Prostate cancer stromal cells and LNCaP cells coordinately activate the androgen receptor through synthesis of testosterone and dihydrotestosterone from dehydroepiandrosterone

Abstract

One of the mechanisms through which advanced prostate cancer (PCa) usually relapses after androgen deprivation therapy (ADT) is the adaptation to residual androgens in PCa tissue. It has been observed that androgen biosynthesis in PCa tissue plays an important role in this adaptation. In the present study, we investigated how stromal cells affect adrenal androgen dehydroepiandrosterone (DHEA) metabolism in androgen-sensitive PCa LNCaP cells. DHEA alone had little effect on prostate-specific antigen (PSA) promoter activity and the proliferation of LNCaP cells. However, the addition of prostate stromal cells or PCa-derived stromal cells (PCaSC) increased DHEA-induced PSA promoter activity via androgen receptor activation in the LNCaP cells. Moreover, PCaSC stimulated the proliferation of LNCaP cells under physiological concentrations of DHEA. Biosynthesis of testosterone or dihydrotestosterone from DHEA in stromal cells and LNCaP cells was involved in this stimulation of LNCaP cell proliferation. Androgen biosynthesis from DHEA depended upon the activity of various steroidogenic enzymes present in stromal cells. Finally, the dual 5a-reductase inhibitor dutasteride appears to function not only as a 5a-reductase inhibitor but also as a 3b-hydroxysteroid dehydrogenase inhibitor in LNCaP cells. Taken together, this coculture assay system provides new insights of coordinate androgen biosynthesis under the microenvironment of PCa cells before and after ADT, and offers a model system for the identification of important steroidogenic enzymes involved in PCa progression and for the development of the corresponding inhibitors of androgen biosynthesis.

<i>Quisqualis indica</i> Improves Benign Prostatic Hyperplasia by Regulating Prostate Cell Proliferation and Apoptosis

“…However, the development and incidence of BPH are associated with dysregulation of androgens, and with increased proliferation and decreased apoptosis of cells in the prostate gland. [4][5][6][7][8][9] Testosterone and dihydrotestosterone (DHT) have key roles in the development and growth of the entire male genital tract, and they stimulate differentiation of the prostate gland. 10,11) The adrenal glands and testes synthesize testosterone, and prostatic 5α-reductase type 2 converts it to DHT.…”

“…12) DHT then binds to the androgen receptor (AR), which is transported to the nucleus, where it regulates genes important for prostate growth and differentiation. 4) BPH development and progression are associated with activation of the AKT pathway, a major growth factor-mediated signal transduction pathways. 6) Over-stimulation of the AKT pathway increases the activity of B-cell lymphoma 2 (Bcl-2) and cyclin D1, leading to increased proliferation and decreased apoptosis of cells, and transformation to the malignant state.…”

Stromal-epithelial interactions are responsible for prostate tumor progression through an androgen-related mechanism

“…Mizokami et al have clarified how prostate and bone stromal cells are able to convert DHEA into testosterone thereby increasing the local concentration of useful androgens within primary tumors and metastases respectively. 6 Moreover, this study provides evidence that dutasteride may inhibit the conversion of DHEA into testosterone.…”

“…such as dehydroepiandrosterone (DHEA) as well as estradiol and androstenediol. 6 ADT may actually be responsible for the aforementioned changes because only those cells that develop the ability to survive in low androgen concentration survive and proliferate. 2 Though it is known that in most cases ADT only partially reduces the original tumor androgen concentration, despite drastic decreases in serum androgen concentration;…”

GnRH agonists and the rapidly increasing use of combined androgen blockade in prostate cancer

“…The enzymatic conversion of DHEA to DHT has been shown to be essential for the activation of AR in LNCaP prostate cancer cells (Evaul et al 2010), while in vitro studies have shown that prostate cancer stromal cells and human LNCaP prostatic cancer cells coordinate activation of AR via synthesis of testosterone and DHT from DHEA (Mizokami et al 2009). In addition, increased expression of genes that code for the enzymes that convert DHEA into testosterone has been observed in CRPC (Stanbrough et al 2006), while cancerous prostatic tissue can synthesize more DHT than does benign prostatic tissue (Nishiyama et al 2007).…”