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A novel communication role for CYP17A1 in the progression of castration‐resistant prostate cancer
Author(s) -
Locke Jennifer A.,
Fazli Ladan,
Adomat Hans,
Smyl Jil,
Weins Kristin,
Lubik Amy A.,
Hales Dale B.,
Nelson Colleen C.,
Gleave Martin E.,
Tomlinson Guns Emma S.
Publication year - 2009
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20940
Subject(s) - cyp17a1 , prostate cancer , androgen , orchiectomy , cancer research , endocrinology , medicine , biology , androgen deprivation therapy , flutamide , testosterone (patch) , cancer , androgen receptor , hormone , enzyme , biochemistry
BACKGROUND CYP17A1 is currently a target for total androgen blockade in advanced prostate cancer (CaP) patients. After castration, or removal of testicular androgens, CYP17A1 can act as a rate‐limiting enzyme in androgen synthesis from cholesterol or other adrenal precursors within the tumor microenvironment ultimately contributing to disease progression. Herein we provide evidence that CYP17A1 could also be a mediator of cell‐to‐cell communication within the CaP tumor microenvironment. METHODS CYP17A1 expression was evaluated by immunohistochemical analysis of human tumor sections and Western blot analysis of CaP patients' serum and exosome isolates. CYP17A1 activity assays were conducted in human serum (and positive control human liver and kidney microsomes) using progesterone as a precursor and an LC‐MS endpoint. RESULTS These studies revealed that the expression pattern of CYP17A1 is typical of a secretory protein as it is localized to the luminal pole of the cells in exocrine secretory mode. CYP17A1 is expressed in human serum and in fact is elevated in the serum of CaP patients as compared to healthy controls. Serum CYP17A1 activity could not be confirmed, however, verification of CYP17A1 expression in exosomes suggests a role in cell‐to‐cell communication within the tumor microenvironment. CONCLUSIONS CYP17A1 is a crucial enzyme for de novo androgen synthesis within the tumor microenvironment after removal of testicular androgens by castration. We provide evidence for a novel role for CYP17A1 in serum and further reiterate the importance of targeting this enzyme in CaP progression. Prostate 69: 928–937, 2009. © 2009 Wiley‐Liss, Inc.