Skip to main content
SpringerLink
Log in

Identification of PARP-1 in cancer stem cells of gastrointestinal cancers: A preliminary study

  • Published:
Journal of Biosciences Aims and scope Submit manuscript

Abstract

Advanced-stage gastrointestinal tumors have high mortality due to chemotherapy limitations. One of the causes of treatment failure is the presence of cancer stem cells (CSCs), which show resistance mechanisms against DNA damage, such as poly (adenosine diphosphate-ribose) polymerase 1 (PARP-1). However, little is known about the relevance of PARP-1 in these tumor cells. Our purpose is to analyze the expression of PARP-1 in cancer cells and CSCs from gastrointestinal tumors, its relationship with the DNA damage repair process and its modulation by cytotoxic and PARP-1 inhibitors. We used pancreatic, liver and colon cancer cell lines and isolated CSCs using Aldefluor technology to analyze PARP-1 expression. In addition, we examined the effect of classic cytotoxic drugs (Doxorubicin, Gemcitabine, Irinotecan and 5-Fluorouracil) and a PARP-1 inhibitor (Olaparib) in cultured cells and 3D tumorspheres. We demonstrated that PARP-1 is highly expressed in pancreatic, liver and colon tumor cells and that this expression was significantly higher in cell populations with CSC characteristics. In addition, Doxorubicin and Gemcitabine increased their cytotoxic effect when administered simultaneously with Olaparib, decreasing the formation of 3D tumorspheres. Our findings suggest that PARP-1 is a common and relevant resistance mechanism in CSCs from gastrointestinal tumors and that the use of PARP-1 inhibitors may be an adjuvant therapy to increase apoptosis in this type of cells which are responsible to cancer recurrence and metastasis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Abdel-Rahman O 2019 ECOG performance score 0 versus 1: impact on efficacy and safety of first-line 5-FU-based chemotherapy among patients with metastatic colorectal cancer included in five randomized trials. Int. J. Colorectal Dis. 34 2143–2150

    Article  PubMed  Google Scholar 

  • Adamska A, Elaskalani O, Emmanouilidi A, Kim M, Abdol Razak NB, Metharom P and Falasca M 2018 Molecular and cellular mechanisms of chemoresistance in pancreatic cancer. Adv. Biol. Regul. 68 77–87

    Article  CAS  PubMed  Google Scholar 

  • Artin E, Wang J, Lohman GJS, Yokoyama K, Yu G, Griffin RG, Bar G and Stubbe JA 2009 Insight into the mechanism of inactivation of ribonucleotide reductase by gemcitabine 5′-diphosphate in the presence or absence of reductant. Biochemistry 48 11622–11629

    Article  CAS  PubMed  Google Scholar 

  • Augustine T, Maitra R, Zhang J, Nayak J and Goel S 2019 Sensitization of colorectal cancer to irinotecan therapy by PARP inhibitor rucaparib. Invest. New Drugs 37 948–960

    Article  CAS  PubMed  Google Scholar 

  • Biancur DE and Kimmelman AC 2018 The plasticity of pancreatic cancer metabolism in tumor progression and therapeutic resistance. Biochim. Biophys. Acta Rev. Cancer 1870 67–75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A 2018 Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA. Cancer J. Clin. 68 394–424

    Article  PubMed  Google Scholar 

  • Bryant HE et al. 2005 Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434 913–917

    Article  CAS  Google Scholar 

  • Dörsam B et al. 2018 PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression. Proc. Natl. Acad. Sci. USA 115 E4061–70

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Dziaman T et al. 2014 PARP-1 expression is increased in colon adenoma and carcinoma and correlates with OGG1. PLoS One 9 e115558

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Engstrom PF et al. 2009 Colon cancer. JNCCN J. Natl. Compr. Cancer Netw. 7 778–831

    Article  Google Scholar 

  • Farago AF et al. 2019 Combination olaparib and temozolomide in relapsed small-cell lung cancer. Cancer Discov. 9 1372–87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fateen W and Ryder S 2017 Screening for hepatocellular carcinoma: patient selection and perspectives. J. Hepatocell. Carcinoma 4 71–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Geng L, Huehls AM, Wagner JM, Huntoon CJ and Karnitz LM 2011 Checkpoint signaling, base excision repair, and PARP promote survival of colon cancer cells treated with 5-fluorodeoxyuridine but not 5-fluorouracil. PLoS One 6 e28862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gilabert M et al. 2014 Poly(ADP-Ribose) polymerase 1 (PARP1) overexpression in human breast cancer stem cells and resistance to olaparib. PLoS One 9 e104302

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Golan T et al. 2019 Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N. Engl. J. Med. 381 317–327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ilmer M, Mazurek N, Byrd JC, Ramirez K, Hafley M, Alt E, Vykoukal J and Bresalier RS 2016 Cell surface galectin-3 defines a subset of chemoresistant gastrointestinal tumor-initiating cancer cells with heightened stem cell characteristics. Cell Death Dis. 7 e2337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang BH et al. 2015 CHD1L Regulated PARP1-Driven Pluripotency and Chromatin Remodeling during the Early-Stage Cell Reprogramming. Stem Cells 33 2961–2972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang Y, Dai H, Li Y, Yin J, Guo S, Lin SY and McGrail DJ 2019 PARP inhibitors synergize with gemcitabine by potentiating DNA damage in non-small-cell lung cancer. Int. J. Cancer 144 1092–1103

    Article  CAS  PubMed  Google Scholar 

  • Kümler I, Balslev E, Stenvang J, Brünner N and Nielsen D 2015 A phase II study of weekly irinotecan in patients with locally advanced or metastatic HER2-negative breast cancer and increased copy numbers of the topoisomerase 1 (TOP1) gene: a study protocol. BMC Cancer 15 78

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kwon M, Jang H, Kim EH and Roh JL 2016 Efficacy of poly (ADP-ribose) polymerase inhibitor olaparib against head and neck cancer cells: Predictions of drug sensitivity based on PAR–p53–NF-κB interactions. Cell Cycle 15 3105–3114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Longley DB, Harkin DP and Johnston PG 2003 5-Fluorouracil: mechanisms of action and clinical strategies. Nat. Rev. Cancer 3 330–338

    Article  CAS  PubMed  Google Scholar 

  • LoRusso PM et al. 2016 Phase I safety, pharmacokinetic, and pharmacodynamic study of the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib (ABT-888) in combination with irinotecan in patients with advanced solid tumors. Clin. Cancer Res. 22 3227–3237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martin-Guerrero SM, Leon J, Quiles-Perez R, Belmonte L, Martin-Oliva D, Ruiz-Extremera A, Salmeron J and Muñoz-Gamez JA 2017 Expression and Single Nucleotide Polymorphism of Poly (ADPRibose) polymerase-1 in gastrointestinal tumours: clinical involvement. Curr. Med. Chem. 24 2156–2173

    Article  CAS  PubMed  Google Scholar 

  • Matulonis UA et al. 2017 Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer. Ann. Oncol. 28 512–518

    Article  CAS  PubMed  Google Scholar 

  • Mikhail S and Zeidan A 2014 Stem cells in gastrointestinal cancers: the road less travelled. World J. Stem Cells 6 606–613

    Article  PubMed  PubMed Central  Google Scholar 

  • Morata-Tarifa C, Jiménez G, García MA, Entrena JM, Griñán-Lisón C, Aguilera M, Picon-Ruiz M and Marchal JA 2016 Low adherent cancer cell subpopulations are enriched in tumorigenic and metastatic epithelial-to-mesenchymal transition-induced cancer stem-like cells. Sci. Rep. 6 18772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nguyen TTT, Lim JSL, Tang RMY, Zhang L and Chen ES 2015 Fitness profiling links topoisomerase II regulation of centromeric integrity to doxorubicin resistance in fission yeast. Sci. Rep. 5 1–10

    Article  Google Scholar 

  • Nosho K et al. 2006 Overexpression of poly(ADP-ribose) polymerase-1 (PARP-1) in the early stage of colorectal carcinogenesis. Eur. J. Cancer 42 2374–2381

    Article  CAS  PubMed  Google Scholar 

  • Ossovskaya V, Koo IC, Kaldjian EP, Alvares C and Sherman BM 2010 Upregulation of poly (ADP-Ribose) polymerase-1 (PARP1) in triple-negative breast cancer and other primary human tumor types. Genes Cancer 1 812–821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park HJ et al. 2018 The PARP inhibitor olaparib potentiates the effect of the DNA damaging agent doxorubicin in osteosarcoma. J. Exp. Clin. Cancer Res. 37 1–15

    Article  CAS  Google Scholar 

  • Pishvaian MJ et al. 2018 A phase 2 study of the PARP inhibitor veliparib plus temozolomide in patients with heavily pretreated metastatic colorectal cancer. Cancer 124 2337–2346

    Article  CAS  PubMed  Google Scholar 

  • Poggio F et al. 2018 Single-agent PARP inhibitors for the treatment of patients with BRCA -mutated HER2-negative metastatic breast cancer: a systematic review and meta-analysis. ESMO Open 3 e000361

    Article  PubMed  PubMed Central  Google Scholar 

  • Raha D et al. 2014 The cancer stem cell marker aldehyde dehydrogenase is required to maintain a drug-tolerant tumor cell subpopulation. Cancer Res. 74 3579–3590

    Article  CAS  PubMed  Google Scholar 

  • Rajawat J, Shukla N and Mishra DP 2017 Therapeutic targeting of poly(ADP-ribose) polymerase-1 (PARP1) in cancer: current developments, therapeutic strategies, and future opportunities. Med. Res. Rev. 37 1461–1491

    Article  CAS  PubMed  Google Scholar 

  • Ramón-López A, Escudero-Ortiz V, Duart-Duart MJ, Pérez-Ruixo JJ and Valenzuela B 2012 Farmacocinética poblacional de gemcitabina aplicada a la personalización de su dosificación en pacientes oncológicos. Farm. Hosp. 36 194–206

    Article  PubMed  Google Scholar 

  • Schiewer MJ et al. 2018 PARP-1 regulates DNA repair factor availability. EMBO Mol. Med. 10 e8816

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shin HJ, Kwon HK, Lee JH, Gui X, Achek A, Kim JH and Choi S 2015 Doxorubicin-induced necrosis is mediated by poly-(ADP-ribose) polymerase 1 (PARP1) but is independent of p53. Sci. Rep. 5 15798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siegel RL, Miller KD and Jemal A 2020 Cancer statistics 2020 CA. Cancer J. Clin. 70 7–30

    Article  Google Scholar 

  • Sukowati CHC 2019 Heterogeneity of hepatic cancer stem cells. Adv. Exp. Med. Biol. 1139 59–81

    Article  CAS  PubMed  Google Scholar 

  • Taniguchi H, Moriya C, Igarashi H, Saitoh A, Yamamoto H, Adachi Y and Imai K 2016 Cancer stem cells in human gastrointestinal cancer. Cancer Sci. 107 1556–1562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tomita H, Tanaka K, Tanaka T and Hara A 2016 Aldehyde dehydrogenase 1A1 in stem cells and cancer. Oncotarget 7 11018–11032

    Article  PubMed  PubMed Central  Google Scholar 

  • Jeught K Van Der, Xu HC, Li YJ, Lu X Bin and Ji G 2018 Drug resistance and new therapies in colorectal cancer. World J. Gastroenterol. 24 3834–3848

    Article  CAS  Google Scholar 

  • Venere M et al. 2014 Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells. Cell Death Differ. 21 258–269

    Article  CAS  PubMed  Google Scholar 

  • Visvader JE and Lindeman GJ 2008 Cancer stem cells in solid tumours: Accumulating evidence and unresolved questions. Nat. Rev. Cancer 8 755–768

    Article  CAS  PubMed  Google Scholar 

  • Xu F, Sun Y, Yang SZ, Zhou T, Jhala N, McDonald J and Chen Y 2019 Cytoplasmic PARP-1 promotes pancreatic cancer tumorigenesis and resistance. Int. J. Cancer 145 474–483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu Y, Wang Y, Xiao X, Cheng W, Hu L, Yao W, Qian Z and Wu W 2019 MiR-204 inhibits hepatocellular cancer drug resistance and metastasis through targeting NUAK1. Biochem. Cell Biol. 97 563–5670

    Article  CAS  PubMed  Google Scholar 

  • Zai W et al. 2019 Targeting PARP and autophagy evoked synergistic lethality in hepatocellular carcinoma. Carcinogenesis 41 345–357

    Article  CAS  Google Scholar 

  • Zhang YJ, Wen CL, Qin YX, Tang XM, Shi MM, Shen BY and Fang Y 2017 Establishment of a human primary pancreatic cancer mouse model to examine and investigate gemcitabine resistance. Oncol. Rep. 38 3335–3346

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by funds from group CTS-107 (Andalusian Government). FQ acknowledges the FPU2018 grant from the Ministerio de Educación, Ciencia y Deporte y Competitividad (Spain). We are grateful for the help provided by Dr. Gustavo Ortiz Ferrón in answering some of the questions raised by the reviewers on cytometry.

Author information

Authors and Affiliations

  1. Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100, Granada, Spain

    Francisco Quiñonero, Ana Cepero, David Urbano, Jose Prados, Consolación Melguizo & Raul Ortiz

  2. Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071, Granada, Spain

    Francisco Quiñonero, Ana Cepero, Jose Prados, Consolación Melguizo & Raul Ortiz

  3. Instituto de Investigación Biosanitaria ibs.GRANADA, 18012, Granada, Spain

    Francisco Quiñonero, Jose Prados, Consolación Melguizo & Raul Ortiz

  4. BD Biosciences, 28750, Madrid, Spain

    José A. Muñoz-Gámez

  5. Department of Cellular Biology, Science Faculty, University of Granada, 18071, Granada, Spain

    Sandra M. Martín-Guerrero & David Martín-Oliva

Authors
  1. Francisco Quiñonero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ana Cepero
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Urbano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. José A. Muñoz-Gámez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sandra M. Martín-Guerrero
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David Martín-Oliva
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jose Prados
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Consolación Melguizo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Raul Ortiz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jose Prados.

Additional information

Communicated by Ullas Kolthur-Seetharam.

Corresponding editor: Ullas Kolthur-Seetharam

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 549 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Quiñonero, F., Cepero, A., Urbano, D. et al. Identification of PARP-1 in cancer stem cells of gastrointestinal cancers: A preliminary study. J Biosci 46, 6 (2021). https://doi.org/10.1007/s12038-020-00135-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12038-020-00135-1

Keywords

Search

Navigation