Dadwal Ushashi C, Chang Eric S, Sankar Uma
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, United States.
Front Endocrinol (Lausanne). 2018 Jun 18;9:335. doi: 10.3389/fendo.2018.00335. eCollection 2018.
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. Ca/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.
骨骼系统在晚期前列腺癌（PCa）中至关重要，因为它是转移的首选部位。PCa细胞依次采用复杂机制归巢至骨骼并在其中定植。骨内的PCa细胞随后募集小生境中的成骨细胞（OBs）、破骨细胞（OCs）和巨噬细胞，形成促进癌细胞生长和存活的实体。由于PCa的生长和存活严重依赖雄激素，雄激素剥夺疗法（ADT）是晚期疾病的标准治疗方法。尽管它显著提高了生存率，但ADT对骨骼健康有不利影响，并显著增加骨折风险。此外，虽然大多数晚期PCa患者对雄激素剥夺反应良好，但大多数患者在ADT治疗1 - 2年内疾病会复发为激素难治性形式。肿瘤通过选择雄激素受体（AR）中的突变来适应在低睾酮条件下存活，这些突变会持续激活AR。因此，AR信号在PCa细胞中仍然活跃，有助于其在低水平循环雄激素下存活，此外还使癌细胞能够操纵骨微环境以促进其生长。因此，AR及其下游效应器是针对PCa进行治疗干预的有吸引力的靶点。钙/钙调蛋白依赖性蛋白激酶激酶2（CaMKK2）最近被确定为AR在协调PCa细胞生长、存活和迁移中的关键下游靶点。此外，这种多功能丝氨酸/苏氨酸蛋白激酶是骨重塑和巨噬细胞功能的关键介质，因此在控制转移性PCa和预防ADT诱导的骨质流失方面，作为AR下游有吸引力的治疗靶点而出现。在这里，我们讨论AR - CaMKK2信号轴在PCa存活、代谢、细胞生长和迁移中的作用，以及CaMKK2在骨微环境中的OBs、OCs和巨噬细胞中的细胞内在作用。
