The importance of non-nuclear AR signaling in prostate cancer progression and therapeutic resistance.
The importance of non-nuclear AR signaling in prostate cancer progression and therapeutic resistance.
复制标题
非核 AR 信号传导在前列腺癌进展和治疗耐药中的重要性。
DOI：
10.1016/j.cellsig.2016.01.013
复制
发表时间：
2016
影响因子：
4.8
通讯作者：
Miranti,CindyK
中科院分区：
文献类型：
--
作者：
Zarif,JelaniC;Miranti,CindyK
雄激素受体 (AR) 仍然是前列腺癌的主要致癌驱动因素，雄激素剥夺疗法 (ADT) 对初治患者的疗效以及第二代 ADT 对去势抵抗性疾病的持续有效性证明了这一点。然而，目前的 ADT 仅限于通过抑制雄激素产生或使用竞争性拮抗剂来干扰 AR 配体结合。最近的研究表明 1) 组成型活性 AR 剪接变体的表达不再依赖于雄激素，2) AR 在细胞质中发出信号的能力独立于其转录活性（非基因组）；因此强调需要考虑其他方式来瞄准 AR。在此，我们回顾了经典的 AR 信号传导，但重点关注 AR 非基因组信号传导、其一些下游靶标以及这些效应器如何影响前列腺癌细胞行为。本次综述的目的是：1) 重新强调 AR 作为主要驱动因素在前列腺癌中的持续重要性，2) 讨论继续使用配体结合作为唯一靶向机制的局限性，3) 讨论 AR 非基因组信号传导在癌症进展和治疗耐药中的影响，4) 解决考虑将非基因组 AR 信号传导机制和途径作为与当前治疗相结合的可行靶向策略的需要。
The androgen receptor (AR) remains the major oncogenic driver of prostate cancer, as evidenced by the efficacy of androgen deprivation therapy (ADT) in naïve patients, and the continued effectiveness of second generation ADTs in castration resistant disease. However, current ADTs are limited to interfering with AR ligand binding, either through suppression of androgen production or the use of competitive antagonists. Recent studies demonstrate 1) the expression of constitutively active AR splice variants that no longer depend on androgen, and 2) the ability of AR to signal in the cytoplasm independently of its transcriptional activity (non-genomic); thus highlighting the need to consider other ways to target AR. Herein, we review canonical AR signaling, but focus on AR non-genomic signaling, some of its downstream targets and how these effectors contribute to prostate cancer cell behavior. The goals of this review are to 1) re-highlight the continued importance of AR in prostate cancer as the primary driver, 2) discuss the limitations in continuing to use ligand binding as the sole targeting mechanism, 3) discuss the implications of AR non-genomic signaling in cancer progression and therapeutic resistance, and 4) address the need to consider non-genomic AR signaling mechanisms and pathways as a viable targeting strategy in combination with current therapies.