Elevated expression of Nrf2 mediates multidrug resistance in CD133+ head and neck squamous cell carcinoma stem cells

Lu,Bao‑Cai; Li,Jing; Yu,Wen‑Fa; Zhang,Guo‑Zheng; Wang,Hui‑Min; Ma,Hui‑Min

doi:10.3892/ol.2016.5269

Elevated expression of Nrf2 mediates multidrug resistance in CD133+ head and neck squamous cell carcinoma stem cells

Authors:
- Bao‑Cai Lu
- Jing Li
- Wen‑Fa Yu
- Guo‑Zheng Zhang
- Hui‑Min Wang
- Hui‑Min Ma
View Affiliations

Affiliations: Department of Ear‑Nose‑Throat, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
Published online on: October 17, 2016 https://doi.org/10.3892/ol.2016.5269
Pages: 4333-4338
Copyright: © Lu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Enhanced expression of the ATP-binding cassette (ABC) transporter protein ABC sub-family G member 2 (ABCG2) in cancer stem cells (CSCs) plays a major role in chemotherapeutic drug efflux, which results in therapy failure and tumor relapse. In addition to downregulating apoptosis in CSCs, it has been reported that the transcriptional upregulation of the redox sensing factor Nrf2 is involved in the upregulation of ABCG2 expression and consequent chemoresistance. The current study investigated the presence of cancer stem‑like side population (SP) cells from head and neck squamous cell carcinoma (HNSCC) samples, and evaluated the Nrf2 expression profile and multidrug resistance properties of HNSCC stem cells. Fluorescence‑activated cell sorting was used for SP cells detection, while reverse transcription‑polymerase chain reaction was used for the analysis of Nrf2 expression. The present study identified ~2.1% SP cells present in HNSCC specimens, which were positive for cluster of differentiation (CD)133 expression and displayed significantly elevated messenger RNA expression of Nrf2, compared with non‑SP cells. These data suggest that the ABC transporter ABCG2 is highly upregulated in SP cells, and this results in multidrug resistance. In addition, these CD133+ cells underwent rapid proliferation and exhibited high self‑renewal and tumorigenic properties. Taken together, the present findings suggest that elevated expression of Nrf2 mediated drug resistance in HNSCC CSCs, which may be one of the causative factors for cancer treatment failure. Therefore, novel anti‑cancer drugs that downregulate the Nrf2 signaling pathway could effectively improve the treatment and survival rate of patients with HNSCC.

View Figures

View References

1	Schoenhals M, Kassambara A, De Vos J, Hose D, Moreaux J and Klein B: Embryonic stem cell markers expression in cancers. Biochem Biophys Res Commun. 383:157–162. 2009. View Article : Google Scholar : PubMed/NCBI
2	Chiou SH, Wang ML, Chou YT, Chen CJ, Hong CF, Hsieh WJ, Chang HT, Chen YS, Lin TW, Hsu HS and Wu CW: Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial-mesenchymal transdifferentiation. Cancer Res. 70:10433–10444. 2010. View Article : Google Scholar : PubMed/NCBI
3	Lino MM, Merlo A and Boulay JL: Notch signaling in glioblastoma: A developmental drug target. BMC Med. 8:722010. View Article : Google Scholar : PubMed/NCBI
4	Zhang XP, Zheng G, Zou L, Liu HL, Hou LH, Zhou P, Yin DD, Zheng QJ, Liang L, Zhang SZ, et al: Notch activation promotes cell proliferation and the formation of neural stem cell-like colonies in human glioma cells. Mol Cell Biochem. 307:101–108. 2008. View Article : Google Scholar : PubMed/NCBI
5	Kawaguchi-Ihara N, Murohashi I, Nara N and Tohda S: Promotion of the self-renewal capacity of human acute leukemia cells by Wnt3A. Anticancer Res. 28:2701–2704. 2008.PubMed/NCBI
6	Khan NI, Bradstock KF and Bendall LJ: Activation of Wnt/beta-catenin pathway mediates growth and survival in B-cell progenitor acute lymphoblastic leukaemia. Br J Haematol. 138:338–348. 2007. View Article : Google Scholar : PubMed/NCBI
7	Salnikov AV, Gladkich J, Moldenhauer G, Volm M, Mattern J and Herr I: CD133 is indicative for a resistance phenotype but does not represent a prognostic marker for survival of non-small cell lung cancer patients. Int J Cancer. 126:950–958. 2010.PubMed/NCBI
8	Singh A and Settleman J: EMT, cancer stem cells and drug resistance: An emerging axis of evil in the war on cancer. Oncogene. 29:4741–4751. 2010. View Article : Google Scholar : PubMed/NCBI
9	Ho MM, Ng AV, Lam S and Hung JY: Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res. 67:4827–4833. 2007. View Article : Google Scholar : PubMed/NCBI
10	Burkert J, Wright NA and Alison MR: Stem cells and cancer: An intimate relationship. J Pathol. 209:287–297. 2006. View Article : Google Scholar : PubMed/NCBI
11	Rehman AO and Wang CY: CXC12/SDF-1 alpha activates NF-kappaB and promotes oral cancer invasion through the Carma3/Bcl10/Malt1 complex. Int J Oral Sci. 1:105–118. 2009. View Article : Google Scholar : PubMed/NCBI
12	Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, Clarke MF and Ailles LE: Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA. 104:973–978. 2007. View Article : Google Scholar : PubMed/NCBI
13	Singh A, Wu H, Zhang P, Happel C, Ma J and Biswal S: Expression of ABCG2 (BCRP) is regulated by Nrf2 in cancer cells that confers side population and chemoresistance phenotype. Mol Cancer Ther. 9:2365–2376. 2010. View Article : Google Scholar : PubMed/NCBI
14	Yang B, Ma YF and Liu Y: Elevated Expression of Nrf-2 and ABCG2 involved in multidrug resistance of lung cancer SP cells. Drug Res (Stuttg). 65:526–531. 2015.PubMed/NCBI
15	Shi Y, Fu X, Hua Y, Han Y, Lu Y and Wang J: The side population in human lung cancer cell line NCI-H460 is enriched in stem-like cancer cells. PLoS One. 7:e333582012. View Article : Google Scholar : PubMed/NCBI
16	Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K and Yamamoto M: Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol. 24:7130–7139. 2004. View Article : Google Scholar : PubMed/NCBI
17	Zhang DD, Lo SC, Cross JV, Templeton DJ and Hannink M: Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol. 24:10941–10953. 2004. View Article : Google Scholar : PubMed/NCBI
18	Singh A, Misra V, Thimmulappa RK, Lee H, Ames S, Hoque MO, Herman JG, Baylin SB, Sidransky D, Gabrielson E, et al: Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med. 3:e4202006. View Article : Google Scholar : PubMed/NCBI
19	Dean M, Fojo T and Bates S: Tumour stem cells and drug resistance. Nat Rev Cancer. 5:275–284. 2005. View Article : Google Scholar : PubMed/NCBI
20	Morrison SJ and Kimble J: Asymmetric and symmetric stem-cell divisions in development and cancer. Nature. 441:1068–1074. 2006. View Article : Google Scholar : PubMed/NCBI
21	Song J, Chang I, Chen Z, Kang M and Wang CY: Characterization of side populations in HNSCC: Highly invasive, chemoresistant and abnormal Wnt signaling. PLoS One. 5:e114562010. View Article : Google Scholar : PubMed/NCBI
22	Bunting KD: ABC transporters as phenotypic markers and functional regulators of stem cells. Stem Cells. 20:11–20. 2002. View Article : Google Scholar : PubMed/NCBI
23	Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, et al: An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun. 236:313–322. 1997. View Article : Google Scholar : PubMed/NCBI
24	Ramos-Gomez M, Kwak MK, Dolan PM, Itoh K, Yamamoto M, Talalay P and Kensler TW: Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci USA. 98:3410–3415. 2001. View Article : Google Scholar : PubMed/NCBI
25	Kwak MK, Kensler TW and Casero RA Jr: Induction of phase 2 enzymes by serum oxidized polyamines through activation of Nrf2. Effect of the polyamine metabolite acrolein. Biochem Biophys Res Commun. 305:662–670. 2003. View Article : Google Scholar : PubMed/NCBI