Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR) reactivation and anti-androgen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood. Experimental Design: The effect of components of the AKT-RUNX2-osteocalcin (OCN)-GPRC6A-CREB signaling axis on expression of steroidogenesis genes CYP11A1 and CYP17A1 and testosterone level were examined in PTEN-null human PCa cell lines. Pten knockout mice were employed to examine the effect of Runx2 heterozygous deletion or abiraterone acetate (ABA), a prodrug of the CYP17A1 inhibitor abiraterone on Cyp11a1 and Cyp17a1 expression, testosterone level and tumor microenvironment (TME) remodeling in vivo. Results: We uncovered that activation of the AKT-RUNX2-OCN-GPRC6A-CREB signaling axis induced expression of CYP11A1 and CYP17A1 and testosterone production in PTEN-null PCa cell lines in culture. Deletion of Runx2 in Pten homozygous knockout prostate tumors decreased Cyp11a1 and Cyp17a1 expression, testosterone level and tumor growth in castrated mice. ABA treatment also inhibited testosterone synthesis and alleviated Pten loss-induced tumorigenesis in vivo. Pten deletion induced TME remodeling, but Runx2 heterozygous deletion or ABA treatment reversed the effect of Pten loss by decreasing expression of the collagenase Mmp9.
Abnormal RUNX2 activation plays a pivotal role in PTEN loss-induced IAS and TME remodeling, suggesting that the identified signaling cascade represents a viable target for effective treatment of PTEN-null PCa including CRPC.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2017 Nov 22 [Epub ahead of print]
Yinhui Yang, Yang Bai, Yundong He, Yu Zhao, Jiaxiang Chen, Linlin Ma, Yunqian Pan, Michael Hinten, Jun Zhang, R Jeffrey Karnes, Manish Kohli, Jennifer J Westendorf, Benyi Li, Runzhi Zhu, Haojie Huang, Wanhai Xu
Urology, The Fourth Hospital of Harbin Medical University., Biochemistry and Molecular Biology, Mayo Clinic., Department of Urology, University of Kansas Medical Center., Mayo Clinic College of Medicine., Biochemistry and Molecular Biology, Mayo Clinic College of Medicine., Laboratory Medicine and Pathology, Mayo Clinic., Department of Urology, Mayo Clinic., Medical Oncology, Mayo Clinic., Departments of Orthopedic Surgery, and Biochemistry and Molecular Biology, Mayo Clinic., Urology, KUMC., Biochemistry and Molecular Biology, Mayo Clinic ., Urology surgery, The Fourth Hospital of Harbin Medical University.