Biomol Ther.  2016 Sep;24(5):482-488. 10.4062/biomolther.2016.145.

Involvement of NRF2 Signaling in Doxorubicin Resistance of Cancer Stem Cell-Enriched Colonospheres

  • 1Department of Pharmacy, Graduate School of The Catholic University of Korea, Republic of Korea.
  • 2BK21 Plus Creative Leader Program for Pharmacomics-based Future Pharmacy, Republic of Korea.
  • 3College of Pharmacy, The Catholic University of Korea, Bucheon 14662, Republic of Korea.


Cancer stem cells (CSCs) are a subset of tumor cells, which are characterized by resistance against chemotherapy and environmental stress, and are known to cause tumor relapse after therapy. A number of molecular mechanisms underlie the chemoresistance of CSCs, including high expression levels of drug efflux transporters. We investigated the role of the antioxidant transcription factor NF-E2-related factor 2 (NRF2) in chemoresistance development, using a CSC-enriched colonosphere system. HCT116 colonospheres were more resistant to doxorubicin-induced cell death and expressed higher levels of drug efflux transporters such as P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) compared to HCT116 monolayers. Notably, levels of NRF2 and expression of its target genes were substantially elevated in colonospheres, and these increases were linked to doxorubicin resistance. When NRF2 expression was silenced in colonospheres, Pgp and BCRP expression was downregulated, and doxorubicin resistance was diminished. Collectively, these results indicate that NRF2 activation contributes to chemoresistance acquisition in CSC-enriched colonospheres through the upregulation of drug efflux transporters.


Cancer stem cells; NRF2; Colonospheres; Drug efflux transporters; Chemoresistance
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