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A Mizokami, Department of Integrative Cancer Therapy and Urology, Kanazawa University, Kanazawa, 920-8640, Japan
E Koh, Department of Integrative Cancer Therapy and Urology, Kanazawa University, Kanazawa, Japan
K Izumi, Department of Integrative Cancer Therapy and Urology, Kanazawa University, Kanazawa, Japan
K Narimoto, Department of Integrative Cancer Therapy and Urology, Kanazawa University, Kanazawa, Japan
M Takeda, Department of Integrative Cancer Therapy and Urology, Kanazawa University, Kanazawa, Japan
S Honma, Teikoku Hormone MFG. Co, Kawasaki, Japan
J Dai, Ann Arbor, United States
E Keller, Departments of Urology and Pathology, University of Michigan, Ann Arbor, United States
M Namiki, Department of Integrative Cancer Therapy and Urology, Kanazawa University, Kanazawa, Japan

Correspondence: Atsushi Mizokami, Email: mizokami{at}med.kanazawa-u.ac.jp

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 DHEA metabolism in androgen-sensitive PCa LNCaP cells. DHEA alone had little effect on PSA promoter activity and the proliferation of LNCaP cells. However, the addition of prostate stromal cells (PrSC) 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 DHT 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 5-reductase inhibitor dutasteride appears to function not only as 5-reductase inhibitor but also as 3β-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.