Intratumoral steroidogenesis is involved in development of castration-resistant prostate cancer (CRPC) as bone metastases. The osteoblast transcription factor RUNX2 influences steroidogenesis and is induced in CRPC cells by osteoblasts. This study investigates osteoclastic influence on RUNX2 in intratumoral steroidogenesis. Steroidogenic enzymes and steroid receptors were detected with immunohistochemistry in xenograft intratibial tumors from CRPC cells. In vitro, expression of RUNX2 was increased by osteoclasts in osteoblastic LNCaP-19 cells, but not in osteolytic PC-3. Silencing of RUNX2 downregulates expression of CYP11A1, CYP17A1 and HSD3B1 in LNCaP-19 cells co-cultured with osteoclasts, leading to inhibition of KLK3 expression. Osteoclasts promoted CYP11A1 and RUNX2 promoted AKR1C3, HSD17B3 and CYP19A1, but suppressed ESR2 in PC-3 cells. This study shows that osteoclasts promote RUNX2 regulated induction of key steroidogenic enzymes, influencing activation of androgen receptor in CRPC cells. The potential of RUNX2 as a target to inhibit progression of skeletal metastases of CRPC needs further investigation.
Keywords: Androgen receptor signaling; Bone metastasis; Castration-resistant prostate cancer; Intratumoral steroidogenesis; Osteoclasts; RUNX2.
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