title: Prolonged exposure to (R)-bicalutamide generates a LNCaP subclone with alteration of mitochondrial genome.
abstract: Advanced prostate cancers, initially sensitive to androgen deprivation therapy, frequently progress to the castration-resistant prostate cancer phenotype (CRPC) through mechanisms not yet fully understood. In this study we investigated mitochondrial involvement in the establishment of refractoriness to hormone therapy. Two human prostate cancer cell lines were used, the parental LNCaP and the resistant LNCaP-Rbic, the latter generated after continuous exposure to 20 μM of (R)-bicalutamide, the active enantiomer of Casodex®. We observed a significant decrease in mtDNA content and a lower expression of 8 mitochondria-encoded gene transcripts involved in respiratory chain complexes in both cell lines. We also found that (R)-bicalutamide differentially modulated dynamin-related protein (Drp-1) expression in LNCaP and LNCaP-Rbic cells. These data seem to indicate that the androgen-independent phenotype in our experimental model was due, at least in part, to alterations in mitochondrial dynamics and to a breakdown in the Drp-1-mediated mitochondrial network.
authors.affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Pignatta
authors.affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Arienti
authors.affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. Electronic address: w.zoli@irst.emr.it.
authors.forename: Wainer
authors.initials: W
authors.lastname: Zoli
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Di Donato
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Castoria
authors.affiliation: Department of General Surgery and Organ Transplantation, University of Bologna, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Gabucci
authors.affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Casadio
authors.affiliation: Department of Human Anatomy and Physiopathology of the Locomotor Apparatus, University of Bologna, Italy.
authors.forename: Mirella
authors.initials: M
authors.lastname: Falconi
authors.affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: De Giorgi
authors.affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Rosella
authors.initials: R
authors.lastname: Silvestrini
authors.affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Tesei
mesh_terms: D000728:Androgens / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D002999:Clone Cells; D004272:DNA, Mitochondrial / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D054629:Genome, Mitochondrial / Q000235:genetics*; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000187:drug effects / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000648:ultrastructure; D014105:Tosyl Compounds / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000728:Androgens; D000813:Anilides; D004272:DNA, Mitochondrial; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D009570:Nitriles; D014105:Tosyl Compounds; C053541:bicalutamide; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins
keywords: (R)-bicalutamide; Hormone-resistance; Mitochondrial fission; MtDNA; Prostate cancer