Novel Functions of NF-kappaB2/p52 in Androgen Receptor Signaling in CRPC.

摘要

Purpose: Prostate cancer is one of the leading causes of cancer-related mortality in men in the United States. Androgen receptor signaling remains active in castration-resistant prostate cancer (CRPC). Here we show that NF-kappaB2/p52 activates the androgen receptor in the absence of ligand, via modulation of microRNA such as let-7c and via activation of intratumoral steroidogenesis by induction of higher levels of steroidogenic enzymes. We also show that NFkappaB2/ p52 induces resistance to anti-androgen therapies by inducing alternative splicing of the androgen receptor to increase levels of constitutively active variants. Scope: The identification of the pathway leading to androgen receptor activation by NF- B2/p52 may have implications for therapeutic applications against CRPC. The finding that p52 induces resistance to anti-androgenic therapies may have implications in the choice of treatment regimen in CRPC. Major Findings: We showed that: Downregulation of p52 reduces intracrine androgen synthesis; p52 regulates expression of steroidogenic enzymes; p52 induces expression of AR splice variants and thereby enhances resistance of prostate cancer cells to anti-androgens; p52 regulates expression of miR-let-7c; miR-let-7c reduces expression of AR; and that the NF-kappaB2/p52:c-Myc:let-7c:Lin28 axis plays a major role in the development of castration resistance. Significance: Current research efforts focus primarily on targeting the androgen receptor in CRPC. But the persistent activation of AR has been suggested to be one of the mechanisms of development of resistance to AR-targeted therapies. Our findings show that p52 plays a significant role in the development of castration and therapy resistance.