5α-androstane-3α,17β-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling

Abstract

5a-Androstane-3a,17b-diol (3a-diol) is reduced from the potent androgen, 5a-dihydrotestosterone (5a-DHT), by reductive 3a-hydroxysteroid dehydrogenases (3a-HSDs) in the prostate. 3a-diol is recognized as a weak androgen with low affinity toward the androgen receptor (AR), but can be oxidized back to 5a-DHT. However, 3a-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, cDNAbased membrane array was used to determine 3a-diol-activated pathways in regulating prostate cancer cell survival and/or proliferation. Several canonical pathways appeared to be affected by 3a-diol-regulated responses in LNCaP cells; among them are apoptosis signaling, PI3K/AKT signaling, and death receptor signaling pathways. Biological analysis confirmed that 3a-diol stimulates AKT activation; and the AKT pathway can be activated independent of the classical AR signaling. These observations sustained our previous observations that 3a-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 3a-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 3a-HSD expression are significantly elevated in localized and advanced prostate cancer, 3a-diol may, therefore, play a critical role for the transition from androgen-dependent to androgen-independent prostate cancer in the presence of androgen deprivation.

Integrating insulin-like growth factor 1 and sex hormones into neuroprotection: Implications for diabetes

“…Metabolites of DHT, 3α-Diol and 3β-Diol, are also bioactive and may bind the ER or insulin-like peptide receptors to initiate MAPK or PI3K signaling cascades. Indeed, research shows that 3α-Diol stimulated PI3K-Akt signaling enhances cell survival in the prostate[ 144 ]. Similarly, DHT metabolites may influence transcriptional activities of nuclear ER by modulating ER-induced MAPK or PI3K signaling cascades.…”

AKR1C2 acts as a targetable oncogene in esophageal squamous cell carcinoma via activating PI3K/AKT signaling pathway

“…[43][44][45][46][47][48][49] In addition, previous studies reported that P) could be chemical synthesized or biosynthesized by diol in vitro. 50,51 As ESCC tissues hardly expresses AR ( Figure 7D), thus, it is reasonable to infer that the metabolites 3α-diol may be reused to biosynthesis PI, known as a precursor of PI3K, 52 following by activating the PI3K/AKT pathway in an AR-independent manner, [43][44][45][46] However, there is insufficient evidence that whether 3α-diol could biosynthesis PI directory in vivo. Collectively, these results suggest that for AR negative AKR1C2 positive (AR − /AKR1C2 + ) ESCC, AKR1C2…”