title: Fludarabine treatment favors the retention of miR-485-3p by prostate cancer cells: implications for survival.
abstract: BACKGROUND
  Circulating microRNAs (miRNAs) have been found in many body fluids and represent reliable markers of several physio-pathological disorders, including cancer. In some cases, circulating miRNAs have been evaluated as markers of the efficacy of anticancer treatment but it is not yet clear if miRNAs are actively released by tumor cells or derive from dead tumor cells.
  
  
  RESULTS
  We showed that a set of prostate cancer secretory miRNAs (PCS-miRNAs) were spontaneously released in the growth medium by DU-145 prostate cancer cells and that the release was greater after treatment with the cytotoxic drug fludarabine. We also found that the miRNAs were associated with exosomes, implying an active mechanism of miRNA release. It should be noted that in fludarabine treated cells the release of miR-485-3p, as well as its association with exosomes, was reduced suggesting that miR-485-3p was retained by surviving cells. Monitoring the intracellular level of miR-485-3p in these cells, we found that miR-485-3p was stably up regulated for several days after treatment. As a possible mechanism we suggest that fludarabine selected cells that harbor high levels of miR-485-3p, which in turn regulates the transcriptional repressor nuclear factor-Y triggering the transcription of topoisomerase IIα, multidrug resistance gene 1 and cyclin B2 pro-survival genes.
  
  
  CONCLUSIONS
  Cytotoxic treatment of DU-145 cells enhanced the release of PCS-miRNAs with the exception of miR-485-3p which was retained by surviving cells. We speculate that the retention of miR-485-3p was a side effect of fludarabine treatment in that the high intracellular level of miR-485-3p plays a role in the sensitivity to fludarabine.
authors.affiliation: Laboratory of Gene and Molecular Therapy, Institute of Clinical Physiology, Area della Ricerca CNR,Via Moruzzi,1, Pisa 56124, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Lucotti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rainaldi
authors.forename: Monica
authors.initials: M
authors.lastname: Evangelista
authors.forename: Milena
authors.initials: M
authors.lastname: Rizzo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C556501:MIRN485 microRNA, human; D035683:MicroRNAs; D014740:Vidarabine; C024352:fludarabine