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Overexpression of 5α‐reductase type 1 increases sensitivity of prostate cancer cells to low concentrations of testosterone
Author(s) -
Thomas Lynn N.,
Douglas Robert C.,
Rittmaster Roger S.,
Too Catherine K.L.
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.20911
Subject(s) - testosterone (patch) , endocrinology , medicine , dihydrotestosterone , prostate , prostate cancer , androgen , transfection , downregulation and upregulation , biology , cell culture , cancer , hormone , gene , genetics , biochemistry
Conversion of testosterone to dihydrotestosterone (DHT) by the enzymes 5α‐reductase types 1 (5αR1) and 2 (5αR2) is important for normal and pathological growth of the prostate. The predominant isoenzyme in normal prostate is 5αR2. However, prostate cancer (PCa) development is accompanied by a decrease in 5αR2 and an increase in 5αR1. The biological significance of increased 5αR1 expression is not fully understood. Therefore, the aim of this study was to determine the effect of overexpression of 5αR1 on growth and prostate‐specific antigen (PSA) production in PCa cells. MATERIALS AND METHODS LNGK‐9 PCa cells, transiently transfected with pTRE‐5αR1 or pTRE alone, were cultured in the presence or absence of testosterone at varying concentrations. Cell growth and PSA secretion were measured after 4–6 days. Cyclin E1, Ki67, and PSA mRNA levels were evaluated using RT‐PCR after 24 hr of treatment. RESULTS 10 pM testosterone increased growth of pTRE‐5αR1 transfectants by 54.1% over cells grown in the absence of testosterone, compared to 25.0% in pTRE transfectants ( P < 0.01). Likewise, PSA secretion was increased by 56‐fold in pTRE‐5αR1 transfectants treated with 10 pM testosterone, compared to 26‐fold in pTRE transfectants ( P < 0.01). At concentrations of testosterone above 10 pM, the stimulatory effect on growth and PSA secretion was not distinguishable between pTRE‐5αR1 and pTRE transfectants. CONCLUSIONS These results demonstrate that upregulation of 5αR1 enhances the cellular response to low, but not high, concentrations of testosterone. This explains one mechanism by which castration‐recurrent PCa can proliferate in the presence of castrate levels of circulating testosterone. Prostate 69:595–602, 2009. © 2009 Wiley‐Liss, Inc.