title: Interaction between c-jun and androgen receptor determines the outcome of taxane therapy in castration resistant prostate cancer.
abstract: Taxane based chemotherapy is the standard of care treatment in castration resistant prostate cancer (CRPC). There is convincing evidence that taxane therapy affects androgen receptor (AR) but the exact mechanisms have to be further elucidated. Our studies identified c-jun as a crucial key player which interacts with AR and thus determines the outcome of the taxane therapy given. Docetaxel (Doc) and paclitaxel (Pac) agents showed different effects on LNCaP and LNb4 evidenced by alteration in the protein and mRNA levels of c-jun, AR and PSA. Docetaxel-induced phophorylation of c-jun occurred before JNK phosphorylation which suggests that c-jun phosphorylation is independent of JNK pathways in prostate cancer cells. A xenograft study showed that mice treated with Pac and bicalutamide showed worse outcome supporting our hypothesis that upregulation of c-jun might act as a potent antiapoptotic factor. We observed in our in vitro studies an inverse regulation of PSA- and AR-mRNA levels in Doc treated LNb4 cells. This was also seen for kallikrein 2 (KLK 2) which followed the same pattern. Given the fact that response to taxane therapy is measured by PSA decrease we have to consider that this might not reflect the true activity of AR in CRPC patients.
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Martina
authors.initials: M
authors.lastname: Tinzl
authors.forename: Binshen
authors.initials: B
authors.lastname: Chen
authors.forename: Shao-Yong
authors.initials: SY
authors.lastname: Chen
authors.forename: Julius
authors.initials: J
authors.lastname: Semenas
authors.forename: Per-Anders
authors.initials: PA
authors.lastname: Abrahamsson
authors.forename: Nishtman
authors.initials: N
authors.lastname: Dizeyi
mesh_terms: D000813:Anilides / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001952:Bridged-Ring Compounds / Q000494:pharmacology* / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009570:Nitriles / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D043823:Taxoids / Q000494:pharmacology* / Q000627:therapeutic use*; D014105:Tosyl Compounds / Q000627:therapeutic use
chemical_list: D000813:Anilides; D001952:Bridged-Ring Compounds; D009570:Nitriles; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D043823:Taxoids; D014105:Tosyl Compounds; C080625:taxane; C053541:bicalutamide