The role of CaMKK2 in prostate cancer progression
Karacosta, Loukia G.
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The androgen receptor (AR) plays a critical role in prostate cancer (PC) progression; however, the molecular mechanisms by which the AR regulates cell proliferation in androgen-dependent and castration-resistant PC (CRPC) are incompletely understood. Identifying signaling molecules that support and drive AR reactivation mechanisms that promote PC progression could be key in developing beneficial therapeutic options for the currently incurable form of the disease, which usually recurs following initial successful androgen deprivation therapy (ADT). Involvement of Ca 2+ /calmodulin-dependent kinase kinase 2 (CaMKK2) in PC has been largely unappreciated, despite the numerous expression studies that have identified CaMKK2 as a gene being overexpressed in PC. Therefore, the goal of this study was to characterize and establish the role of CaMKK2 in PC, in terms of its expression, regulation and the signaling pathways it regulates during PC advancement to CRPC. Through this project I was able to demonstrate that CaMKK2 expression increases during PC progression and becomes perinuclear/nuclear in advanced disease in human and mouse PC specimens. In addition, I found that dihydrotestosterone (DHT) not only stimulates CaMKK2 expression - confirming reports that CaMKK2 is an AR gene target - but also induces CaMKK2 nuclear translocation. By treating PC cells with either CaMKK2 siRNA or a CaMKK2 inhibitor I identified a regulatory role of CaMKK2 in PC cell proliferation and AR transcriptional activity. These findings collectively describe a novel regulatory feedback loop in which the AR feeds forward to induce CaMKK2 expression and CaMKK2 in turn, feeds back to positively regulate AR transcriptional activity. Therefore, this project reveals a possible mechanism triggered in relapsed tumors to maintain growth and cell proliferation that are initially hindered due to androgen ablation therapy. In order to delineate the molecular mechanism by which CaMKK2 modulates AR transcriptional activity, I proceeded to examine the nuclear functions of CaMKK2 in advanced PC. Unexpectedly, my research revealed a physical interaction between CaMKK2 and a component of the nuclear pore complex, nucleoporin 62 (Nup62). Furthermore, I provide evidence that this complex directly modulates AR activity in the nucleus of castrate recurrent PC cells. This provides a mechanistic perspective of CaMKK2 regulation of AR transcriptional activity, which for the first time identifies novel AR nuclear co-regulators in both CaMKK2 and Nup62. Taken together, the research presented here, describes a multifunctional role of CaMKK2 in PC and reveals a novel molecular mechanism of action in relation to the AR. This may lead to establishing CaMKK2 as a key PC biomarker or more importantly, as a promising therapeutic target in PC therapy. This could be potentially effective in combination with androgen ablation and could be utilized in both androgen-dependent and castrate-recurrent PC to suppress CaMKK2-related escape routes that the AR utilizes to drive PC progression.