Reversing paclitaxel resistance in ovarian cancer cells via inhibition of the ABCB1 expressing side population
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The majority of deaths in ovarian cancer are caused by recurrent metastatic disease which is usually multidrug resistant. This progression has been hypothesised to be due in part to the presence of cancer stem cells, a subset of cells which are capable of self-renewal and are able to survive chemotherapy and migrate to distant sites. Side population (SP) cells, identified by the efflux of the DNA-binding dye Hoechst 33342 through ATP-binding cassette (ABC) transporters, are a known adult stem cell group and have been suggested as a cancer stem cell in various cancers. Despite the identification of SP cells in cancer cell lines and patient samples, little attention has been paid to the identification of specific ABC transporters within this cell fraction which efflux Hoechst dye and thus may facilitate drug resistance. In this study, we demonstrate that SP cells can be detected in both ovarian cancer cell lines and ascitic fluid samples, and these SP cells possess stem cell and drug resistance properties. We show that ABCB1 is the functioning ABC transporter in ovarian cancer cell lines, and expression of ABCB1 is associated with a paclitaxel-resistant phenotype. Moreover, silencing of ABCB1 using a specific morpholino oligonucleotide results in an inhibition of the SP phenotype and a sensitising of ovarian cancer cell lines to paclitaxel. ABCB1 should therefore be considered as a therapeutic target in ovarian cancer.
KeywordsOvarian cancer Side population cells Paclitaxel ABCB1
STR DNA fingerprinting was done by the Cancer Centre Support Grant-funded Characterized Cell Line core, NCI # CA016672.
Rachel Eyre was supported by a Dr. William Edmund Harker Foundation Studentship.
Conflict of interest
R.E. performed experimental work, assisted in experimental design and wrote manuscript. I.H performed experiments. K.S.-H. authenticated and provided cell lines. T.W.J.L. provided clinical expertise and assisted with manuscript writing. A.T.-C. assisted in study design and writing of manuscript. A.P.M.: study design and wrote the manuscript. All authors approved the submitted version of the manuscript.
- 2.Fallowfield L, Fleissig A, Barrett J, Menon U, Jacobs T, Kilkerr J, et al. Awareness of ovarian cancer risk factors, beliefs and attitudes towards screening: baseline survey of 21 715 women participating in the UK Collaborative Trial of Ovarian Cancer Screening. Br J Cancer. 2010;103:454–61.PubMedCentralCrossRefPubMedGoogle Scholar
- 9.Zhang Y, Piao, B., Zhang, Y., Hua, B., Hou, W., Xu, W., Qi, X., Zhu, X., Pei, Y., Lin, H. Oxymatrine diminishes the side population and inhibits the expression of β-catenin in MCF-7 breast cancer cells. Med Oncol. 2010.Google Scholar
- 23.Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, Dinulescu DM, Connolly D, Foster R, et al. Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. Proc Natl Acad Sci U S A. 2006;103(30):11154–9.PubMedCentralCrossRefPubMedGoogle Scholar
- 28.Zhang J, Zhao J, Zhang W, Liu G, Yin D, Li J, et al. Establishment of paclitaxel-resistant cell line and the underlying mechanism on drug resistance. Int J Gynecol Cancer Off J Int Gynecol Cancer Soc. 2012;22(9):1450–6.Google Scholar
- 29.Chen J, Wang J, Zhang Y, Chen D, Yang C, Kai C, et al. Observation of ovarian cancer stem cell behavior and investigation of potential mechanisms of drug resistance in three-dimensional cell culture. J Biosci Bioeng. 2014 Mar 27.Google Scholar
- 31.Johnatty SE, Beesley J, Gao B, Chen X, Lu Y, Law MH, et al. ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: a comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas. Gynecol Oncol. 2013;131(1):8–14.PubMedCentralCrossRefPubMedGoogle Scholar
- 32.Cirak S, Arechavala-Gomeza V, Guglieri M, Feng L, Torelli S, Anthony K, et al. Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study. Lancet. 2011;378(9791):595–605.PubMedCentralCrossRefPubMedGoogle Scholar