It has long been known that the AR is regulated not only by its cognate steroid hormone, but also by interactions with a constellation of co-regulatory and signaling molecules. Checkpoint kinase 2 (CHK2) is a serine/threonine protein kinase whose main function is regulating the DNA damage response (DDR) triggered by double-strand DNA breaks. The androgen receptor (AR) is a major driver of prostate cancer, even at the castrationresistant stage of the disease. Our research suggests a CHK2CDC25CCDK1AR phosphoS308 signaling pathway in the regulation of AR activity and prostate cancer cell growth. We have now uncovered novel molecular interactions between CHK2 and AR that provide mechanistic insight into our observation that CHK2 regulates prostate cancer growth. The AR directly interacts with CHK2, and that interaction increases with radiation. We found that the interaction of CHK2 and AR occurs at sites of DNA damage. The binding of CHK2 with AR can be disrupted with CHK2 kinase inhibitors suggesting that the kinase activity of CHK2 is required. This was verified using kinaseimpaired CHK2 variants, including the K373E variant associated with 4.2% of prostate cancer. Furthermore, the radiationinduced increase in CHK2AR requires AR phosphorylation on both serine 81 and serine 308. Interestingly, CHK2-depletion in LNCaP cells increases ionizing radiation induced AR expression, AR regulation of DDR genes, and DNA damage. Together, these data provide the rationale for targeting the CHK2AR signaling axis to improve the effectiveness of prostate cancer therapies. The combination of CHK2, Aurora, or CDK1 inhibitors with androgen deprivation therapy (ADT) and radiation enhances repression of tumor cell growth. Our data substantiates a new role for CHK2 signaling and directly links a critical member of the DDR with ARmediated transcription and proliferation in prostate cancer. The data suggest that the CHK2AR interaction functions to downregulate the AR mediated DDR. These findings are clinically relevant since nearly every patient with disseminated prostate cancer will relapse following ADT and develop incurable castrationresistant prostate cancer. These data may assist in the rational application of existing therapies and lead to the development of novel prostate cancer therapeutics.
27 Feb - 02 Mar 2018
Nuclear Receptors Conference