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.
Highlights
Prostate cancer (PCa) is the second leading cause of cancer-related deaths in American men and accounts for 15% of all cancers diagnosed in men worldwide [1, 2]
Metastatic prostate cancer (PCa) becomes lodged in the bone marrow (BM)-rich axial skeleton, which provides the perfect “soil” for the disease to develop to an advanced form often termed “castrateresistant PCa (CRPC)” as it is resistant to hormone-ablation
androgen receptor (AR) signaling remains critical for PCa cell survival even under androgen-deprivation therapy (ADT) and this creates selective pressure for calmodulin-dependent protein kinase kinase 2 (CaMKK2)-CaMK1 signaling regulates cytokine/chemokine production by macrophages
Summary
Prostate cancer (PCa) is the second leading cause of cancer-related deaths in American men and accounts for 15% of all cancers diagnosed in men worldwide [1, 2]. A unique feature of bonelodged PCa cells is that they stimulate the OBs to produce weak woven bone instead of the strong lamellar bone that is normally synthesized Such skeletal-related events (SREs) triggered by PCa in the bone culminate in pathological fractures, spinal cord compression, and sclerosis, detrimentally affecting the overall quality of life and survival rate among patients [5,6,7,8]. Most patients with locally advanced or metastatic PCa receive androgen-deprivation therapy (ADT) as a gold standard treatment [9] It significantly improves survival rates, ADT detrimentally affects skeletal health, causing tremendous bone loss and rendering the patients at risk for fragility fractures [10]. We will discuss recent findings that identify Ca2+/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2), an AR-regulated gene with additional roles in bone remodeling and inflammation, as a novel therapeutic target to inhibit PCa growth and prevention of ADT-associated bone loss
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