Advertisement

Functional mismatch repair and inactive p53 drive sensitization of colorectal cancer cells to irinotecan via the IAP antagonist BV6

  • Maja T. TomicicEmail author
  • Christian Steigerwald
  • Birgit Rasenberger
  • Anamaria Brozovic
  • Markus Christmann
Molecular Toxicology

Abstract

A common strategy to overcome acquired chemotherapy resistance is the combination of a specific anticancer drug (e.g., topoisomerase I inhibitor irinotecan) together with a putative sensitizer. The purpose of this study was to analyze the cytostatic/cytotoxic response of colorectal carcinoma (CRC) cells to irinotecan, depending on the mismatch repair (MMR) and p53 status and to examine the impact of BV6, a bivalent antagonist of inhibitors of apoptosis c-IAP1/c-IAP2, alone or combined with irinotecan. Therefore, several MSH2- or MSH6-deficient cell lines were complemented for MMR deficiency, or MSH6 was knocked out/down in MMR-proficient cells. Upon irinotecan, MMR-deficient/p53-mutated lines repaired DNA double-strand breaks by homologous recombination less efficiently than MMR-proficient/p53-mutated lines and underwent elevated caspase-9-dependent apoptosis. Opposite, BV6-mediated sensitization was achieved only in MMR-proficient/p53-mutated cells. In those cells, c-IAP1 and c-IAP2 were effectively degraded by BV6, caspase-8 was fully activated, and both canonical and non-canonical NF-κB signaling were triggered. The results were confirmed ex vivo in tumor organoids from CRC patients. Therefore, the particular MMR+/p53mt signature, often found in non-metastasizing (stage II) CRC might be used as a prognostic factor for an adjuvant therapy using low-dose irinotecan combined with a bivalent IAP antagonist.

Keywords

IAP antagonist Irinotecan Colorectal cancer Mismatch repair p53 NF-κB 

Notes

Acknowledgements

We thank Anna Frumkina for conducting neutral comet assay. The work was financed by Dr. Mildred Scheel Stiftung für Krebsforschung to MTT.

Author contributions

MTT: study design, experimental work, data analysis, paper writing. CS: experimental work. BR: technical assistance, experimental work. AB: contribution to a new model/methodology. MC: discussion and consulting.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

204_2019_2513_MOESM1_ESM.pptx (2.3 mb)
Supplementary material 1 (PPTX 2394 kb)

References

  1. Aasland D, Gotzinger L, Hauck L et al (2018) Temozolomide induces senescence and repression of DNA repair pathways in glioblastoma cells via activation of ATR-CHK1, p21, and NF-kB. Cancer Res.  https://doi.org/10.1158/0008-5472.can-18-1733 Google Scholar
  2. Bhonde MR, Hanski ML, Budczies J et al (2006) DNA damage-induced expression of p53 suppresses mitotic checkpoint kinase hMps1: the lack of this suppression in p53MUT cells contributes to apoptosis. J Biol Chem 281(13):8675–8685CrossRefGoogle Scholar
  3. Bhonde MR, Hanski ML, Stehr J et al (2010) Mismatch repair system decreases cell survival by stabilizing the tetraploid G1 arrest in response to SN-38. Int J Cancer 126(12):2813–2825.  https://doi.org/10.1002/ijc.24893 Google Scholar
  4. Christmann M, Diesler K, Majhen D et al (2017) Integrin alphaVbeta3 silencing sensitizes malignant glioma cells to temozolomide by suppression of homologous recombination repair. Oncotarget 8(17):27754–27771.  https://doi.org/10.18632/oncotarget.10897 CrossRefGoogle Scholar
  5. Fallik D, Borrini F, Boige V et al (2003) Microsatellite instability is a predictive factor of the tumor response to irinotecan in patients with advanced colorectal cancer. Cancer Res 63(18):5738–5744Google Scholar
  6. Fedier A, Schwarz VA, Walt H, Carpini RD, Haller U, Fink D (2001) Resistance to topoisomerase poisons due to loss of DNA mismatch repair. Int J Cancer 93(4):571–576CrossRefGoogle Scholar
  7. Fulda S (2014) Regulation of cell migration, invasion and metastasis by IAP proteins and their antagonists. Oncogene 33(6):671–676.  https://doi.org/10.1038/onc.2013.63 CrossRefGoogle Scholar
  8. Fulda S, Vucic D (2012) Targeting IAP proteins for therapeutic intervention in cancer. Nat Rev Drug Discov 11(2):109–124.  https://doi.org/10.1038/nrd3627 CrossRefGoogle Scholar
  9. Gryfe R, Kim H, Hsieh ET et al (2000) Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. New Engl J Med 342(2):69–77.  https://doi.org/10.1056/NEJM200001133420201 CrossRefGoogle Scholar
  10. Guo J, Verma UN, Gaynor RB, Frenkel EP, Becerra CR (2004) Enhanced chemosensitivity to irinotecan by RNA interference-mediated down-regulation of the nuclear factor-kappaB p65 subunit. Clin Cancer Res 10(10):3333–3341.  https://doi.org/10.1158/1078-0432.CCR-03-0366 CrossRefGoogle Scholar
  11. Hausner P, Venzon DJ, Grogan L, Kirsch IR (1999) The ``comparative growth assay”: examining the interplay of anti-cancer agents with cells carrying single gene alterations. Neoplasia 1(4):356–367CrossRefGoogle Scholar
  12. Hird AW, Aquila BM, Hennessy EJ, Vasbinder MM, Yang B (2015) Small molecule inhibitor of apoptosis proteins antagonists: a patent review. Expert Opin Ther Pat 25(7):755–774.  https://doi.org/10.1517/13543776.2015.1041922 CrossRefGoogle Scholar
  13. Jacob S, Aguado M, Fallik D, Praz F (2001) The role of the DNA mismatch repair system in the cytotoxicity of the topoisomerase inhibitors camptothecin and etoposide to human colorectal cancer cells. Cancer Res 61(17):6555–6562Google Scholar
  14. Jaquith JB (2014) Targeting the inhibitor of apoptosis protein BIR3 binding domains. Pharm Patent Anal 3(3):297–312.  https://doi.org/10.4155/ppa.14.16 CrossRefGoogle Scholar
  15. Lee EW, Seong D, Seo J, Jeong M, Lee HK, Song J (2015) USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to smac mimetics. Cell Death Differ 22(9):1463–1476.  https://doi.org/10.1038/cdd.2014.234 CrossRefGoogle Scholar
  16. Magrini R, Bhonde MR, Hanski ML et al (2002) Cellular effects of CPT-11 on colon carcinoma cells: dependence on p53 and hMLH1 status. Int J Cancer 101(1):23–31CrossRefGoogle Scholar
  17. Reich TR, Switzeny OJ, Renovanz M et al (2017) Epigenetic silencing of XAF1 in high-grade gliomas is associated with IDH1 status and improved clinical outcome. Oncotarget 8(9):15071–15084.  https://doi.org/10.18632/oncotarget.14748 CrossRefGoogle Scholar
  18. Roig AI, Eskiocak U, Hight SK et al (2010) Immortalized epithelial cells derived from human colon biopsies express stem cell markers and differentiate in vitro. Gastroenterology 138(3):1012–1021.  https://doi.org/10.1053/j.gastro.2009.11.052 CrossRefGoogle Scholar
  19. Shiovitz S, Bertagnolli MM, Renfro LA et al (2014) CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer. Gastroenterology 147(3):637–645.  https://doi.org/10.1053/j.gastro.2014.05.009 CrossRefGoogle Scholar
  20. Steigerwald C, Rasenberger B, Christmann M, Tomicic MT (2018) Sensitization of colorectal cancer cells to irinotecan by the Survivin inhibitor LLP3 depends on XAF1 proficiency in the context of mutated p53. Arch Toxicol 92(8):2645–2648.  https://doi.org/10.1007/s00204-018-2240-x CrossRefGoogle Scholar
  21. Tomicic MT, Kaina B (2013) Topoisomerase degradation, DSB repair, p53 and IAPs in cancer cell resistance to camptothecin-like topoisomerase I inhibitors. Biochim Biophys Acta 1835(1):11–27Google Scholar
  22. Tomicic MT, Bey E, Wutzler P, Thust R, Kaina B (2002) Comparative analysis of DNA breakage, chromosomal aberrations and apoptosis induced by the anti-herpes purine nucleoside analogues aciclovir, ganciclovir and penciclovir. Mutat Res 505(1–2):1–11CrossRefGoogle Scholar
  23. Tomicic MT, Christmann M, Kaina B (2005) Topotecan-triggered degradation of topoisomerase I is p53-dependent and impacts cell survival. Cancer Res 65(19):8920–8926CrossRefGoogle Scholar
  24. van de Wetering M, Francies HE, Francis JM et al (2015) Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161(4):933–945.  https://doi.org/10.1016/j.cell.2015.03.053 CrossRefGoogle Scholar
  25. Varfolomeev E, Blankenship JW, Wayson SM et al (2007) IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell 131(4):669–681.  https://doi.org/10.1016/j.cell.2007.10.030 CrossRefGoogle Scholar
  26. Vilar E, Scaltriti M, Balmana J et al (2008) Microsatellite instability due to hMLH1 deficiency is associated with increased cytotoxicity to irinotecan in human colorectal cancer cell lines. Br J Cancer 99(10):1607–1612.  https://doi.org/10.1038/sj.bjc.6604691 CrossRefGoogle Scholar
  27. Volcic M, Karl S, Baumann B et al (2012) NF-kappaB regulates DNA double-strand break repair in conjunction with BRCA1-CtIP complexes. Nucleic Acids Res 40(1):181–195.  https://doi.org/10.1093/nar/gkr687 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of ToxicologyUniversity Medical Center MainzMainzGermany
  2. 2.Division of Molecular BiologyRuđer Bošković InstituteZagrebCroatia

Personalised recommendations