protein were examined by RT-PCR and western blotting, respectively, in human ovarian cancer cells line (HO-8910). Sensitivity of HO-8910 to paclitaxel was determined with methyl thiazolyl tetrazolium (MTT). Suppression of GRP78 expression was performed using specific small-interfering RNA (siRNA) in HO-8910 cells, and cell apoptosis was assessed by flow cytometry. Statistical analysis was performed using the SPSS 15.0 statistical package. Results: HO-8910 cells, with high basal levels of GRP78, exhibited low sensitivity to paclitaxel. The mRNA and protein levels of GRP78 were dramatically decreased at 24h, 48h and 72h after transfection and the sensitivity to paclitaxel was increased when the GRP78 gene was disturbed by specific siRNA transfection. Conclusions: The results suggested that high GRP78 expression might be one of the molecular mechanisms causing resistance to paclitaxel, and therefore siRNA of GRP78 may be useful in tumor-specific gene therapy for ovarian cancer.


Glucose regulated protein 78;paclitaxel-resistance;human ovarian cancer cell;siRNA


Supported by : Heilongjiang Province of China


  1. Belfi CA, Chatterjee S, Gosky DM, et al (1999). Increased sensitivity of human colon cancer cells to DNA cross-linking agents after GRP78 up-regulation. Biochem Biophys Res Commun, 257, 361-8.
  2. Foti DM, Welihinda A, Kaufman RJ, et al (1999).Conservation and divergence of the yeast and mammalian unfolded protein response. Activation of specific mammalian endoplasmic reticulum stress element of the grp78/BiP promoter by yeast Hac1. J Biol Chem, 274, 30402-9.
  3. Fu W, Wu X, Li J, et al (2010). Upregulation of GRP78 in renal cell carcinoma and its significance. Urology, 75, 603-7.
  4. Gazit G, Lu J, Lee AS (1999). De-regulation of GRP stress protein expression in human breast cancer cell lines. Breast Cancer Res Treat, 54, 135-46.
  5. Gething MJ, Sambrook J (1992). Protein folding in the cell. Nature, 355, 33-45.
  6. Gregory-Bass RC, Olatinwo M, Xu W, et al (2008). Prohibitin silencing reverses stabilization of mitochondrial integrity and chemoresistance in ovarian cancer cells by increasing their sensitivity to apoptosis. Int J Cancer, 122, 1923-30.
  7. Huang TT, Chen JY, Tseng CE, et al (2010). Decreased GRP78 protein expression is a potential prognostic marker of oral squamous cell carcinoma in Taiwan. J Formos Med Assoc, 109, 326-37.
  8. Kozutsumi Y, Segal M, Normington K, et al (1988).The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature, 332, 462-4.
  9. Lee AS (2001). The glucose-regulated proteins: stress induction and clinical applications. Trends Biochem Sci, 26, 504-10.
  10. Lee E, Nichols P, Groshen S, et al (2011).GRP78 as potential predictor for breast cancer response to adjuvant taxane therapy. Int J Cancer, 128, 726-31.
  11. Li LJ, Li X, Ferrario A, et al (1992). Establishment of a Chinese hamster ovary cell line that expresses grp78 antisense transcripts and suppresses A23187 induction of both GRP78 and GRP94. J Cell Physiol, 153, 575-82.
  12. Liu S, Wang H, Yang Z, et al (2005). Enhancement of cancer radiation therapy by use of adenovirus-mediated secretable glucose-regulated protein 94/gp96 expression. Cancer Res, 65, 9126-31.
  13. Manjili MH, Wang XY, Park J, et al (2002). Immunotherapy of cancer using heat shock proteins. Front Biosci, 7, 43-52.
  14. Martin S, Hill DS, Paton JC, et al (2010).Targeting GRP78 to enhance melanoma cell death. Pigment Cell Melanoma Res, 23, 675-82.
  15. Nakagawa T, Yuan J (2000). Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J Cell Biol, 150, 887-94.
  16. Roy B, Lee AS (1999). The mammalian endoplasmic reticulum stress response element consists of an evolutionarily conserved tripartite structure and interacts with a novel stress-inducible complex. Nucleic Acids Res, 27, 1437-43.
  17. Saranya C, Siriwan T, Jakkapan K, et al (2014). Treatment outcomes of gemcitabine in refractory or recurrent epithelial ovarian cancer patients. Asian Pac J Cancer Prev, 15, 5215-21.
  18. Sevim KA, Burcu K, Hakan Y, et al (2014). Impact of prognostic factors on survival rates in patients with ovarian carcinoma. Asian Pac J Cancer Prev, 15, 6087-94.
  19. Shen J, Hughes C, Chao C, et al (1987). Coinduction of glucoseregulated proteins and doxorubicin resistance in Chinese hamster cells. Proc Natl Acad Sci USA, 84, 3278-82.
  20. Shiu RP, Pastan IH (1979). Properties and purification of a glucose-regulated protein from chick embryo fibroblasts. Biochim Biophys Acta, 576, 141-50.
  21. Siegel R, Naishadham D, Jemal A (2013). Cancer statistics. CA Cancer J Clin, 63, 11-30.
  22. Somersan S, Larsson M, Fonteneau JF, et al (2001). Primary tumor tissue lysates are enriched in heat shock proteins and induce the maturation of human dendritic cells. J Immunol, 167, 4844-52.
  23. Srivastava PK (1993). Peptide-binding heat shock proteins in the endoplasmic reticulum: role in immune response to cancer and in antigen presentation. Adv Cancer Res, 62, 153-77.
  24. Srivastava PK, DeLeo AB, Old LJ (1986). Tumor rejection antigens of chemically induced sarcomas of inbred mice. Proc Natl Acad Sci U S A, 83, 3407-11.
  25. Su R, Li Z, Li H, et al (2010). Grp78 promotes the invasion of hepatocellular carcinoma. BMC cancer, 10, 20.
  26. Tomida A, Yun J, Tsuruo T (1996). Glucose-regulated stresses induce resistance to camptothecin in human cancer cells. Int J Cancer, 68, 391-6.<391::AID-IJC19>3.0.CO;2-B
  27. Vincenza C, Barbara K, Salvatore L, et al (2014). The emerging role of anti-angiogenic therapy in ovarian cancer (Review). Int J Oncol, 44, 1417-24.
  28. Wang Q, He Z, Zhang J, et al (2005). Overexpression of endoplasmic reticulum molecular chaperone GRP94 and GRP78 in human lung cancer tissues and its significance. Cancer Detect Prev, 29, 544-51.
  29. Zhang LH, Zhang X (2010). Roles of GRP78 in physiology and cancer. J Cell Biochem, 110, 1299-305.

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