FBW7 Upregulation Enhances Cisplatin Cytotoxicity in Non-small Cell Lung Cancer Cells

  • Yu, Hao-Gang (Department of Radiation Oncology, the First Affiliated Hospital, School of Medicine, Zhejiang University) ;
  • Wei, Wei (Department of Radiation Oncology, the First Affiliated Hospital, School of Medicine, Zhejiang University) ;
  • Xia, Li-Hong (Department of Radiation Oncology, the First Affiliated Hospital, School of Medicine, Zhejiang University) ;
  • Han, Wei-Li (Department of Cardiothoracic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University) ;
  • Zhao, Peng (Department of Radiation Oncology, the First Affiliated Hospital, School of Medicine, Zhejiang University) ;
  • Wu, Sheng-Jun (Department of Cardiothoracic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University) ;
  • Li, Wei-Dong (Department of Cardiothoracic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University) ;
  • Chen, Wei (Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University)
  • Published : 2013.11.30


Introduction: Lung cancer is extremely harmful to human health and has one of the highest worldwide incidences of all malignant tumors. Approximately 80% of lung cancers are classified as non-small cell lung cancers (NSCLCs). Cisplatin-based multidrug chemotherapy regimen is standard for such lesions, but drug resistance is an increasing problem. 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. Methods: We used cell viability assays, Western blotting, and immunofluorescence combined with siRNA interference or plasmid transfection to investigate the underlying mechanism of cisplatin resistance in NSCLC cells. Results: We found that FBW7 upregulation significantly increased cisplatin chemosensitivity and that cells expressing low levels of FBW7, such as NCI-H1299 cells, have a mesenchymal phenotype. Furthermore, siRNA-mediated silencing or plasmid-mediated upregulation of FBW7 resulted in altered epithelial-mesenchymal transition (EMT) patterns in NSCLC cells. These data support a role for FBW7 in regulating the EMT in NSCLC cells. Conclusion: FBW7 is a potential drug target for combating drug resistance and regulating the EMT in NSCLC cells.


FBW7;NSCLC cells;cisplatin;epithelial-mesenchymal transition;drug resistance


  1. Akhoondi S, Sun D, von der Lehr N, et al (2007). FBXW7/hCDC4 is a general tumor suppressor in human cancer. Cancer Res, 67, 9006-12.
  2. Anzi S, Finkin S, Shaulian E (2008). Transcriptional repression of c-Jun's E3 ubiquitin ligases contributes to c-Jun induction by UV. Cell Signal, 20, 862-71.
  3. Bonetti P, Davoli T, Sironi C, et al (2008). Nucleophosmin and its AML-associated mutant regulate c-Myc turnover through Fbw7 gamma. J Cell Biol, 182, 19-26.
  4. Byers LA, Diao L, Wang J, et al (2013). An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin Cancer Res, 19, 279-90.
  5. Calhoun ES, Jones JB, Ashfaq R, et al (2003). BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets. Am J Pathol, 163, 1255-60.
  6. Cassia R, Moreno-Bueno G, Rodriguez-Perales S, et al (2003). Cyclin E gene (CCNE) amplification and hCDC4 mutations in endometrial carcinoma. J Pathol, 201, 589-95.
  7. Cortot AB, Repellin CE, Shimamura T, et al (2013). Resistance to irreversible EGF receptor tyrosine kinase inhibitors through a multistep mechanism involving the IGF1R pathway. Cancer Res, 73, 834-43.
  8. Fruh M (2011). The search for improved systemic therapy of non-small cell lung cancer--what are today's options? Lung Cancer, 72, 265-70.
  9. Grim JE, Gustafson MP, Hirata RK, et al (2008). Isoform- and cell cycle-dependent substrate degradation by the Fbw7 ubiquitin ligase. J Cell Biol, 181, 913-20.
  10. Grunert S, Jechlinger M,Beug H (2003). Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat Rev Mol Cell Biol, 4, 657-65.
  11. Hoshino H, Miyoshi N, Nagai K, et al (2009). Epithelial-mesenchymal transition with expression of SNAI1-induced chemoresistance in colorectal cancer. Biochem Biophys Res Commun, 390, 1061-5.
  12. Inuzuka H, Fukushima H, Shaik S, et al (2011). Mcl-1 ubiquitination and destruction. Oncotarget, 2, 239-44.
  13. Inuzuka H, Shaik S, Onoyama I, et al (2011). SCF (FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature, 471, 104-9.
  14. Jemal A, Murray T, Samuels A, et al (2003). Cancer statistics, 2003. CA Cancer J Clin, 53, 5-26.
  15. Kitagawa K, Hiramatsu Y, Uchida C, et al (2009). Fbw7 promotes ubiquitin-dependent degradation of c-Myb: involvement of GSK3-mediated phosphorylation of Thr-572 in mouse c-Myb. Oncogene, 28, 2393-405.
  16. Kurrey NK, Jalgaonkar SP, Joglekar AV, et al (2009). Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells, 27, 2059-68.
  17. Kwak EL, Moberg KH, Wahrer DC, et al (2005). Infrequent mutations of Archipelago (hAGO, hCDC4, Fbw7) in primary ovarian cancer. Gynecol Oncol, 98, 124-8.
  18. Lee MS, Kim HP, Kim TY,Lee JW (2012). Gefitinib resistance of cancer cells correlated with TM4SF5-mediated epithelial-mesenchymal transition. Biochim Biophys Acta, 1823, 514-23.
  19. Maitah MY, Ali S, Ahmad A, Gadgeel S,Sarkar FH (2011). Up-regulation of sonic hedgehog contributes to TGF-beta1-induced epithelial to mesenchymal transition in NSCLC cells. PLoS One, 6, e16068.
  20. Mao JH, Perez-Losada J, Wu D, et al (2004). Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene. Nature, 432, 775-9.
  21. Melguizo C, Prados J, Luque R, et al (2013). Modulation of multidrug resistance gene expression in peripheral blood mononuclear cells of lung cancer patients and evaluation of their clinical significance. Cancer Chemother Pharmacol, 71, 537-41.
  22. Moreno-Bueno G, Peinado H, Molina P, et al (2009). The morphological and molecular features of the epithelial-to-mesenchymal transition. Nat Protoc, 4, 1591-613.
  23. Nash P, Tang X, Orlicky S, et al (2001). Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication. Nature, 414, 514-21.
  24. Nateri AS, Riera-Sans L, Da Costa C,Behrens A (2004). The ubiquitin ligase SCFFbw7 antagonizes apoptotic JNK signaling. Science, 303, 1374-8.
  25. Neel DS,Bivona TG (2013). Secrets of drug resistance in NSCLC exposed by new molecular definition of EMT. Clin Cancer Res, 19, 3-5.
  26. Nozawa N, Hashimoto S, Nakashima Y, et al (2006). Immunohistochemical alpha- and beta-catenin and E-cadherin expression and their clinicopathological significance in human lung adenocarcinoma. Pathol Res Pract, 202, 639-50.
  27. O’Neil J, Grim J, Strack P, et al (2007). FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J Exp Med, 204, 1813-24.
  28. Song JH, Schnittke N, Zaat A, Walsh CS,Miller CW (2008). FBXW7 mutation in adult T-cell and B-cell acute lymphocytic leukemias. Leuk Res, 32, 1751-5.
  29. Spruck CH, Strohmaier H, Sangfelt O, et al (2002). hCDC4 gene mutations in endometrial cancer. Cancer Res, 62, 4535-9.
  30. Thiery JP (2002). Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer, 2, 442-54.
  31. Thiery JP (2003). Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol, 15, 740-6.
  32. Thiery JP, Acloque H, Huang RY,Nieto MA (2009). Epithelial-mesenchymal transitions in development and disease. Cell, 139, 871-90.
  33. Thompson BJ, Buonamici S, Sulis ML, et al (2007). The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. J Exp Med, 204, 1825-35.
  34. Thomson S, Buck E, Petti F, et al (2005). Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res, 65, 9455-62.
  35. Wertz IE, Kusam S, Lam C, et al (2011). Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature, 471, 110-4.
  36. Willmarth NE, Albertson DG,Ethier SP (2004). Chromosomal instability and lack of cyclin E regulation in hCdc4 mutant human breast cancer cells. Breast Cancer Res, 6, R531-9.
  37. Wozniak AJ,Gadgeel SM (2007). Adjuvant treatment of non-small-cell lung cancer: how do we improve the cure rates further? Oncology (Williston Park), 21, 163-71; discussion 71, 74, 79-82.
  38. Yauch RL, Januario T, Eberhard DA, et al (2005). Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. Clin Cancer Res, 11, 8686-98.
  39. Zeisberg M,Neilson EG (2009). Biomarkers for epithelial-mesenchymal transitions. J Clin Invest, 119, 1429-37.
  40. Zhang W,Koepp DM (2006). Fbw7 isoform interaction contributes to cyclin E proteolysis. Mol Cancer Res, 4, 935-43.
  41. Zhang Z, Lee JC, Lin L, et al (2012). Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet, 44, 852-60.

Cited by

  1. Knockdown of Med19 Suppresses Proliferation and Enhances Chemo-sensitivity to Cisplatin in Non-small Cell Lung Cancer Cells vol.16, pp.3, 2015,
  2. FBW7 increases drug sensitivity to cisplatin in human nasopharyngeal carcinoma by downregulating the expression of multidrug resistance-associated protein vol.36, pp.6, 2015,
  3. Upregulation of Id3 inhibits cell proliferation and induces apoptosis in A549/DDP human lung cancer cells in vitro vol.14, pp.1, 2016,
  4. Drug resistance originating from a TGF-β/FGF-2-driven epithelial-to-mesenchymal transition and its reversion in human lung adenocarcinoma cell lines harboring an EGFR mutation vol.48, pp.5, 2016,
  5. TAZ overexpression is associated with epithelial-mesenchymal transition in cisplatin-resistant gastric cancer cells vol.51, pp.1, 2017,
  6. Artemisinin inhibits angiogenesis by regulating p38 MAPK/CREB/TSP-1 signaling pathway in osteosarcoma pp.07302312, 2019,