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Jean D Wilson - One of the best experts on this subject based on the ideXlab platform.
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5α androstane 3α 17β Diol is formed in tammar wallaby pouch young testes by a pathway involving 5α pregnane 3α 17α Diol 20 one as a key intermediate
Endocrinology, 2003Co-Authors: Jean D Wilson, Richard J Auchus, Michael W Leihy, Oleg Guryev, Ronald W Estabrook, Susan M Osborn, Geoffrey Shaw, Marilyn B RenfreeAbstract:The synthetic pathway by which 5α-androstane-3α,17β-Diol (5α-aDiol) is formed in the testes of tammar wallaby pouch young was investigated by incubating testes from d 20–40 males with various radioactive precursors and analyzing the metabolites by thin-layer chromatography and HPLC. [3H]Progesterone was converted to 17-hydroxyprogesterone, which was converted to 5α-aDiol by two pathways: One involves the formation of testosterone and dihydrotestosterone as intermediates, and the other involves formation of 5α-pregnane-3α,17α-Diol-20-one (5α-pDiol) and androsterone as intermediates. Formation of 5α-aDiol from both [3H]testosterone and [3H]progesterone was blocked by the 5α-reductase inhibitor 4MA. The addition of nonradioactive 5α-pDiol blocked the conversion of [3H]progesterone to 5α-aDiol, and [3H]5α-pDiol was efficiently converted to androsterone and 5α-aDiol. We conclude that expression of steroid 5α-reductase in the developing wallaby testes allows formation of 5α-reduced androgens by a pathway that d...
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administration of 5α androstane 3α 17β Diol to female tammar wallaby pouch young causes development of a mature prostate and male urethra
Endocrinology, 2002Co-Authors: Michael W Leihy, Jean D Wilson, Geoffrey Shaw, Marilyn B RenfreeAbstract:Secretion of 5α-androstane-3α,17β-Diol (5α-aDiol) by the testes of the tammar wallaby is responsible for initiation of prostatic development after d 20 in male pouch young. To ascertain the role of this hormone in the subsequent growth and differentiation of the prostate and in the development of the male phallus, 5α-aDiol was administered to tammar female pouch young in two regimens. Administration of the hormone by mouth (8 μg/g body weight·wk) between d 70 and 150 of pouch life caused prostate development equivalent to that in d 150 males and promoted growth and differentiation of the penis, but not masculinization of the urethra. Treatment with a small dose of 5α-aDiol enanthate (1 μg/g body weight·wk) from d 20–150 produced similar results. However, administration of larger doses of 5α-aDiol enanthate (10 or 100 μg/g body weight·wk) from d 20–150 caused supraphysiological growth of the prostate, development of a male-type urethra, and penile growth. These results indicate that prostatic development a...
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virilization of the urogenital sinus of the tammar wallaby is not unique to 5α androstane 3α 17β Diol
Molecular and Cellular Endocrinology, 2001Co-Authors: Michael W Leihy, Jean D Wilson, Geoffrey Shaw, Marilyn B RenfreeAbstract:The androgen 5alpha-androstane-3alpha,17beta-Diol (5alpha-aDiol) is synthesized in testes and secreted into plasma of male tammar wallaby pouch young and appears to virilize the urogenital sinus. To provide insight into its mechanism of action, a dose response study showed that administration of 1 microg 5alpha-aDiol monoenanthate per g body wt. per week for 3 weeks to 24-day-old female pouch young induced prostate bud formation equivalent to that of males of the same age. Administration of this same dose of the enanthates of testosterone, dihydrotestosterone, and 5alpha-aDiol to female pouch young caused equivalent virilization of the urogenital sinus. The fact that 5alpha-aDiol does not exert a unique effect, together with our earlier findings in this species that 5alpha-aDiol and testosterone are converted to dihydrotestosterone in the urogenital sinus and that virilization of the urogenital sinus is prevented by the androgen receptor antagonist flutamide, suggest that 5alpha-aDiol is a circulating precursor for dihydrotestosterone formation in this tissue.
Marcella Motta - One of the best experts on this subject based on the ideXlab platform.
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the androgen derivative 5α androstane 3β 17β Diol inhibits prostate cancer cell migration through activation of the estrogen receptor β subtype
Cancer Research, 2005Co-Authors: Vittoria Guerini, Daniela Sau, Paola Rusmini, Paolo Ciana, Adriana Maggi, Paolo G V Martini, Eugenia Scaccianoce, L Martini, Marcella MottaAbstract:Prostate cancer growth depends, in its earlier stages, on androgens and is usually pharmacologically modulated with androgen blockade. However, androgen-ablation therapy may generate androgen-independent prostate cancer, often characterized by an increased invasiveness. We have found that the 5α-reduced testosterone derivative, dihydrotestosterone (the most potent natural androgen) inhibits cell migration with an androgen receptor–independent mechanism. We have shown that the dihydrotestosterone metabolite 5α-androstane-3β,17β-Diol (3β-ADiol), a steroid which does not bind androgen receptors, but efficiently binds the estrogen receptor β (ERβ), exerts a potent inhibition of prostate cancer cell migration through the activation of the ERβ signaling. Very surprisingly, estraDiol is not active, suggesting the existence of different pathways for ERβ activation in prostate cancer cells. Moreover, 3β-ADiol, through ERβ, induces the expression of E-cadherin, a protein known to be capable of blocking metastasis formation in breast and prostate cancer cells. The inhibitory effects of 3β-ADiol on prostate cancer cell migration is counteracted by short interfering RNA against E-cadherin. Altogether, the data showed that ( a ) circulating testosterone may act with estrogenic effects downstream in the catabolic process present in the prostate, and ( b ) that the estrogenic effect of testosterone derivatives (ERβ-dependent) results in the inhibition of cell migration, although it is apparently different from that linked to estraDiol on the same receptor and may be protective against prostate cancer invasion and metastasis. These results also shed some light on clinical observations suggesting that alterations in genes coding for 3β-hydroxysteroid dehydrogenases (the enzymes responsible for 3β-ADiol formation) are strongly correlated with hereditary prostate cancer.
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the androgen derivative 5alpha androstane 3beta 17beta Diol inhibits prostate cancer cell migration through activation of the estrogen receptor beta subtype
Cancer Research, 2005Co-Authors: Vittoria Guerini, Benita S. Katzenellenbogen, Daniela Sau, Paola Rusmini, Paolo Ciana, Adriana Maggi, Eugenia Scaccianoce, Paolo Martini, L Martini, Marcella MottaAbstract:Prostate cancer growth depends, in its earlier stages, on androgens and is usually pharmacologically modulated with androgen blockade. However, androgen-ablation therapy may generate androgen-independent prostate cancer, often characterized by an increased invasiveness. We have found that the 5alpha-reduced testosterone derivative, dihydrotestosterone (the most potent natural androgen) inhibits cell migration with an androgen receptor-independent mechanism. We have shown that the dihydrotestosterone metabolite 5alpha-androstane-3beta,17beta-Diol (3beta-ADiol), a steroid which does not bind androgen receptors, but efficiently binds the estrogen receptor beta (ERbeta), exerts a potent inhibition of prostate cancer cell migration through the activation of the ERbeta signaling. Very surprisingly, estraDiol is not active, suggesting the existence of different pathways for ERbeta activation in prostate cancer cells. Moreover, 3beta-ADiol, through ERbeta, induces the expression of E-cadherin, a protein known to be capable of blocking metastasis formation in breast and prostate cancer cells. The inhibitory effects of 3beta-ADiol on prostate cancer cell migration is counteracted by short interfering RNA against E-cadherin. Altogether, the data showed that (a) circulating testosterone may act with estrogenic effects downstream in the catabolic process present in the prostate, and (b) that the estrogenic effect of testosterone derivatives (ERbeta-dependent) results in the inhibition of cell migration, although it is apparently different from that linked to estraDiol on the same receptor and may be protective against prostate cancer invasion and metastasis. These results also shed some light on clinical observations suggesting that alterations in genes coding for 3beta-hydroxysteroid dehydrogenases (the enzymes responsible for 3beta-ADiol formation) are strongly correlated with hereditary prostate cancer.
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the androgen derivative 5alpha androstane 3beta 17beta Diol 3beta aDiol inhibits migration of prostate cancer cell by activation of the estrogen receptor beta
Cancer Research, 2005Co-Authors: Vittoria Guerini, Benita S. Katzenellenbogen, Daniela Sau, Paola Rusmini, Paolo Ciana, Adriana Maggi, Paolo G V Martini, Marcella Motta, Angelo PolettiAbstract:297 In earlier stages, prostate cancer (PC) depends on androgens and may be reduced with androgen blockade. Androgen-ablation therapy often induces androgen-independent PC, characterized by an increased invasiveness. We have found that the the testosterone derivative, dihydrotestosterone inhibits cell migration with an androgen receptor (AR)-independent mechanism. This effect has been linked to its metabolite 5alpha-androstane-3beta,17beta-Diol (3beta-ADiol), a steroid which does not bind AR, but interact with the estrogen receptor beta (ERbeta). 3beta-ADiol inhibits cell migration of PC through the activation of the ERbeta signalling, while estraDiol is not active, suggesting the existence of different pathways for ERbeta activation in PC cells. Moreover, 3beta-ADiol induces the expression of E-cadherin, a protein known to be capable to reduce metastasis formation of breast cancer and PC cells. The inhibitory effects of 3beta-ADiol on PC cell migration is counteracted by siRNA against E-cadherin. The present data demonstrated that 1) testosterone may exert an estrogenic effects downstream in the catabolic process present in the prostate; 2) the estrogenic effect of testosterone derivatives (ERbeta-dependent) inhihits cell migration, although it is apparently different from that linked to estraDiol on the same receptor and may be protective against PC invasion and metastasis. These results may help to explain some clinical observations which reported that alterations in gene coding for 3beta-HSDs (the enzymes responsible for 3beta-ADiol formation) are strongly correlated with hereditary PC.
Vittoria Guerini - One of the best experts on this subject based on the ideXlab platform.
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the androgen derivative 5α androstane 3β 17β Diol inhibits prostate cancer cell migration through activation of the estrogen receptor β subtype
Cancer Research, 2005Co-Authors: Vittoria Guerini, Daniela Sau, Paola Rusmini, Paolo Ciana, Adriana Maggi, Paolo G V Martini, Eugenia Scaccianoce, L Martini, Marcella MottaAbstract:Prostate cancer growth depends, in its earlier stages, on androgens and is usually pharmacologically modulated with androgen blockade. However, androgen-ablation therapy may generate androgen-independent prostate cancer, often characterized by an increased invasiveness. We have found that the 5α-reduced testosterone derivative, dihydrotestosterone (the most potent natural androgen) inhibits cell migration with an androgen receptor–independent mechanism. We have shown that the dihydrotestosterone metabolite 5α-androstane-3β,17β-Diol (3β-ADiol), a steroid which does not bind androgen receptors, but efficiently binds the estrogen receptor β (ERβ), exerts a potent inhibition of prostate cancer cell migration through the activation of the ERβ signaling. Very surprisingly, estraDiol is not active, suggesting the existence of different pathways for ERβ activation in prostate cancer cells. Moreover, 3β-ADiol, through ERβ, induces the expression of E-cadherin, a protein known to be capable of blocking metastasis formation in breast and prostate cancer cells. The inhibitory effects of 3β-ADiol on prostate cancer cell migration is counteracted by short interfering RNA against E-cadherin. Altogether, the data showed that ( a ) circulating testosterone may act with estrogenic effects downstream in the catabolic process present in the prostate, and ( b ) that the estrogenic effect of testosterone derivatives (ERβ-dependent) results in the inhibition of cell migration, although it is apparently different from that linked to estraDiol on the same receptor and may be protective against prostate cancer invasion and metastasis. These results also shed some light on clinical observations suggesting that alterations in genes coding for 3β-hydroxysteroid dehydrogenases (the enzymes responsible for 3β-ADiol formation) are strongly correlated with hereditary prostate cancer.
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the androgen derivative 5alpha androstane 3beta 17beta Diol inhibits prostate cancer cell migration through activation of the estrogen receptor beta subtype
Cancer Research, 2005Co-Authors: Vittoria Guerini, Benita S. Katzenellenbogen, Daniela Sau, Paola Rusmini, Paolo Ciana, Adriana Maggi, Eugenia Scaccianoce, Paolo Martini, L Martini, Marcella MottaAbstract:Prostate cancer growth depends, in its earlier stages, on androgens and is usually pharmacologically modulated with androgen blockade. However, androgen-ablation therapy may generate androgen-independent prostate cancer, often characterized by an increased invasiveness. We have found that the 5alpha-reduced testosterone derivative, dihydrotestosterone (the most potent natural androgen) inhibits cell migration with an androgen receptor-independent mechanism. We have shown that the dihydrotestosterone metabolite 5alpha-androstane-3beta,17beta-Diol (3beta-ADiol), a steroid which does not bind androgen receptors, but efficiently binds the estrogen receptor beta (ERbeta), exerts a potent inhibition of prostate cancer cell migration through the activation of the ERbeta signaling. Very surprisingly, estraDiol is not active, suggesting the existence of different pathways for ERbeta activation in prostate cancer cells. Moreover, 3beta-ADiol, through ERbeta, induces the expression of E-cadherin, a protein known to be capable of blocking metastasis formation in breast and prostate cancer cells. The inhibitory effects of 3beta-ADiol on prostate cancer cell migration is counteracted by short interfering RNA against E-cadherin. Altogether, the data showed that (a) circulating testosterone may act with estrogenic effects downstream in the catabolic process present in the prostate, and (b) that the estrogenic effect of testosterone derivatives (ERbeta-dependent) results in the inhibition of cell migration, although it is apparently different from that linked to estraDiol on the same receptor and may be protective against prostate cancer invasion and metastasis. These results also shed some light on clinical observations suggesting that alterations in genes coding for 3beta-hydroxysteroid dehydrogenases (the enzymes responsible for 3beta-ADiol formation) are strongly correlated with hereditary prostate cancer.
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the androgen derivative 5alpha androstane 3beta 17beta Diol 3beta aDiol inhibits migration of prostate cancer cell by activation of the estrogen receptor beta
Cancer Research, 2005Co-Authors: Vittoria Guerini, Benita S. Katzenellenbogen, Daniela Sau, Paola Rusmini, Paolo Ciana, Adriana Maggi, Paolo G V Martini, Marcella Motta, Angelo PolettiAbstract:297 In earlier stages, prostate cancer (PC) depends on androgens and may be reduced with androgen blockade. Androgen-ablation therapy often induces androgen-independent PC, characterized by an increased invasiveness. We have found that the the testosterone derivative, dihydrotestosterone inhibits cell migration with an androgen receptor (AR)-independent mechanism. This effect has been linked to its metabolite 5alpha-androstane-3beta,17beta-Diol (3beta-ADiol), a steroid which does not bind AR, but interact with the estrogen receptor beta (ERbeta). 3beta-ADiol inhibits cell migration of PC through the activation of the ERbeta signalling, while estraDiol is not active, suggesting the existence of different pathways for ERbeta activation in PC cells. Moreover, 3beta-ADiol induces the expression of E-cadherin, a protein known to be capable to reduce metastasis formation of breast cancer and PC cells. The inhibitory effects of 3beta-ADiol on PC cell migration is counteracted by siRNA against E-cadherin. The present data demonstrated that 1) testosterone may exert an estrogenic effects downstream in the catabolic process present in the prostate; 2) the estrogenic effect of testosterone derivatives (ERbeta-dependent) inhihits cell migration, although it is apparently different from that linked to estraDiol on the same receptor and may be protective against PC invasion and metastasis. These results may help to explain some clinical observations which reported that alterations in gene coding for 3beta-HSDs (the enzymes responsible for 3beta-ADiol formation) are strongly correlated with hereditary PC.
Marilyn B Renfree - One of the best experts on this subject based on the ideXlab platform.
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5α androstane 3α 17β Diol is formed in tammar wallaby pouch young testes by a pathway involving 5α pregnane 3α 17α Diol 20 one as a key intermediate
Endocrinology, 2003Co-Authors: Jean D Wilson, Richard J Auchus, Michael W Leihy, Oleg Guryev, Ronald W Estabrook, Susan M Osborn, Geoffrey Shaw, Marilyn B RenfreeAbstract:The synthetic pathway by which 5α-androstane-3α,17β-Diol (5α-aDiol) is formed in the testes of tammar wallaby pouch young was investigated by incubating testes from d 20–40 males with various radioactive precursors and analyzing the metabolites by thin-layer chromatography and HPLC. [3H]Progesterone was converted to 17-hydroxyprogesterone, which was converted to 5α-aDiol by two pathways: One involves the formation of testosterone and dihydrotestosterone as intermediates, and the other involves formation of 5α-pregnane-3α,17α-Diol-20-one (5α-pDiol) and androsterone as intermediates. Formation of 5α-aDiol from both [3H]testosterone and [3H]progesterone was blocked by the 5α-reductase inhibitor 4MA. The addition of nonradioactive 5α-pDiol blocked the conversion of [3H]progesterone to 5α-aDiol, and [3H]5α-pDiol was efficiently converted to androsterone and 5α-aDiol. We conclude that expression of steroid 5α-reductase in the developing wallaby testes allows formation of 5α-reduced androgens by a pathway that d...
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administration of 5α androstane 3α 17β Diol to female tammar wallaby pouch young causes development of a mature prostate and male urethra
Endocrinology, 2002Co-Authors: Michael W Leihy, Jean D Wilson, Geoffrey Shaw, Marilyn B RenfreeAbstract:Secretion of 5α-androstane-3α,17β-Diol (5α-aDiol) by the testes of the tammar wallaby is responsible for initiation of prostatic development after d 20 in male pouch young. To ascertain the role of this hormone in the subsequent growth and differentiation of the prostate and in the development of the male phallus, 5α-aDiol was administered to tammar female pouch young in two regimens. Administration of the hormone by mouth (8 μg/g body weight·wk) between d 70 and 150 of pouch life caused prostate development equivalent to that in d 150 males and promoted growth and differentiation of the penis, but not masculinization of the urethra. Treatment with a small dose of 5α-aDiol enanthate (1 μg/g body weight·wk) from d 20–150 produced similar results. However, administration of larger doses of 5α-aDiol enanthate (10 or 100 μg/g body weight·wk) from d 20–150 caused supraphysiological growth of the prostate, development of a male-type urethra, and penile growth. These results indicate that prostatic development a...
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virilization of the urogenital sinus of the tammar wallaby is not unique to 5α androstane 3α 17β Diol
Molecular and Cellular Endocrinology, 2001Co-Authors: Michael W Leihy, Jean D Wilson, Geoffrey Shaw, Marilyn B RenfreeAbstract:The androgen 5alpha-androstane-3alpha,17beta-Diol (5alpha-aDiol) is synthesized in testes and secreted into plasma of male tammar wallaby pouch young and appears to virilize the urogenital sinus. To provide insight into its mechanism of action, a dose response study showed that administration of 1 microg 5alpha-aDiol monoenanthate per g body wt. per week for 3 weeks to 24-day-old female pouch young induced prostate bud formation equivalent to that of males of the same age. Administration of this same dose of the enanthates of testosterone, dihydrotestosterone, and 5alpha-aDiol to female pouch young caused equivalent virilization of the urogenital sinus. The fact that 5alpha-aDiol does not exert a unique effect, together with our earlier findings in this species that 5alpha-aDiol and testosterone are converted to dihydrotestosterone in the urogenital sinus and that virilization of the urogenital sinus is prevented by the androgen receptor antagonist flutamide, suggest that 5alpha-aDiol is a circulating precursor for dihydrotestosterone formation in this tissue.
Chawnshang Chang - One of the best experts on this subject based on the ideXlab platform.
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suppression of delta 5 androsteneDiol induced androgen receptor transactivation by selective steroids in human prostate cancer cells
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Hongchiang Chang, Hiroshi Miyamoto, Shuyuan Yeh, Chawnshang Chang, Padma Marwah, Henry A Lardy, Ko En HuangAbstract:Our earlier report suggested that androst-5-ene-3beta,7beta-Diol (Delta(5)-androsteneDiol or ADiol) is a natural hormone with androgenic activity and that two potent antiandrogens, hydroxyflutamide (Eulexin) and bicalutamide (Casodex), fail to block completely the ADiol-induced androgen receptor (AR) transactivation in prostate cancer cells. Here, we report the development of a reporter assay to screen several selective steroids with anti-ADiol activity. Among 22 derivatives/metabolites of dehydroepiandrosterone, we found 4 steroids [no. 4, 1,3,5(10)-estratriene-17alpha-ethynyl-3, 17beta-Diol; no. 6, 17alpha-ethynyl-androstene-Diol; no. 8, 3beta, 17beta-dihydroxy-androst-5-ene-16-one; and no. 10, 3beta-methylcarbonate-androst-5-ene-7,17-dione] that have no androgenic activity and could also block the ADiol-induced AR transactivation in prostate cancer PC-3 cells. Interestingly, these compounds, in combination with hydroxyflutamide, further suppressed the ADiol-induced AR transactivation. Reporter assays further showed that these four anti-ADiol steroids have relatively lower glucocorticoid, progesterone, and estrogenic activity. Together, these data suggest some selective steroids might have anti-ADiol activity, which may have potential clinical application in the battle against the androgen-dependent prostate cancer growth.
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δ5 androsteneDiol is a natural hormone with androgenic activity in human prostate cancer cells
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Hiroshi Miyamoto, Shuyuan Yeh, Henry Lardy, Edward M Messing, Chawnshang ChangAbstract:It is known that androst-5-ene-3β,17β-Diol (ADiol), a precursor of testosterone (T), can activate estrogen target genes. The androgenic activity of ADiol itself, however, is poorly understood. Using a transient transfection assay, we here demonstrate in human prostate cancer cells that ADiol can activate androgen receptor (AR) target genes in the presence of AR, and that AR coactivator ARA70 can further enhance this ADiol-induced AR transcriptional activity. In contrast to this finding, an active metabolite of dehydroepiandrosterone, 7-oxo-dehydroepiandrosterone, does not activate AR target gene in the absence or presence of ARA70. Thin layer chromatography analysis reveals that T, dihydrotestosterone, and 17β-estraDiol are undetectable in human prostate cancer DU145 cells after treatment with ADiol. Additionally, a proteolysis assay shows that a distinct ligand-receptor conformational difference exists between T-AR and ADiol-AR. Together, the above findings and the fact that T, but not ADiol, can induce transcriptional activity in a mutant AR (mtAR708), suggest that, without being metabolized into T, ADiol itself may represent a natural hormone with androgenic activity in human prostate cancer cells. Because two potent antiandrogens, hydroxyflutamide (Eulexin), and bicalutamide (casodex), that are widely used for the treatment of prostate cancer, fail to block ADiol-mediated induction of AR transcriptional activity in prostate cancer cells, the effectiveness of so-called “total androgen blockage,” a standard treatment for prostate cancer, may need to be reevaluated.
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d 5 androsteneDiol is a natural hormone with androgenic activity in human prostate cancer cells ara70yhydroxyf lutamideycasodexytestosteroney7 oxo dhea
1998Co-Authors: Hiroshi Miyamoto, Shuyuan Yeh, Henry Lardy, Dward E Messing, Chawnshang ChangAbstract:It is known that androst-5-ene-3b,17b-Diol (ADiol), a precursor of testosterone (T), can activate estrogen target genes. The androgenic activity of ADiol itself, however, is poorly understood. Using a transient transfection assay, we here demonstrate in human prostate cancer cells that ADiol can activate androgen receptor (AR) target genes in the presence of AR, and that AR coactivator ARA70 can further enhance this ADiol-induced AR transcriptional activity. In contrast to this finding, an active metabolite of dehydroepi- androsterone, 7-oxo-dehydroepiandrosterone, does not acti- vate AR target gene in the absence or presence of ARA70. Thin layer chromatography analysis reveals that T, dihydrotestos- terone, and 17b-estraDiol are undetectable in human prostate cancer DU145 cells after treatment with ADiol. Additionally, a proteolysis assay shows that a distinct ligand-receptor conformational difference exists between T-AR and ADiol-AR. Together, the above findings and the fact that T, but not ADiol, can induce transcriptional activity in a mutant AR (mtAR708), suggest that, without being metabolized into T, ADiol itself may represent a natural hormone with androgenic activity in human prostate cancer cells. Because two potent antiandrogens, hydroxyf lutamide (Eulexin), and bicaluta- mide (casodex), that are widely used for the treatment of prostate cancer, fail to block ADiol-mediated induction of AR transcriptional activity in prostate cancer cells, the effective- ness of so-called ''total androgen blockage,'' a standard treatment for prostate cancer, may need to be reevaluated.
