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Cellular mechanisms of taxane therapy in castration resistant prostate cancer

Tinzl, Martina LU (2014) In Lund University, Faculty of Medicine Doctoral Dissertation Series 119.
Abstract
Chemotherapy of castration resistant prostate cancer (CRPC) is based on taxane formulations worldwide. Only 30-50 % of patients respond to this therapy and the exact cellular mechanisms of taxane resistance in PC cells are not fully elucidated. There is convincing evidence that androgen receptor (AR) is affected by exposure to these compounds. The studies presented in this doctoral thesis identify c-jun, a proto-oncogene as a crucial key player which interacts with AR and thus determines the outcome of taxane therapy. We show that AR and c-jun physically interact on protein and gene level and this interaction is taxane specific. This results in different expression levels of AR regulated genes evidenced in alterations of PSA, KLK2 and... (More)
Chemotherapy of castration resistant prostate cancer (CRPC) is based on taxane formulations worldwide. Only 30-50 % of patients respond to this therapy and the exact cellular mechanisms of taxane resistance in PC cells are not fully elucidated. There is convincing evidence that androgen receptor (AR) is affected by exposure to these compounds. The studies presented in this doctoral thesis identify c-jun, a proto-oncogene as a crucial key player which interacts with AR and thus determines the outcome of taxane therapy. We show that AR and c-jun physically interact on protein and gene level and this interaction is taxane specific. This results in different expression levels of AR regulated genes evidenced in alterations of PSA, KLK2 and NKX3.1 in a castration resistant cell model. Sustained downregulation of c-jun results in a significant increased efficacy of taxane therapy confirming that c-jun acts as a potent antiapoptotic factor. A major drawback of taxane compound is also their ability to reach the tumor cells in sufficient concentration. Studies performed in a xenograft model showed that a novel liquid crystal nanoparticle formulation of docetaxel (LNCP/docetaxel) more efficiently decreased tumor size with less side effects than the commercially available docetaxel. Taken together, our stydies identify c-jun as a key regulator of taxnae therapy. Targeting c-jun in combination with taxane treatment may increase efficacy of chemotherapy in future. (Less)
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author
supervisor
opponent
  • Prof Guido, Jenster, Erasmus MC, Rotterdam
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Prostate cancer, chemotherapy, taxane, c-jun, androgen receptor, PSA
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
119
pages
120 pages
publisher
Division of urological research
defense location
CRC Aula, Jan Waldenströmsgata 35, Skånes Universitetssjukhus i Malmö.
defense date
2014-11-08 09:00
ISSN
1652-8220
ISBN
978-91-7619-048-7
language
English
LU publication?
yes
id
ca233025-848f-4c76-96a8-11b228a0cc6d (old id 4698349)
date added to LUP
2014-10-20 13:42:46
date last changed
2016-09-19 08:44:50
@phdthesis{ca233025-848f-4c76-96a8-11b228a0cc6d,
  abstract     = {Chemotherapy of castration resistant prostate cancer (CRPC) is based on taxane formulations worldwide. Only 30-50 % of patients respond to this therapy and the exact cellular mechanisms of taxane resistance in PC cells are not fully elucidated. There is convincing evidence that androgen receptor (AR) is affected by exposure to these compounds. The studies presented in this doctoral thesis identify c-jun, a proto-oncogene as a crucial key player which interacts with AR and thus determines the outcome of taxane therapy. We show that AR and c-jun physically interact on protein and gene level and this interaction is taxane specific. This results in different expression levels of AR regulated genes evidenced in alterations of PSA, KLK2 and NKX3.1 in a castration resistant cell model. Sustained downregulation of c-jun results in a significant increased efficacy of taxane therapy confirming that c-jun acts as a potent antiapoptotic factor. A major drawback of taxane compound is also their ability to reach the tumor cells in sufficient concentration. Studies performed in a xenograft model showed that a novel liquid crystal nanoparticle formulation of docetaxel (LNCP/docetaxel) more efficiently decreased tumor size with less side effects than the commercially available docetaxel. Taken together, our stydies identify c-jun as a key regulator of taxnae therapy. Targeting c-jun in combination with taxane treatment may increase efficacy of chemotherapy in future.},
  author       = {Tinzl, Martina},
  isbn         = {978-91-7619-048-7},
  issn         = {1652-8220},
  keyword      = {Prostate cancer,chemotherapy,taxane,c-jun,androgen receptor,PSA},
  language     = {eng},
  pages        = {120},
  publisher    = {Division of urological research},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Cellular mechanisms of taxane therapy in castration resistant prostate cancer},
  volume       = {119},
  year         = {2014},
}