A pivotal role of androgen signaling in Notch-responsive cells in prostate development, maturation, and regeneration

Abstract

Androgen signaling is essential for prostate development, morphogenesis, and regeneration. Emerging evidence also indicates a regulatory role of Notch signaling in prostate development, differentiation, and growth. However, the collaborative regulatory mechanisms of androgen and Notch signaling during prostate development, growth, and regeneration are largely unknown. Hairy and Enhancer of Split 1 (Hes1) is a transcriptional regulator of Notch signaling pathways, and its expression is responsive to Notch signaling. Hes1-expressing cells have been shown to possess the regenerative capability to repopulate a variety of adult tissues. In this study, we developed new mouse models to directly assess the role of the androgen receptor in prostatic Hes1-expressing cells. Selective deletion of AR expression in embryonic Hes1-expressing cells impeded early prostate development both in vivo and in tissue xenograft experiments.Prepubescent deletion of AR expression in Hes1-expressing cells resulted in prostate glands containing abnormalities in cell morphology and gland architecture. A population of castrationresistant Hes1-expressing cells was revealed in the adult prostate, with the ability to repopulate prostate epithelium following androgen supplementation. Deletion of AR in Hes1-expressing cells diminishes their regenerative ability. These lines of evidence demonstrate a critical role for the AR in Notch-responsive cells during the course of prostate development, morphogenesis, and regeneration, and implicate a mechanism underlying interaction between the androgen and Notch signaling pathways in the mouse prostate.

Tumor-associated macrophages in direct contact with prostate cancer cells promote malignant proliferation and metastasis through NOTCH1 pathway

“…It has been recently identified that the NOTCH pathway is not a simple linear sequence of events, as it can have crosstalk with other pathways to construct an extremely complex network [32]. Though AR pathway was crucial for PCa progression and involved in NOTCH signaling activation in PCa cells [19], we did not observe alterations in AR-dependent transcriptional activity after direct coculture with TAMs. Interestingly, we did not observe alterations in NOTCH ligands and receptors after direct coculture.…”

“…Although recent studies demonstrated that AR signaling was involved in NOTCH signaling activation [19], GSEA results did not indicate that PCa cell AR signaling was significantly changed in a direct contact manner (Figure S3A). In addition, AR and PSA protein expression was not altered after direct contact (Figure S3B).…”

Crosstalk between Androgen-ZIP9 Signaling and Notch Pathway in Rodent Sertoli Cells

“…Long-term testosterone enanthate treatment increased the expression of activated Notch1 in muscle satellite cells of older men consistent with increased satellite cell replication [28]. The importance for androgen-Notch interaction for the course of prostate development and morphogenesis was also demonstrated [29,30]. DeFalco et al [31] found that in mice testosterone plays a role in maintaining the balance between progenitor cells and differentiated fetal Leydig cells, regulating levels of JAG1 and Notch2.…”

The comprehensive role of E-cadherin in maintaining prostatic epithelial integrity during oncogenic transformation and tumor progression

“…Slides were developed with fluorescent-conjugated secondary antibodies and then mounted with coverslips using Vectashield Mounting Medium with DAPI (H-1200, Vector Laboratories). The mTmG assay was performed as previously described [48]. Briefly, sections from OCT embedded tissues were washed with PBS, pH 7.3, and then developed with Vectashield Mounting Medium with DAPI (H-1200, Vector Laboratories).…”