Androgen Receptor-CaMKK2 Axis in Prostate Cancer and Bone Microenvironment

Abstract

The skeletal system is of paramount importance in advanced stage prostate cancer (PCa) as it is the preferred site of metastasis. Complex mechanisms are employed sequentially by PCa cells to home to and colonize the bone. Bone-resident PCa cells then recruit osteoblasts (OBs), osteoclasts (OCs), and macrophages within the niche into entities that promote cancer cell growth and survival. Since PCa is heavily reliant on androgens for growth and survival, androgen-deprivation therapy (ADT) is the standard of care for advanced disease. Although it significantly improves survival rates, ADT detrimentally affects bone health and significantly increases the risk of fractures. Moreover, whereas the majority patients with advanced PCa respond favorably to androgen deprivation, most experience a relapse of the disease to a hormone-refractory form within 1-2 years of ADT. The tumor adapts to surviving under low testosterone conditions by selecting for mutations in the androgen receptor (AR) that constitutively activate it. Thus, AR signaling remains active in PCa cells and aids in its survival under low levels of circulating androgens and additionally allows the cancer cells to manipulate the bone microenvironment to fuel its growth. Hence, AR and its downstream effectors are attractive targets for therapeutic interventions against PCa. Ca²⁺/calmodulin-dependent protein kinase kinase 2 (CaMKK2), was recently identified as a key downstream target of AR in coordinating PCa cell growth, survival, and migration. Additionally, this multifunctional serine/threonine protein kinase is a critical mediator of bone remodeling and macrophage function, thus emerging as an attractive therapeutic target downstream of AR in controlling metastatic PCa and preventing ADT-induced bone loss. Here, we discuss the role played by AR-CaMKK2 signaling axis in PCa survival, metabolism, cell growth, and migration as well as the cell-intrinsic roles of CaMKK2 in OBs, OCs, and macrophages within the bone microenvironment.

Keywords: CAMKK2; androgen-deprivation therapy; bone–tumor microenvironment; castrate-resistant prostate cancer; treatment induced bone loss.

Figure 1

CAMKK2 as a molecular hub downstream in the bone–prostate cancer (PCa) microenvironment. In PCa cells, the androgen receptor (AR) binds to androgen response element (ARE) on CaMKK2 promoter which is situated upstream of the transcriptional start site. Thus, CaMKK2 is a direct transcriptional target of AR and its expression is highly elevated in metastatic PCa. Once transcribed and translated, CaMKK2 binds to AR initiating a positive feedback loop to stimulate AR transcriptional activity in the activation of AR-dependent genes that regulate cell cycle progression such as cyclin D. Additionally, CaMKK2 through its activation of AMPK regulates PCa cell migration. CaMKK2-AMPK signaling pathway also regulates cellular glycolysis via the activation of phosphofructokinase (PFK). This drives PCa cell anabolism and in turn promotes cell proliferation and tumor growth. Furthermore, in CRPCs, CaMKK2 binds to nucleoporin 62 (NUP62) to enter the nucleus, where it along with AR and NUP62 are recruited to the ARE in the promoters of downstream targets such as prostate serum antigen (PSA). PCa cells that metastasize to the bone physically interacts with OBs to alter their organization and function. Although both AR and CaMKK2 are expressed in OBs, whether CaMKK2 operates downstream of AR in these cells is not known. In OBs, CaMKK2 signaling inhibits cyclic adenosine monophosphate (cAMP) production and protein kinase A (PKA) activation. PKA is an important regulator of OB differentiation. Thus, the inhibition of CaMKK2 would relieve this inhibition of PKA signaling and OB differentiation. In osteoclasts (OCs), CaMKK2 signaling through CaMKIV-pCREB activates nuclear factor of activated T cells c1 (NFATc1), which is the master regulator of OC differentiation. In macrophages, CaMKK2 regulates cytoskeletal rearrangement via its regulation of Pyk2. Moreover, CaMKK2-CaMK1 signaling regulates cytokine/chemokine production by macrophages. Thus, CaMKK2 is a key component of AR signaling in PCa cells and additionally regulates multiple cell types that constitute the tumor microenvironment within the bone.