Molecular and Cellular Biochemistry

, Volume 398, Issue 1–2, pp 175–183 | Cite as

TCRP1 contributes to cisplatin resistance by preventing Pol β degradation in lung cancer cells

  • Xiaorong Liu
  • Chengkun Wang
  • Yixue Gu
  • Zhijie Zhang
  • Guopei Zheng
  • Zhimin He


Cisplatin (DDP) is the first-line chemotherapy drug widely used for the treatment of lung cancer patients, whereas the majority of cancer patients will eventually show resistance to DDP. The mechanisms responsible for DDP resistance are not fully understood. Tongue cancer resistance-associated protein 1 (TCRP1) gene was recently cloned and reported to specially mediate DDP resistance in human oral squamous cell carcinoma (OSCC) cells. However, the mechanisms of TCRP1-mediated DDP resistance are far from clear, and whether TCRP1 participates in DDP resistance in lung cancer cells remains unknown. Here, we show that TCRP1 contributes to DDP resistance in lung cancer cells. Knockdown of TCRP1 sensitizes the cells to DDP and increases the DDP-induced DNA damage. We have identified that Pol β is associated with DDP resistance, and Pol β knockdown delays the repair of DDP-induced DNA damage in A549/DDP cells. We find TCRP1 interacts with Pol β in lung cancer cells. Moreover, TCRP1 knockdown decreases the level of Pol β and increases the level of its ubiquitination. These results suggest that TCRP1 contributes to DDP resistance through the prevention of Pol β degradation in lung cancer cells. These findings provide new insights into chemoresistance and may contribute to prevention and reversal of DDP resistance in treatment of lung cancer in the future.


TCRP1 DDP resistance Pol β DNA repair 



This work was supported by research grants from the Natural Science Foundation of China (30873088), Natural Science Foundation of Guangdong Province (S2012010008995), and Doctoral fund of Education Ministry of China (20124423110003).

Supplementary material

11010_2014_2217_MOESM1_ESM.docx (371 kb)
Supplementary material 1 (DOCX 370 kb)


  1. 1.
    Ferlay JSI, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2013) GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer.
  2. 2.
    Bray F, Ren JS, Masuyer E, Ferlay J (2013) Global estimates of cancer prevalence for 27 sites in the adult population in 2008. Int J Cancer 132:1133–1145PubMedCrossRefGoogle Scholar
  3. 3.
    Novello S, Besse B, Felip E, Barlesi F, Mazieres J et al (2014) A phase II randomized study evaluating the addition of iniparib to gemcitabine plus cisplatin as first-line therapy for metastatic non-small cell lung cancer. Ann OncolGoogle Scholar
  4. 4.
    Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP et al (2004) Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350:351–360PubMedCrossRefGoogle Scholar
  5. 5.
    Siddik ZH (2003) Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 22:7265–7279PubMedCrossRefGoogle Scholar
  6. 6.
    Enoiu M, Jiricny J, Scharer OD (2012) Repair of cisplatin-induced DNA interstrand crosslinks by a replication-independent pathway involving transcription-coupled repair and translesion synthesis. Nucleic Acids Res 40:8953–8964PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Martin LP, Hamilton TC, Schilder RJ (2008) Platinum resistance: the role of DNA repair pathways. Clin Cancer Res 14:1291–1295PubMedCrossRefGoogle Scholar
  8. 8.
    Dasari S, Bernard Tchounwou P (2014) Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J Pharmacol 740C:364–378CrossRefGoogle Scholar
  9. 9.
    Galluzzi L, Vitale I, Michels J, Brenner C, Szabadkai G et al (2014) Systems biology of cisplatin resistance: past, present and future. Cell Death Dis 5:e1257PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Stordal B, Davey M (2007) Understanding cisplatin resistance using cellular models. IUBMB Life 59:696–699PubMedCrossRefGoogle Scholar
  11. 11.
    Shen DW, Pouliot LM, Hall MD, Gottesman MM (2012) Cisplatin resistance: a cellular self-defense mechanism resulting from multiple epigenetic and genetic changes. Pharmacol Rev 64:706–721PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Gu Y, Fan S, Xiong Y, Peng B, Zheng G et al (2011) Cloning and functional characterization of TCRP1, a novel gene mediating resistance to cisplatin in an oral squamous cell carcinoma cell line. FEBS Lett 585:881–887PubMedCrossRefGoogle Scholar
  13. 13.
    Peng B, Gu Y, Xiong Y, Zheng G, He Z (2012) Microarray-assisted pathway analysis identifies MT1X & NFkappaB as mediators of TCRP1-associated resistance to cisplatin in oral squamous cell carcinoma. PLoS ONE 7:e51413PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Gu Y, Fan S, Liu B, Zheng G, Yu Y et al (2011) TCRP1 promotes radioresistance of oral squamous cell carcinoma cells via Akt signal pathway. Mol Cell Biochem 357:107–113PubMedCrossRefGoogle Scholar
  15. 15.
    Peng B, Yi S, Gu Y, Zheng G, He Z (2012) Purification and biochemical characterization of a novel protein-tongue cancer chemotherapy resistance-associated protein1 (TCRP1). Protein Expr Purif 82:360–367PubMedCrossRefGoogle Scholar
  16. 16.
    Olive PL, Banath JP (2009) Kinetics of H2AX phosphorylation after exposure to cisplatin. Cytom B Clin Cytom 76:79–90CrossRefGoogle Scholar
  17. 17.
    Muid KA, Karakaya HC, Koc A (2014) Absence of superoxide dismutase activity causes nuclear DNA fragmentation during the aging process. Biochem Biophys Res Commun 444:260–263PubMedCrossRefGoogle Scholar
  18. 18.
    Olive PL, Banath JP (2006) The comet assay: a method to measure DNA damage in individual cells. Nat Protoc 1:23–29PubMedCrossRefGoogle Scholar
  19. 19.
    Kang TH, Lindsey-Boltz LA, Reardon JT, Sancar A (2010) Circadian control of XPA and excision repair of cisplatin-DNA damage by cryptochrome and HERC2 ubiquitin ligase. Proc Natl Acad Sci U S A 107:4890–4895PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Basu A, Krishnamurthy S (2010) Cellular responses to Cisplatin-induced DNA damage. J Nucleic Acids 2010Google Scholar
  21. 21.
    Li K, Li W (2013) Association between polymorphisms of XRCC1 and ADPRT genes and ovarian cancer survival with platinum-based chemotherapy in Chinese population. Mol Cell Biochem 372:27–33PubMedCrossRefGoogle Scholar
  22. 22.
    Freudenthal BD, Beard WA, Shock DD, Wilson SH (2013) Observing a DNA polymerase choose right from wrong. Cell 154:157–168PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Pei DS, Yang XJ, Liu W, Guikema JE, Schrader CE et al (2011) A novel regulatory circuit in base excision repair involving AP endonuclease 1, Creb1 and DNA polymerase beta. Nucleic Acids Res 39:3156–3165PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Sobol RW (2012) Genome instability caused by a germline mutation in the human DNA repair gene POLB. PLoS Genet 8:e1003086PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Bergoglio V, Canitrot Y, Hogarth L, Minto L, Howell SB et al (2001) Enhanced expression and activity of DNA polymerase beta in human ovarian tumor cells: impact on sensitivity towards antitumor agents. Oncogene 20:6181–6187PubMedCrossRefGoogle Scholar
  26. 26.
    Iwatsuki M, Mimori K, Yokobori T, Tanaka F, Tahara K et al (2009) A platinum agent resistance gene, POLB, is a prognostic indicator in colorectal cancer. J Surg Oncol 100:261–266PubMedCrossRefGoogle Scholar
  27. 27.
    Parsons JL, Tait PS, Finch D, Dianova II, Allinson SL et al (2008) CHIP-mediated degradation and DNA damage-dependent stabilization regulate base excision repair proteins. Mol Cell 29:477–487PubMedCrossRefGoogle Scholar
  28. 28.
    Parsons JL, Tait PS, Finch D, Dianova II, Edelmann MJ et al (2009) Ubiquitin ligase ARF-BP1/Mule modulates base excision repair. EMBO J 28:3207–3215PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Parsons JL, Dianova II, Khoronenkova SV, Edelmann MJ, Kessler BM et al (2011) USP47 is a deubiquitylating enzyme that regulates base excision repair by controlling steady-state levels of DNA polymerase beta. Mol Cell 41:609–615PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Xiaorong Liu
    • 1
  • Chengkun Wang
    • 2
  • Yixue Gu
    • 2
  • Zhijie Zhang
    • 2
  • Guopei Zheng
    • 2
  • Zhimin He
    • 1
    • 2
  1. 1.Cancer Research Institute, Xiangya School of MedicineCentral South UniversityChangshaChina
  2. 2.Affiliated Cancer Hospital and Cancer Research InstituteGuangzhou Medical UniversityGuangzhouChina

Personalised recommendations