Tumor Biology

, Volume 36, Issue 6, pp 4197–4202 | Cite as

FBW7 increases drug sensitivity to cisplatin in human nasopharyngeal carcinoma by downregulating the expression of multidrug resistance-associated protein

  • Yan Song
  • Xinjia Zhou
  • Weiliang Bai
  • Xiulan Ma
Research Article


F-box/WD repeat-containing protein 7 (FBW7) is a member of the F-box protein family that regulates cell cycle progression and cell growth and differentiation. FBW7 also functions as a tumor suppressor. A cisplatin (CDDP)-based multidrug chemotherapy regimen is standard for nasopharyngeal carcinoma (NPC), but drug resistance is an increasing problem. Here, we evaluated the relationship between FBW7 and multidrug resistance-associated protein (MRP), and its correlation with drug resistance in NPC, and explored the mechanism underlying drug resistance to CDDP in this disease. We used cell viability assays, Western blotting, and small interfering RNA (siRNA) interference to investigate the underlying mechanism underlying CDDP resistance in a NPC cell line. The expression of FBW7 and MRP was detected by Western blotting after siRNA interference in the CDDP-resistant NPC cell line, CNE2-CDDP. The 3-(4 5-dimethyl-2-thiazolyl)-2 5-diphenyl-2-H-tetrazolium bromide (MTT) assay was used to evaluate drug sensitivity of various types of antitumor drugs, including paclitaxel (PCX), CDDP, fluorouracil (5-FU), and vincristine (VCR). We found that siRNA-mediated upregulation of FBW7 significantly increased CDDP chemosensitivity. The IC50 values of CDDP in siRNA-FBW7-CNE2-CDDP and FBW7-CNE2-CDDP-NC cells were 2.485 ± 0.155 and 4.867 ± 0.442 μmol/mL, respectively. The IC50 values of PCX, CDDP, 5-FU, and VCR were significantly decreased in siRNA-FBW7-CNE2 than in FBW7-CNE2-NC (3.46 ± 0.14 vs. 46.21 ± 6.03 μmol/mL; 3.76 ± 0.54 vs. 39.45 ± 0.96 μmol/mL; 2.14 ± 1.67 vs. 28.76 ± 1.89 μmol/mL; 4.43 ± 0.89 vs. 87.90 ± 3.45 μmol/mL, respectively). The IC50 of CDDP was significantly less in siRNA-FBW7-CNE2-CDDP than in FBW7-CNE2-CDDP-NC. The level of FBW7 expression in CNE2 cells was correlated with CDDP chemosensitivity. siRNA-mediated upregulation of FBW7 expression downregulated the expression of MRP, significantly increasing drug sensitivity in CNE2 cells.


FBW7 Cisplatin Drug resistance Multidrug resistance-associated protein (MRP) siRNA interference 



The authors wish to express their sincere thanks to Dr. Di Na for his technical assistance. This study was supported by the China Natural Science Foundation (81241083).

Conflicts of interest



  1. 1.
    Song Y, Yang J, Bai W-L, Ji W-Y. Anti-tumor and immunoregulatory effects of astragalus on nasopharyngeal carcinoma in vivo and in vitro. Phytother Res. 2011;25:909–15.CrossRefPubMedGoogle Scholar
  2. 2.
    Hu CM, Zhang L. Nanoparticle-based combination therapy toward overcoming drug resistance in cancer. Biochem Pharmacol. 2012;83(8):1104–11.CrossRefPubMedGoogle Scholar
  3. 3.
    Wu Z, Li X, Zeng Y, et al. In vitro and in vivo inhibition of MRP gene expression and reversal of multidrug resistance by siRNA. Basic Clin Pharmacol Toxicol. 2011;108(3):177–84.CrossRefPubMedGoogle Scholar
  4. 4.
    Yu H-G, Wei W, Xia L-H, Han W-L, Zhao P, Wu S-J, et al. FBW7 upregulation enhances cisplatin cytotoxicity in nonsmall cell lung cancer cells. Asian Pac J Cancer Prev. 2013;14:6321–6.CrossRefPubMedGoogle Scholar
  5. 5.
    Wertz IE, Kusam S, Lam C, Okamoto T, Sandoval W, Anderson DJ, et al. Sensitivity to antitubulin chemotherapeutics is regulated by MCL 1 and FBW7. Nature. 2011;471:110–4.CrossRefPubMedGoogle Scholar
  6. 6.
    Nateri AS, Riera-Sans L, Da Costa C, Behrens A. The ubiquitin ligase SCFFbw7 antagonizes apoptotic JNK signaling. Science. 2004;303:1374–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Akhoondi S, Sun D, von der Lehr N, Apostolidou S, Klotz K, Maljukova A, et al. FBXW7/hCDC4 is a general tumor suppressor in human cancer. Cancer Res. 2007;67:9006–12.CrossRefPubMedGoogle Scholar
  8. 8.
    O’Neil J, Grim J, Strack P, Rao S, Tibbitts D, Winter C, et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J Exp Med. 2007;204:1813–24.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Anzi S, Finkin S, Shaulian E. Transcriptional repression of c-Jun’s E3 ubiquitin ligases contributes to c-Jun induction by UV. Cell Signal. 2008;20:862–71.CrossRefPubMedGoogle Scholar
  10. 10.
    Bonetti P, Davoli T, Sironi C, Amati B, Pelicci PG, Colombo E. Nucleophosmin and its AML-associated mutant regulate c-Myc turnover through Fbw7 gamma. J Cell Biol. 2008;182:19–26.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Kitagawa K, Hiramatsu Y, Uchida C, Isobe T, Hattori T, Oda T, et al. Fbw7 promotes ubiquitin-dependent degradation of c-Myb: involvement of GSK3-mediated phosphorylation of Thr-572 in mouse c-Myb. Oncogene. 2009;28:2393–405.CrossRefPubMedGoogle Scholar
  12. 12.
    Welcker M, Clurman BE. FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer. 2008;8(2):83–93.CrossRefPubMedGoogle Scholar
  13. 13.
    Minella AC, Clurman BE. Mechanisms of tumor suppression by the SCF(Fbw7). Cell Cycle. 2005;4(10):1356–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Lau AW, Fukushima H, Wei W. The Fbw7 and betaTRCP E3 ubiquitin ligases and their roles in tumorigenesis. Front Biosci. 2012;17:2197–212.CrossRefGoogle Scholar
  15. 15.
    Spruck CH, Strohmaier H, Sangfelt O, Müller HM, Hubalek M, Müller-Holzner E, et al. hCDC4 gene mutations in endometrial cancer. Cancer Res. 2004;62:4535–9.Google Scholar
  16. 16.
    Schülein-Völk C, Wolf E, Zhu J, Xu W, Taranets L, Hellmann A, et al. Dual regulation of fbw7 function and oncogenic transformation by usp28. Cell Rep. 2014;9(3):1099–109.CrossRefPubMedGoogle Scholar
  17. 17.
    Wang Z, Inuzuka H, Zhong J, Wan L, Fukushima H, Sarkar FH, et al. Tumor suppressor functions of FBW7 in cancer development and progression. FEBS Lett. 2012;586(10):1409–18.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Cheng Y, Li G. Role of the ubiquitin ligase Fbw7 in cancer progression. Cancer Metastasis Rev. 2012;31(1–2):75–87.CrossRefPubMedGoogle Scholar
  19. 19.
    Wang Z, Fukushima H, Gao D, Inuzuka H, Wan L, Lau AW, et al. The two faces of FBW7 in cancer drug resistance. Bioessays. 2011;33(11):851–9.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Wang Z, Inuzuka H, Fukushima H, Wan L, Gao D, Shaik S, et al. Emerging roles of the FBW7 tumour suppressor in stem cell differentiation. EMBO Rep. 2012;13(1):36–43.CrossRefGoogle Scholar
  21. 21.
    Calhoun ES, Jones JB, Ashfaq R, Adsay V, Baker SJ, Valentine V, et al. BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets. Am J Pathol. 2003;163:1255–60.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Cassia R, Moreno-Bueno G, Rodríguez-Perales S, Hardisson D, Cigudosa JC, Palacios J. Cyclin E gene (CCNE) amplification and hCDC4 mutations in endometrial carcinoma. J Pathol. 2003;201:589–95.CrossRefPubMedGoogle Scholar
  23. 23.
    Willmarth NE, Albertson DG, Ethier SP. Chromosomal instability and lack of cyclin E regulation in hCdc4 mutant human breast cancer cells. Breast Cancer Res. 2004;6:R531–9.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kwak EL, Moberg KH, Wahrer DC, Quinn JE, Gilmore PM, Graham CA, et al. Infrequent mutations of Archipelago (hAGO, hCDC4, Fbw7) in primary ovarian cancer. Gynecol Oncol. 2005;98:124–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Song JH, Schnittke N, Zaat A, Walsh CS, Miller CW. FBXW7 mutation in adult T-cell and B-cell acute lymphocytic leukemias. Leuk Res. 2008;32:1751–5.CrossRefPubMedGoogle Scholar
  26. 26.
    Jacob NK, Cooley JV, Shirai K. Survivin splice variants are not essential for mitotic progression or inhibition of apoptosis induced by doxorubicin and radiation. Onco Targets Ther. 2012;5:7–20.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Hu W, Ding W, Yang H, Shao M, Wang B, Wang J, et al. Weekly paclitaxel with concurrent radiotherapy followed by adjuvant chemotherapy in locally advanced nasopharyngeal carcinoma. Radiother Oncol. 2009;93(3):488–91.CrossRefPubMedGoogle Scholar
  28. 28.
    Jiang D, Sui M, Zhong W, et al. Different administration strategies with paclitaxel induce distinct phenotypes of multidrug resistance in breast cancer cells [J]. Cancer Lett. 2013;335(2):404–11.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Jiang D, Sui M, Zhong W, Huang Y, Fan W. Mcl-1 ubiquitination and destruction. Oncotarget. 2011;2:239–44.CrossRefGoogle Scholar
  30. 30.
    Zhou J, Zhao WY, Ma X, Ju RJ, Li XY, Li N, et al. The anticancer efficacy of paclitaxel liposomes modified with mitochondrial targeting conjugate in resistant lung cancer. Biomaterials. 2013;34(14):3626–38.CrossRefPubMedGoogle Scholar
  31. 31.
    Lo KW, Chung GT, To KF. Deciphering the molecular genetic basis of NPC through molecular, cytogenetic, and epigenetic approaches. Semin Cancer Biol. 2012;22(2):79–86.CrossRefPubMedGoogle Scholar
  32. 32.
    Greenberg RM. Schistosome ABC multidrug transporters: from pharmacology to physiology. Int J Parasitol Drugs Drug Resist. 2014;4(3):301–9.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Tebra S, Kallel A, Boussen H, Bouaouina N. Medical treatment of nasopharyngeal cancers. Tunis Med. 2011;89(4):326–31.PubMedGoogle Scholar
  34. 34.
    Bedford L, Lowe J, Dick LR, Mayer RJ, Brownell JE. Ubiquitin-like protein conjugation and the ubiquitin-proteasome system as drug targets. Nat Rev Drug Discov. 2011;10:29–46.CrossRefPubMedGoogle Scholar
  35. 35.
    Weissman AM, Shabek N, Ciechanover A. The predator becomes the prey: regulating the ubiquitin system by ubiquitylation and degradation. Nat Rev Mol Cell Biol. 2011;12:605–20.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Cassavaugh JM, Hale SA, Wellman TL, Howe AK, Wong C, Lounsbury KM. Negative regulation of HIF-1alpha by an FBW7-mediated degradation pathway during hypoxia. J Cell Biochem. 2011;112:3882–90.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Fruh M. The search for improved systemic therapy of non-small cell lung cancer—what are today’s options? Lung Cancer. 2011;72:265–70.CrossRefPubMedGoogle Scholar
  38. 38.
    Kitagawa K, Kotake Y, Hiramatsu Y, Liu N, Suzuki S, Nakamura S, et al. GSK3 regulates the expressions of human and mouse c-Myb via different mechanisms. Cell Div. 2010;5:27.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Inuzuka H, Shaik S, Onoyama I, Gao D, Tseng A, Maser RS, et al. SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature. 2011;471:104–9.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Yan Song
    • 1
  • Xinjia Zhou
    • 1
  • Weiliang Bai
    • 1
  • Xiulan Ma
    • 1
  1. 1.Department of Otorhinolaryngology, Sheng Jing HospitalChina Medical UniversityShenyangChina

Personalised recommendations