TY - JOUR
T1 - Inhibition of dihydrotestosterone synthesis in prostate cancer by combined frontdoor and backdoor pathway blockade
AU - Fiandalo, Michael V.
AU - Stocking, John J.
AU - Pop, Elena A.
AU - Wilton, John H.
AU - Mantione, Krystin M.
AU - Li, Yun
AU - Attwood, Kristopher M.
AU - Azabdaftari, Gissou
AU - Wu, Yue
AU - Watt, David S.
AU - Wilson, Elizabeth M.
AU - Mohler, James L.
N1 - Publisher Copyright:
© Fiandalo et al.
PY - 2018
Y1 - 2018
N2 - Androgen deprivation therapy (ADT) is palliative and prostate cancer (CaP) recurs as lethal castration-recurrent/resistant CaP (CRPC). One mechanism that provides CaP resistance to ADT is primary backdoor androgen metabolism, which uses up to four 3α-oxidoreductases to convert 5α-androstane-3α, 17β-diol (DIOL) to dihydrotestosterone (DHT). The goal was to determine whether inhibition of 3α-oxidoreductase activity decreased conversion of DIOL to DHT. Protein sequence analysis showed that the four 3α-oxidoreductases have identical catalytic amino acid residues. Mass spectrometry data showed combined treatment using catalytically inactive 3α-oxidoreductase mutants and the 5α-reductase inhibitor, dutasteride, decreased DHT levels in CaP cells better than dutasteride alone. Combined blockade of frontdoor and backdoor pathways of DHT synthesis provides a therapeutic strategy to inhibit CRPC development and growth.
AB - Androgen deprivation therapy (ADT) is palliative and prostate cancer (CaP) recurs as lethal castration-recurrent/resistant CaP (CRPC). One mechanism that provides CaP resistance to ADT is primary backdoor androgen metabolism, which uses up to four 3α-oxidoreductases to convert 5α-androstane-3α, 17β-diol (DIOL) to dihydrotestosterone (DHT). The goal was to determine whether inhibition of 3α-oxidoreductase activity decreased conversion of DIOL to DHT. Protein sequence analysis showed that the four 3α-oxidoreductases have identical catalytic amino acid residues. Mass spectrometry data showed combined treatment using catalytically inactive 3α-oxidoreductase mutants and the 5α-reductase inhibitor, dutasteride, decreased DHT levels in CaP cells better than dutasteride alone. Combined blockade of frontdoor and backdoor pathways of DHT synthesis provides a therapeutic strategy to inhibit CRPC development and growth.
KW - 3a-oxidoreductases
KW - Androgen deprivation therapy
KW - Androstanediol
KW - Dihydrotestosterone
KW - Dutasteride
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U2 - 10.18632/oncotarget.24107
DO - 10.18632/oncotarget.24107
M3 - Article
AN - SCOPUS:85042147616
SN - 1949-2553
VL - 9
SP - 11227
EP - 11242
JO - Oncotarget
JF - Oncotarget
IS - 13
ER -
