Center for Cell Signaling, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
Mol Cell Biol. 2010 Mar;30(5):1243-53. doi: 10.1128/MCB.01891-08. Epub 2010 Jan 4.
Prostate cancer progression to the androgen-independent (AI) state involves acquisition of pathways that allow tumor growth under low-androgen conditions. We hypothesized that expression of molecular chaperones that modulate androgen binding to AR might be altered in prostate cancer and contribute to progression to the AI state. Here, we report that the Hsp90 cochaperone FKBP51 is upregulated in LAPC-4 AI tumors grown in castrated mice and describe a molecular mechanism by which FKBP51 regulates AR activity. Using recombinant proteins, we show that FKBP51 stimulates recruitment of the cochaperone p23 to the ATP-bound form of Hsp90, forming an FKBP51-Hsp90-p23 superchaperone complex. In cells, FKBP51 expression promotes superchaperone complex association with AR and increases the number of AR molecules that undergo androgen binding. FKBP51 stimulates androgen-dependent transcription and cell growth, and FKBP51 is part of a positive feedback loop that is regulated by AR and androgen. Finally, depleting FKBP51 levels by short hairpin RNA reduces the transcript levels of genes regulated by AR and androgen. Because the superchaperone complex plays a critical role in determining the ligand-binding competence and transcription function of AR, it provides an attractive target for inhibiting AR activity in prostate cancer cells.
前列腺癌向雄激素非依赖（AI）状态的进展涉及获得允许肿瘤在低雄激素条件下生长的途径。我们假设调节雄激素与 AR 结合的分子伴侣的表达可能在前列腺癌中发生改变，并有助于向 AI 状态进展。在这里，我们报告 HSP90 共伴侣 FKBP51 在去势小鼠中生长的 LAPC-4 AI 肿瘤中上调，并描述了 FKBP51 调节 AR 活性的分子机制。使用重组蛋白，我们表明 FKBP51 刺激共伴侣 p23 募集到 HSP90 的 ATP 结合形式，形成 FKBP51-Hsp90-p23 超级伴侣复合物。在细胞中，FKBP51 表达促进超级伴侣复合物与 AR 的结合，并增加经历雄激素结合的 AR 分子的数量。FKBP51 刺激雄激素依赖性转录和细胞生长，并且 FKBP51 是受 AR 和雄激素调节的正反馈回路的一部分。最后，通过短发夹 RNA 耗尽 FKBP51 水平会降低受 AR 和雄激素调节的基因的转录水平。由于超级伴侣复合物在确定 AR 的配体结合能力和转录功能方面起着至关重要的作用，因此它为抑制前列腺癌细胞中的 AR 活性提供了一个有吸引力的目标。
