Mikhail G Dozmorov, Qing Yang, Adam Matwalli, Robert E Hurst, Daniel J Culkin, Bradley P Kropp, Hsueh-Kung Lin
{"title":"5 α -雄烷-3 α,17 β -二醇选择性激活典型的PI3K/AKT通路:雄激素激活细胞质信号传导的生物信息学证据。","authors":"Mikhail G Dozmorov, Qing Yang, Adam Matwalli, Robert E Hurst, Daniel J Culkin, Bradley P Kropp, Hsueh-Kung Lin","doi":"10.1007/s11568-008-9018-9","DOIUrl":null,"url":null,"abstract":"<p><p>5alpha-Androstane-3alpha,17beta-diol (3alpha-diol) is reduced from the potent androgen, 5alpha-dihydrotestosterone (5alpha-DHT), by reductive 3alpha-hydroxysteroid dehydrogenases (3alpha-HSDs) in the prostate. 3alpha-diol is recognized as a weak androgen with low affinity toward the androgen receptor (AR), but can be oxidized back to 5alpha-DHT. However, 3alpha-diol may have potent effects by activating cytoplasmic signaling pathways, stimulating AR-independent prostate cell growth, and, more importantly, providing a key signal for androgen-independent prostate cancer progression. A cancer-specific, cDNA-based membrane array was used to determine 3alpha-diol-activated pathways in regulating prostate cancer cell survival and/or proliferation. Several canonical pathways appeared to be affected by 3alpha-diol-regulated responses in LNCaP cells; among them are apoptosis signaling, PI3K/AKT signaling, and death receptor signaling pathways. Biological analysis confirmed that 3alpha-diol stimulates AKT activation; and the AKT pathway can be activated independent of the classical AR signaling. These observations sustained our previous observations that 3alpha-diol continues to support prostate cell survival and proliferation regardless the status of the AR. We provided the first systems biology approach to demonstrate that 3alpha-diol-activated cytoplasmic signaling pathways are important components of androgen-activated biological functions in human prostate cells. Based on the observations that levels of reductive 3alpha-HSD expression are significantly elevated in localized and advanced prostate cancer, 3alpha-diol may, therefore, play a critical role for the transition from androgen-dependent to androgen-independent prostate cancer in the presence of androgen deprivation.</p>","PeriodicalId":87975,"journal":{"name":"Genomic medicine","volume":null,"pages":null},"PeriodicalIF":3.5000,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s11568-008-9018-9","citationCount":"4","resultStr":"{\"title\":\"5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling.\",\"authors\":\"Mikhail G Dozmorov, Qing Yang, Adam Matwalli, Robert E Hurst, Daniel J Culkin, Bradley P Kropp, Hsueh-Kung Lin\",\"doi\":\"10.1007/s11568-008-9018-9\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>5alpha-Androstane-3alpha,17beta-diol (3alpha-diol) is reduced from the potent androgen, 5alpha-dihydrotestosterone (5alpha-DHT), by reductive 3alpha-hydroxysteroid dehydrogenases (3alpha-HSDs) in the prostate. 3alpha-diol is recognized as a weak androgen with low affinity toward the androgen receptor (AR), but can be oxidized back to 5alpha-DHT. However, 3alpha-diol may have potent effects by activating cytoplasmic signaling pathways, stimulating AR-independent prostate cell growth, and, more importantly, providing a key signal for androgen-independent prostate cancer progression. A cancer-specific, cDNA-based membrane array was used to determine 3alpha-diol-activated pathways in regulating prostate cancer cell survival and/or proliferation. Several canonical pathways appeared to be affected by 3alpha-diol-regulated responses in LNCaP cells; among them are apoptosis signaling, PI3K/AKT signaling, and death receptor signaling pathways. Biological analysis confirmed that 3alpha-diol stimulates AKT activation; and the AKT pathway can be activated independent of the classical AR signaling. These observations sustained our previous observations that 3alpha-diol continues to support prostate cell survival and proliferation regardless the status of the AR. We provided the first systems biology approach to demonstrate that 3alpha-diol-activated cytoplasmic signaling pathways are important components of androgen-activated biological functions in human prostate cells. Based on the observations that levels of reductive 3alpha-HSD expression are significantly elevated in localized and advanced prostate cancer, 3alpha-diol may, therefore, play a critical role for the transition from androgen-dependent to androgen-independent prostate cancer in the presence of androgen deprivation.</p>\",\"PeriodicalId\":87975,\"journal\":{\"name\":\"Genomic medicine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2007-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1007/s11568-008-9018-9\",\"citationCount\":\"4\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Genomic medicine\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1007/s11568-008-9018-9\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2008/2/27 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"EDUCATION & EDUCATIONAL RESEARCH\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genomic medicine","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1007/s11568-008-9018-9","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2008/2/27 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"EDUCATION & EDUCATIONAL RESEARCH","Score":null,"Total":0}
5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling.
5alpha-Androstane-3alpha,17beta-diol (3alpha-diol) is reduced from the potent androgen, 5alpha-dihydrotestosterone (5alpha-DHT), by reductive 3alpha-hydroxysteroid dehydrogenases (3alpha-HSDs) in the prostate. 3alpha-diol is recognized as a weak androgen with low affinity toward the androgen receptor (AR), but can be oxidized back to 5alpha-DHT. However, 3alpha-diol may have potent effects by activating cytoplasmic signaling pathways, stimulating AR-independent prostate cell growth, and, more importantly, providing a key signal for androgen-independent prostate cancer progression. A cancer-specific, cDNA-based membrane array was used to determine 3alpha-diol-activated pathways in regulating prostate cancer cell survival and/or proliferation. Several canonical pathways appeared to be affected by 3alpha-diol-regulated responses in LNCaP cells; among them are apoptosis signaling, PI3K/AKT signaling, and death receptor signaling pathways. Biological analysis confirmed that 3alpha-diol stimulates AKT activation; and the AKT pathway can be activated independent of the classical AR signaling. These observations sustained our previous observations that 3alpha-diol continues to support prostate cell survival and proliferation regardless the status of the AR. We provided the first systems biology approach to demonstrate that 3alpha-diol-activated cytoplasmic signaling pathways are important components of androgen-activated biological functions in human prostate cells. Based on the observations that levels of reductive 3alpha-HSD expression are significantly elevated in localized and advanced prostate cancer, 3alpha-diol may, therefore, play a critical role for the transition from androgen-dependent to androgen-independent prostate cancer in the presence of androgen deprivation.