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MMR-proficient and MMR-deficient colorectal cancer cells: 5-Fluorouracil treatment response and correlation to CD133 and MGMT expression

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Abstract

Cancer stem cells (CSCs) from colorectal cancer (CRC), characterized by CD133 expression, have been associated with 5-fluorouracile (5-FU) chemoresistance. DNA repair mechanisms, such as O6-alkylguanine DNA alkyltransferase (MGMT) and mismatch repair (MMR) systems, have also been correlated to 5-FU resistance in CRC. The aim of this study was to evaluate the modulation of CD133 and MGMT in MMR-proficient and MMR-deficient CRC cells under 5-FU treatment and the effect of this drug in CSCs. CD133 and MGMT methylation status were determined in MMR-proficient (SW480 and HT29) and MMR-deficient (RKO and HCT116) cell lines by methylation-specific PCRs. SW480 and RKO were selected to determine modulation of CD133, MGMT and MMR expression after 5-FU treatment by qPCR. In addition, CD133, MGMT and MMR were analyze in SW480 and RKO CSCs. No association between promoter methylation and MGMT and CD133 expression was found. 5-FU treatment increased CD133 expression independently to MMR status in SW480 and RKO and was able to increase hMLH1 expression in RKO, a MMR-deficient cell line. RKO/CSCs overexpressed CD133 and MMR (hMSH2 and hMSH6) while SW480/CSCs showed a significant increase in CD133, MMR (hMLH1, hMSH2 and hMSH6) and MGMT, moreover 5-FU resistance than parental cell lines. Thus, although CSCs 5-FU chemoresistance appears to be independently to MMR status, hMLH1 might play a key role in CSC response to 5-FU. New drugs exploding these differences could benefit the prognostic of patients with CRC.

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Acknowledgements

Thanks are due to the Centro de Instrumentación Cientifica (CIC) personnel of the University of Granada for technical assistance. This work was supported by Project PI-0102-2017 from Consejería de Salud de la Junta de Andalucía, Project PI19/01478 from Instituto de Salud Carlos III (ISCIII) (FEDER) and funds from group CTS-107 (Andalusian Government).

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  1. These authors contributed equality to this work.

Authors and Affiliations

  1. Center for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, UK

    Jaime A. Oliver

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

    Jaime A. Oliver, Raúl Ortiz, Cristina Jiménez-Luna, Laura Cabeza, Gloria Perazzoli, Octavio Caba, Cristina Mesas, Consolación Melguizo & Jose Prados

  3. Department of Anatomy and Embryology, University of Granada, Granada, Spain

    Raúl Ortiz, Cristina Jiménez-Luna, Laura Cabeza, Octavio Caba, Cristina Mesas, Consolación Melguizo & Jose Prados

  4. Biosanitary Institute of Granada (ibs.GRANADA), SAS-Universidad de Granada, Granada, Spain

    Raúl Ortiz, Laura Cabeza, Gloria Perazzoli, Octavio Caba, Cristina Mesas, Consolación Melguizo & Jose Prados

  5. Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, 1066, Epalinges, Switzerland

    Cristina Jiménez-Luna

  6. Department of Medicine, University of Almeria, 04120, Almería, Spain

    Gloria Perazzoli

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  1. Jaime A. Oliver
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  8. Consolación Melguizo
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Corresponding author

Correspondence to Consolación Melguizo.

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Corresponding editor: BJ Rao

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Oliver, J.A., Ortiz, R., Jiménez-Luna, C. et al. MMR-proficient and MMR-deficient colorectal cancer cells: 5-Fluorouracil treatment response and correlation to CD133 and MGMT expression. J Biosci 45, 121 (2020). https://doi.org/10.1007/s12038-020-00093-8

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