A novel communication role for CYP17A1 in the progression of castration-resistant prostate cancer.
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.
Locke
Jennifer A
JA
Department of Urologic Sciences, University of British Columbia, The Prostate Centre at Vancouver General Hospital, Vancouver, British Columbia, Canada.
Fazli
Ladan
L
Adomat
Hans
H
Smyl
Jil
J
Weins
Kristin
K
Lubik
Amy A
AA
Hales
Dale B
DB
Nelson
Colleen C
CC
Gleave
Martin E
ME
Tomlinson Guns
Emma S
ES
D000306:Adrenal Cortex Neoplasms; D000728:Androgens / Q000096:biosynthesis*; D002450:Cell Communication / Q000502:physiology; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism; D018450:Disease Progression; D004789:Enzyme Activation / Q000502:physiology; D055354:Exosomes / Q000201:enzymology; D006801:Humans; D007668:Kidney / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery*; D013254:Steroid 17-alpha-Hydroxylase / Q000097:blood* / Q000378:metabolism
D000728:Androgens; D002784:Cholesterol; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D009251:NADPH-Ferrihemoprotein Reductase