LAUSR

Abstract Background Multipotent cancer stem cells (CSC) are involved in micro-evolutionary tumor adaptation to therapeutic regimens. Due to their drug-resistance, they represent a promising target for treatment strategies of advanced prostate tumors. Fenofibrate (FF) has recently been pinpointed as a potential metronomic agent that augments the sensitivity of cancer cells to chemotherapeutic drugs. Here, we hypothesized that FF interferes with the drug-resistance of prostate cancer cell populations through the interference with the functions of cancer stem cell-like (SCL) cells. Methods Naive and drug-resistant DU145 cells cultivated in control conditions and in the presence of DCX and/or FF were immunostained against pluripotency markers and analyzed with fluorescent microscopy, fluorescent activated cell sorting (FACS) and image stream. Results FACS analyses of naive and docetaxel (DCX)-resistant DU145 cells revealed minute sub-populations of CD133+/CD44-, CD133+/CD44+ and CD133-/CD44+ SCL cells. SCL fractions were elevated within DCX-treated naive and DCX-resistant DU145 cell line populations. More prominent increase of SCL-fraction was also observed in naive, and to lower extent, in drug-resistant DU145 lineages upon combined DCX/FF treatment, which confirms their drug-resistance. CD44+ cells formed the aggregates of round and loosely attached cells, surrounded by morphologically diverse cellular clusters. These SCL cells offspring displayed neoplastic and invasive phenotype similar to that of parental cells; however, they showed increased, P-gp-dependent DCX- but not DCX/FF resistance. Loss of drug-resistance over time of SCL cells offspring was accompanied by induction of their EMT and invasive potential, and combined DCX/FF treatment interfered with this process. Conclusions These observations confirm the phenotypic plasticity of SCL cells and its role in the maintenance of prostate cancer cell heterogeneity and drug-resistance. FF can enhance the efficiency of palliative prostate cancer therapies through the interference with the function of cancer stem cells. Legal entity responsible for the study Jagiellonian University, Faculty of Biochemistry, Biophysics and Biotechnology. Funding National Science Centre Poland. Disclosure All authors have declared no conflicts of interest.