Androgen deprivation by activating the liver X receptor.
Prostate cancer is the most commonly diagnosed and the second leading cause of cancer death in men. The androgens-androgen receptor signaling plays an important role in normal prostate development, as well as in prostatic diseases, such as benign hyperplasia and prostate cancer. Accordingly, androgen ablation has been the most effective endocrine therapy for hormone-dependent prostate cancer. Here, we report a novel nuclear receptor-mediated mechanism of androgen deprivation. Genetic or pharmacological activation of the liver X receptor (LXR) in vivo lowered androgenic activity by inducing the hydroxysteroid sulfotransferase 2A1, an enzyme essential for the metabolic deactivation of androgens. Activation of LXR also inhibited the expression of steroid sulfatase in the prostate, which may have helped to prevent the local conversion of sulfonated androgens back to active metabolites. Interestingly, LXR also induced the expression of selected testicular androgen synthesizing enzymes. At the physiological level, activation of LXR in mice inhibited androgen-dependent prostate regeneration in castrated mice. Treatment with LXR agonists inhibited androgen-dependent proliferation of prostate cancer cells in a LXR- and sulfotransferase 2A1-dependent manner. In summary, we have revealed a novel function of LXR in androgen homeostasis, an endocrine role distinct to the previously known sterol sensor function of this receptor. LXR may represent a novel therapeutic target for androgen deprivation, and may aid in the treatment and prevention of hormone-dependent prostate cancer.
Lee
Jung Hoon
JH
Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Gong
Haibiao
H
Khadem
Shaheen
S
Lu
Yi
Y
Gao
Xiang
X
Li
Song
S
Zhang
Jian
J
Xie
Wen
W
D000728:Androgens / Q000096:biosynthesis* / Q000494:pharmacology; D000818:Animals; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D001596:Benzylamines / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology / Q000627:therapeutic use*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D011467:Prostate / Q000187:drug effects / Q000502:physiology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012038:Regeneration / Q000187:drug effects; D015238:Sulfotransferases / Q000235:genetics; D013739:Testosterone / Q000097:blood
D000728:Androgens; D001565:Benzoates; D001596:Benzylamines; D004268:DNA-Binding Proteins; C473027:GW 3965; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; C003585:22-hydroxycholesterol; D013739:Testosterone; D015238:Sulfotransferases; C028152:alcohol sulfotransferase