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FEN1 inhibitor synergizes with low-dose camptothecin to induce increased cell killing via the mitochondria mediated apoptotic pathway

Abstract

Camptothecin has been used in tumor therapy for a long time but its antitumor effect is rather limited due to the side effect and the drug resistance. FEN1, a major component of DNA repair systems, plays important roles in maintaining genomic stability via DNA replication and repair. Here we found that FEN1 inhibitor greatly sensitizes cancer cells to low-dose camptothecin. The combinative treatment of FEN1 inhibitor and 1 nM camptothecin induced a synthetic lethal effect, which synergistically suppressed cancer cell proliferation and significantly mediated apoptosis both in vitro and in vivo. Our study suggested that targeting FEN1 could be a potent strategy for tumor-targeting cancer therapy.

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Fig. 1: Co-treatment of low-dose CPT with FEN1 inhibitor SC13 can inhibit the proliferation of cancer cells.
Fig. 2: Effects of CPT or SC13 alone and in combination on cancer cell growth and cycle distribution.
Fig. 3: Effects of CPT or SC13 alone and in combination on apoptosis.
Fig. 4: DNA damage induced by treatment with CPT or SC13 alone and in combination on PC3 cells.
Fig. 5: Combination of CPT and SC13 induces mitochondrial damage.
Fig. 6: Co-treatment with CPT and SC13 suppressed tumor growth of mouse xenografts.

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References

  1. Li FZ, Jiang T, Li QY, Ling X. Camptothecin (CPT) and its derivatives are known to target topoisomerase I (Top1) as their mechanism of action: did we miss something in CPT analogue molecular targets for treating human disease such as cancer? Am J Cancer Res. 2017;7:2350–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Abelson HT, Penman S. Selective interruption of high molecular weight RNA synthesis in HeLa cells by camptothecin. Nature: New Biol. 1972;237:144–6.

    CAS  Google Scholar 

  3. Hosoya N, Miyagawa K. Targeting DNA damage response in cancer therapy. Cancer Sci. 2014;105:370–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ciccia A, Elledge SJ. The DNA damage response: making it safe to play with knives. Mol Cell. 2010;40:179–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hoeijmakers JH. DNA damage, aging, and cancer. New Engl J Med. 2009;361:1475–85.

    Article  CAS  PubMed  Google Scholar 

  6. Durkacz BW, Omidiji O, Gray DA, Shall S. (ADP-ribose)n participates in DNA excision repair. Nature. 1980;283:593–6.

    Article  CAS  PubMed  Google Scholar 

  7. Tsutakawa SE, Lafrance-Vanasse J, Tainer JA. The cutting edges in DNA repair, licensing, and fidelity: DNA and RNA repair nucleases sculpt DNA to measure twice, cut once. DNA Repair (Amst). 2014;19:95–107.

    Article  CAS  Google Scholar 

  8. Velic D, Couturier AM, Ferreira MT, Rodrigue A, Poirier GG, Fleury F, et al. DNA Damage Signalling and Repair Inhibitors: the Long-Sought-After Achilles’ Heel of Cancer. Biomolecules. 2015;5:3204–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zheng L, Jia J, Finger LD, Guo Z, Zer C, Shen B. Functional regulation of FEN1 nuclease and its link to cancer. Nucleic Acids Res. 2010;39:781–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Zheng L, Dai H, Zhou M, Li M, Singh P, Qiu J, et al. Fen1 mutations result in autoimmunity, chronic inflammation and cancers. Nature Med. 2007;13:812–9.

    Article  CAS  PubMed  Google Scholar 

  11. Kim IS, Lee MY, Lee IH, Shin SL, Lee SY. Gene expression of flap endonuclease-1 during cell proliferation and differentiation. Biochimica et Biophysica Acta. 2000;1496:333–40.

    Article  CAS  PubMed  Google Scholar 

  12. Warbrick E, Coates PJ, Hall PA. Fen1 expression: a novel marker for cell proliferation. J Pathol. 1998;186:319–24.

    Article  CAS  PubMed  Google Scholar 

  13. Nikolova T, Christmann M, Kaina B. FEN1 is overexpressed in testis, lung and brain tumors. Anticancer Res. 2009;29:2453–9.

    CAS  PubMed  Google Scholar 

  14. Lam JS, Seligson DB, Yu H, Li A, Eeva M, Pantuck AJ, et al. Flap endonuclease 1 is overexpressed in prostate cancer and is associated with a high Gleason score. BJU Int. 2006;98:445–51.

    Article  CAS  PubMed  Google Scholar 

  15. Sato M, Girard L, Sekine I, Sunaga N, Ramirez RD, Kamibayashi C, et al. Increased expression and no mutation of the Flap endonuclease (FEN1) gene in human lung cancer. Oncogene. 2003;22:7243–6.

    Article  CAS  PubMed  Google Scholar 

  16. Zheng L, Dai H, Zhou M, Li M, Singh P, Qiu J, et al. Fen1 mutations result in autoimmunity, chronic inflammation and cancers. Nature Med. 2007;13:812–9.

    Article  CAS  PubMed  Google Scholar 

  17. Helleday T, Petermann E, Lundin C, Hodgson B, Sharma RA. DNA repair pathways as targets for cancer therapy. Nature Rev Cancer. 2008;8:193–204.

    Article  CAS  Google Scholar 

  18. He L, Zhang Y, Sun H, Jiang F, Yang H, Wu H, et al. Targeting DNA Flap Endonuclease 1 to Impede Breast Cancer Progression. EBioMedicine. 2016;14:32–43.

    Article  PubMed  PubMed Central  Google Scholar 

  19. McManus KJ, Barrett IJ, Nouhi Y, Hieter P. Specific synthetic lethal killing of RAD54B-deficient human colorectal cancer cells by FEN1 silencing. Proc Natl Acad Sci USA. 2009;106:3276–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhao L, Wientjes MG, Au JL. Evaluation of combination chemotherapy: integration of nonlinear regression, curve shift, isobologram, and combination index analyses. Clin Cancer Res. 2004;10:7994–8004.

    Article  CAS  PubMed  Google Scholar 

  21. Elakoum R, Gauchotte G, Oussalah A, Wissler MP, Clement-Duchene C, Vignaud JM, et al. CARM1 and PRMT1 are dysregulated in lung cancer without hierarchical features. Biochimie. 2014;97:210–8.

    Article  CAS  PubMed  Google Scholar 

  22. Wu SG, Chang YL, Lin JW, Wu CT, Chen HY, Tsai MF, et al. Including total EGFR staining in scoring improves EGFR mutations detection by mutation-specific antibodies and EGFR TKIs response prediction. PLoS ONE. 2011;6:e23303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sun H, He L, Wu H, Pan F, Wu X, Zhao J, et al. The FEN1 L209P mutation interferes with long-patch base excision repair and induces cellular transformation. Oncogene. 2017;36:194–207.

    Article  CAS  PubMed  Google Scholar 

  24. He L, Yang H, Zhou S, Zhu H, Mao H, Ma Z, et al. Synergistic antitumor effect of combined paclitaxel with FEN1 inhibitor in cervical cancer cells. DNA Repair. 2018;63:1–9.

    Article  CAS  PubMed  Google Scholar 

  25. Tomicic MT, Kaina B. Topoisomerase degradation, DSB repair, p53 and IAPs in cancer cell resistance to camptothecin-like topoisomerase I inhibitors. Bba-Rev Cancer. 2013;1835:11–27.

    CAS  Google Scholar 

  26. Li JL, Wang JP, Chang H, Deng SM, Du JH, Wang XX, et al. FEN1 inhibitor increases sensitivity of radiotherapy in cervical cancer cells. Cancer Med. 2019;8:7774–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. He L, Luo L, Zhu H, Yang H, Zhang Y, Wu H, et al. FEN1 promotes tumor progression and confers cisplatin resistance in non-small cell lung cancer. Mol Oncol. 2017;11:640–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Deans AJ, West SC. DNA interstrand crosslink repair and cancer. Nature Rev Cancer. 2011;11:467–80.

    Article  CAS  Google Scholar 

  29. Helleday T, Petermann E, Lundin C, Hodgson B, Sharma RA. DNA repair pathways as targets for cancer therapy. Nature Rev Cancer. 2008;8:193–204.

    Article  CAS  Google Scholar 

  30. Balakrishnan L, Bambara RA. Flap endonuclease 1. Annual Rev Biochem. 2013;82:119–38.

    Article  CAS  Google Scholar 

  31. Klungland A, Lindahl T. Second pathway for completion of human DNA base excision-repair: reconstitution with purified proteins and requirement for DNase IV (FEN1). EMBO J. 1997;16:3341–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fehrmann RS, Karjalainen JM, Krajewska M, Westra HJ, Maloney D, Simeonov A, et al. Gene expression analysis identifies global gene dosage sensitivity in cancer. Nat Genet. 2015;47:115–25.

    Article  CAS  PubMed  Google Scholar 

  33. Kikuchi K, Taniguchi Y, Hatanaka A, Sonoda E, Hochegger H, Adachi N, et al. Fen-1 facilitates homologous recombination by removing divergent sequences at DNA break ends. Mol Cell Biol. 2005;25:6948–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu S, Lu G, Ali S, Liu W, Zheng L, Dai H, et al. Okazaki fragment maturation involves alpha-segment error editing by the mammalian FEN1/MutSalpha functional complex. EMBO J. 2015;34:1829–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mocquet V, Laine JP, Riedl T, Yajin Z, Lee MY, Egly JM. Sequential recruitment of the repair factors during NER: the role of XPG in initiating the resynthesis step. EMBO J. 2008;27:155–67.

    Article  CAS  PubMed  Google Scholar 

  36. Exell JC, Thompson MJ, Finger LD, Shaw SJ, Debreczeni J, Ward TA, et al. Cellularly active N-hydroxyurea FEN1 inhibitors block substrate entry to the active site. Nature Chem Biol. 2016;12:815–21.

    Article  CAS  Google Scholar 

  37. van Pel DM, Barrett IJ, Shimizu Y, Sajesh BV, Guppy BJ, Pfeifer T, et al. An evolutionarily conserved synthetic lethal interaction network identifies FEN1 as a broad-spectrum target for anticancer therapeutic development. PLoS Genet. 2013;9:e1003254.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Singh P, Yang M, Dai H, Yu D, Huang Q, Tan W, et al. Overexpression and hypomethylation of flap endonuclease 1 gene in breast and other cancers. Mol Cancer Res. 2008;6:1710–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang K, Xie C, Chen D. Flap endonuclease 1 is a promising candidate biomarker in gastric cancer and is involved in cell proliferation and apoptosis. Int J Mol Med. 2014;33:1268–74.

    Article  CAS  PubMed  Google Scholar 

  40. Iacobuzio-Donahue CA, Maitra A, Olsen M, Lowe AW, van Heek NT, Rosty C, et al. Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays. Am J Pathol. 2003;162:1151–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Krause A, Combaret V, Iacono I, Lacroix B, Compagnon C, Bergeron C, et al. Genome-wide analysis of gene expression in neuroblastomas detected by mass screening. Cancer Lett. 2005;225:111–20.

    Article  CAS  PubMed  Google Scholar 

  42. Abdel-Fatah TM, Russell R, Albarakati N, Maloney DJ, Dorjsuren D, Rueda OM, et al. Genomic and protein expression analysis reveals flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer. Mol Oncol. 2014;8:1326–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Poruchynsky MS, Komlodi-Pasztor E, Trostel S, Wilkerson J, Regairaz M, Pommier Y, et al. Microtubule-targeting agents augment the toxicity of DNA-damaging agents by disrupting intracellular trafficking of DNA repair proteins. Proc Natl Acad Sci USA. 2015;112:1571–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gokduman K. Strategies Targeting DNA Topoisomerase I in Cancer Chemotherapy: Camptothecins, Nanocarriers for Camptothecins, Organic Non-Camptothecin Compounds and Metal Complexes. Current Drug Targets. 2016;17:1928–39.

    Article  CAS  PubMed  Google Scholar 

  45. Guo E, Ishii Y, Mueller J, Srivatsan A, Gahman T, Putnam CD, et al. FEN1 endonuclease as a therapeutic target for human cancers with defects in homologous recombination. Proc Natl Acad Sci USA. 2020;117:19415–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mengwasser KE, Adeyemi RO, Leng Y, Choi MY, Clairmont C, D’Andrea AD, et al. Genetic Screens Reveal FEN1 and APEX2 as BRCA2 Synthetic Lethal Targets. Mol Cell. 2019;73:885–99 e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Correspondence to Lingfeng He, Fei-Yan Pan or Zhigang Guo.

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Wu, T., Zhu, H., Zhang, M. et al. FEN1 inhibitor synergizes with low-dose camptothecin to induce increased cell killing via the mitochondria mediated apoptotic pathway. Gene Ther 29, 407–417 (2022). https://doi.org/10.1038/s41434-020-00215-9

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