Divisions of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
J Investig Med. 2010 Dec;58(8):938-44. doi: 10.231/JIM.0b013e3181ff6bb8.
Despite the clinical regression that typifies the initial response of advanced prostate cancer to gonadal testosterone depletion, tumors eventually progress. However, evidence supports the concept that signaling via the androgen receptor (AR) is important in progression to castration-resistant prostate cancer (CRPC).Steroid hormones are synthesized from cholesterol in a series of tightly regulated steps involving the cleavage of carbon-carbon bonds, the introduction of functional groups derived from activated molecular oxygen, and the oxidation and reduction of carbon-carbon and carbon-oxygen bonds. In the adrenal cortex and gonads, steroidogenesis is tightly regulated, very efficient, and highly directional. In contrast, steroid metabolism in peripheral tissues is characterized by competing enzymes and pathways, low efficiency, and great variability. Many steps are mechanistically and functionally irreversible, but some are not, and the repertoire of specific enzymes, intracellular redox state, and access to hormone precursors all contribute to steroid flux and accumulation.The investigation of steroid metabolizing enzymes in CRPC often assumes that the pathways and the patterns of metabolism mirror those defined in the adrenals and the gonads and validated by human deficiency syndromes. Unfortunately, several potential pathways using different enzymes might contribute substantially to androgen synthesis in CRPC. Finally, a number of mechanisms have been reported by which the AR is activated independent of ligand. Recent observations have suggested that AR forms with constitutive activity occur in CRPC, stimulating transcription without a requirement for ligand. This overview outlines a broad view of how the mechanisms by which the AR may be activated, whether by alternate pathways of androgen synthesis or the production of alternate forms of the AR, with an emphasis on what aspects must be accounted for when using model systems to explore the biology of human prostate cancer.
尽管晚期前列腺癌对睾丸睾酮耗竭的初始反应表现为临床消退，但肿瘤最终会进展。然而，有证据支持这样的概念，即通过雄激素受体（AR）的信号转导在向去势抵抗性前列腺癌（CRPC）的进展中很重要。甾体激素是从胆固醇通过一系列紧密调节的步骤合成的，这些步骤涉及碳-碳键的断裂、从活化的分子氧衍生的功能基团的引入、以及碳-碳和碳-氧键的氧化和还原。在肾上腺皮质和性腺中，甾体生成受到严格调控，效率非常高，且具有高度方向性。相比之下，外周组织中的类固醇代谢的特点是存在竞争酶和途径、效率低且变异性大。许多步骤在机制和功能上是不可逆的，但有些是可逆的，特定酶的 repertoire、细胞内氧化还原状态以及激素前体的可及性都有助于类固醇的流动和积累。在 CRPC 中对类固醇代谢酶的研究通常假设途径和代谢模式反映了在肾上腺和性腺中定义的、并通过人类缺陷综合征验证的那些模式。不幸的是，几种潜在的途径可能使用不同的酶对 CRPC 中的雄激素合成做出重大贡献。最后，据报道，有许多机制可以使 AR 独立于配体而被激活。最近的观察结果表明，在 CRPC 中存在具有组成型活性的 AR 形成，刺激转录而无需配体。本综述概述了 AR 可能被激活的机制，无论是通过雄激素合成的替代途径还是 AR 的替代形式的产生，重点介绍了在使用模型系统探索人类前列腺癌生物学时必须考虑哪些方面。
