PTEN Loss Promotes Intratumoral Androgen Synthesis and Tumor Microenvironment Remodeling via Aberrant Activation of RUNX2 in Castration-Resistant Prostate Cancer.

Abstract

<b>Purpose:</b> Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR) reactivation and antiandrogen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood.<b>Experimental Design:</b> The effect of components of the AKT-RUNX2-osteocalcin (OCN)-GPRC6A-CREB signaling axis on expression of steroidogenesis genes <i>CYP11A1</i> and <i>CYP17A1</i> and testosterone level were examined in PTEN-null human prostate cancer cell lines. <i>Pten</i> knockout mice were used to examine the effect of <i>Runx2</i> heterozygous deletion or abiraterone acetate (ABA), a prodrug of the CYP17A1 inhibitor abiraterone on <i>Cyp11a1</i> and <i>Cyp17a1</i> expression, testosterone level and tumor microenvironment (TME) remodeling <i>in vivo</i><b>Results:</b> We uncovered that activation of the AKT-RUNX2-OCN-GPRC6A-CREB signaling axis induced expression of <i>CYP11A1</i> and <i>CYP17A1</i> and testosterone production in PTEN-null prostate cancer cell lines in culture. Deletion of <i>Runx2</i> in <i>Pten</i> homozygous knockout prostate tumors decreased <i>Cyp11a1</i> and <i>Cyp17a1</i> expression, testosterone level, and tumor growth in castrated mice. ABA treatment also inhibited testosterone synthesis and alleviated Pten loss-induced tumorigenesis <i>in vivo</i><i>Pten</i> deletion induced TME remodeling, but <i>Runx2</i> heterozygous deletion or ABA treatment reversed the effect of Pten loss by decreasing expression of the collagenase Mmp9.<b>Conclusions:</b> 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 prostate cancer, including CRPC. <i>Clin Cancer Res; 24(4); 834-46. ©2017 AACR</i>.