Drug resistance of bladder cancer cells through activation of ABCG2 by FOXM1

  • Roh, Yun-Gil (Department of Biological Science, College of Natural Science, Dong-A University) ;
  • Mun, Mi-Hye (Department of Biological Science, College of Natural Science, Dong-A University) ;
  • Jeong, Mi-So (Department of Biological Science, College of Natural Science, Dong-A University) ;
  • Kim, Won-Tae (Department of Biological Science, College of Natural Science, Dong-A University) ;
  • Lee, Se-Ra (Division of Drug Development & Optimization, Osong Medical Innovation Foundation (KBio)) ;
  • Chung, Jin-Woong (Department of Biological Science, College of Natural Science, Dong-A University) ;
  • Kim, Seung Il (Drug & Disease Target Team, Korea Basic Science Institute) ;
  • Kim, Tae Nam (Department of Urology, Medical Research Institute, Pusan National University Hospital) ;
  • Nam, Jong Kil (Department of Urology, Research Institute for Convergence of Biochemical Science and Technology, Pusan National University Yangsan Hospital) ;
  • Leem, Sun-Hee (Department of Biological Science, College of Natural Science, Dong-A University)
  • Received : 2017.11.24
  • Accepted : 2018.02.02
  • Published : 2018.02.28


Recurrence is a serious problem in patients with bladder cancer. The hypothesis for recurrence was that the proliferation of drug-resistant cells was reported, and this study focused on drug resistance due to drug efflux. Previous studies have identified FOXM1 as the key gene for recurrence. We found that FOXM1 inhibition decreased drug efflux activity and increased sensitivity to Doxorubicin. Therefore, we examined whether the expression of ABC transporter gene related to drug efflux is regulated by FOXM1. As a result, ABCG2, one of the genes involved in drug efflux, has been identified as a new target for FOXM1. We also demonstrated direct transcriptional regulation of ABCG2 by FOXM1 using ChIP assay. Consequently, in the presence of the drug, FOXM1 is proposed to directly activate ABCG2 to increase the drug efflux activation and drug resistance, thereby involving chemoresistance of bladder cancer cells. Therefore, we suggest that FOXM1 and ABCG2 may be useful targets and important parameters in the treatment of bladder cancer.


ABCG2;Bladder cancer;Cancer recurrence;Drug resistance;FOXM1


Supported by : National Research Foundation of Korea (NRF), Korea Health Industry Development Institute (KHIDI), National Council of Science & Technology (NST)


  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A (2015) Global cancer statistics,2012. CA Cancer J Clin 65, 87-108
  2. Youssef RF and Lotan Y (2011) Predictors of outcome of non-muscle-invasive and muscle-invasive bladder cancer. ScientificWorldJournal 11, 369-381
  3. Sylvester RJ, van der Meijden AP, Oosterlinck W et al (2006) Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 49, 466-465; discussion 475-467
  4. Hall MC, Chang SS, Dalbagni G et al (2007) Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J Urol 178, 2314-2330
  5. Woldu SL, Bagrodia A and Lotan Y (2017) Guideline of guidelines: non-muscle-invasive bladder cancer. BJU Int 119, 371-380
  6. van Rhijn BW, Burger M, Lotan Y et al (2009) Recurrence and progression of disease in non-muscle-invasive bladder cancer: from epidemiology to treatment strategy. Eur Urol 56, 430-442
  7. Chen Y, Zhu G, Wu K et al (2016) FGF2-mediated reciprocal tumor cell-endothelial cell interplay contributes to the growth of chemoresistant cells: a potential mechanism for superficial bladder cancer recurrence. Tumour Biol 37, 4313-4321
  8. Chang JC (2016) Cancer stem cells: Role in tumor growth, recurrence, metastasis, and treatment resistance. Medicine (Baltimore) 95, S20-25
  9. Salehan MR and Morse HR (2013) DNA damage repair and tolerance: a role in chemotherapeutic drug resistance. Br J Biomed Sci 70, 31-40
  10. Ryu J, Yoon NA, Seong H et al (2015) Resveratrol Induces Glioma Cell Apoptosis through Activation of Tristetraprolin. Mol Cells 38, 991-997
  11. Millour J, de Olano N, Horimoto Y et al (2011) ATM and p53 regulate FOXM1 expression via E2F in breast cancer epirubicin treatment and resistance. Mol Cancer Ther 10, 1046-1058
  12. Rosenfeldt MT, Bell LA, Long JS et al (2014) E2F1 drives chemotherapeutic drug resistance via ABCG2. Oncogene 33, 4164-4172
  13. Costa RH (2005) FoxM1 dances with mitosis. Nat Cell Biol 7, 108-110
  14. Kim SK, Roh YG, Park K et al (2014) Expression signature defined by FOXM1-CCNB1 activation predicts disease recurrence in non-muscle-invasive bladder cancer. Clin Cancer Res 20, 3233-3243
  15. Park YY, Jung SY, Jennings NB et al (2012) FOXM1 mediates Dox resistance in breast cancer by enhancing DNA repair. Carcinogenesis 33, 1843-1853
  16. Nestal de Moraes G, Bella L, Zona S, Burton MJ and Lam EW (2016) Insights into a Critical Role of the FOXO3a-FOXM1 Axis in DNA Damage Response and Genotoxic Drug Resistance. Curr Drug Targets 17, 164-177
  17. Khongkow P, Gomes AR, Gong C et al (2016) Paclitaxel targets FOXM1 to regulate KIF20A in mitotic catastrophe and breast cancer paclitaxel resistance. Oncogene 35, 990-1002
  18. Gemenetzidis E, Elena-Costea D, Parkinson EK, Waseem A, Wan H and Teh MT (2010) Induction of human epithelial stem/progenitor expansion by FOXM1. Cancer Res 70, 9515-9526
  19. Zahreddine H and Borden KL (2013) Mechanisms and insights into drug resistance in cancer. Front Pharmacol 4, 28
  20. Fletcher JI, Haber M, Henderson MJ and Norris MD (2010) ABC transporters in cancer: more than just drug efflux pumps. Nat Rev Cancer 10, 147-156
  21. Ding XW, Wu JH and Jiang CP (2010) ABCG2: a potential marker of stem cells and novel target in stem cell and cancer therapy. Life Sci 86, 631-637
  22. Mo W and Zhang JT (2012) Human ABCG2: structure, function, and its role in multidrug resistance. Int J Biochem Mol Biol 3, 1-27
  23. An Y and Ongkeko WM (2009) ABCG2: the key to chemoresistance in cancer stem cells? Expert Opin Drug Metab Toxicol 5, 1529-1542
  24. Robey RW, To KK, Polgar O et al (2009) ABCG2: a perspective. Adv Drug Deliv Rev 61, 3-13
  25. Guzel E, Karatas OF, Duz MB, Solak M, Ittmann M and Ozen M (2014) Differential expression of stem cell markers and ABCG2 in recurrent prostate cancer. Prostate 74, 1498-1505
  26. Hu J, Li J, Yue X et al (2017) Expression of the cancer stem cell markers ABCG2 and OCT-4 in right-sided colon cancer predicts recurrence and poor outcomes. Oncotarget 8, 28463-28470
  27. Costa C, Pereira S, Lima L et al (2015) Abnormal Protein Glycosylation and Activated PI3K/Akt/mTOR Pathway: Role in Bladder Cancer Prognosis and Targeted Therapeutics. PLoS One 10, e0141253
  28. Natarajan K, Xie Y, Baer MR and Ross DD (2012) Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance. Biochem Pharmacol 83, 1084-1103
  29. Teh MT (2012) FOXM1 coming of age: time for translation into clinical benefits? Front Oncol 2, 146
  30. Damiani D, Tiribelli M, Geromin A et al (2015) ABCG2 overexpression in patients with acute myeloid leukemia: Impact on stem cell transplantation outcome. Am J Hematol 90, 784-789
  31. Kim DH, Roh YG, Lee HH et al (2013) The E2F1 oncogene transcriptionally regulates NELL2 in cancer cells. DNA Cell Biol 32, 517-523

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