Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Prostate. 2010 Mar 1;70(4):390-400. doi: 10.1002/pros.21072.
Emerging evidence suggests that androgens and the androgen receptor (AR) are important mediators of castration-resistant prostate cancer (CRPC) progression. Increased expression of several enzymes responsible for cholesterol synthesis and conversion into downstream androgens has been documented in human CRPC tumors in comparison to primary tumors. Based on these observations it is hypothesized that cholesterol and its overall regulation within the cell are altered, thus modifying precursor levels for de novo androgen synthesis within the castrate tumoral environment.
Tumoral steroid levels were assessed by LC-MS. Free and esterified cholesterol was quantified by LC-MS and a fluorescent assay. Gene and protein expression were assessed by RT-PCR and immunoblotting.
Herein, using a prostate cancer xenograft mouse model it is demonstrated by Western blot analysis that proteins responsible for cholesterol regulation (LDL-r, SR-B1, HMG-CoA reductase, ACAT1,2, ABCA1) are altered during disease progression to increase influx and synthesis of cholesterol as well as free cholesterol formation from cholesteryl ester stores. In turn this can provide increased amounts of precursor for intratumoral steroidogenesis after castration. Androgens- testosterone and dihydrotestosterone- coincidently increase at CRPC to physiologically relevant levels leading to the induction of AR expression and PSA production. Furthermore, cellular cholesterol homeostasis is maintained by increased cholesterol efflux at CRPC so that excess free cholesterol does not cause toxicity to the tumor cells.
Cellular cholesterol regulation processes are altered during progression to CRPC. Free cholesterol from increased biosynthesis or uptake is likely a precursor for intratumoral de novo androgen synthesis.
越来越多的证据表明雄激素和雄激素受体（AR）是去势抵抗性前列腺癌（CRPC）进展的重要介质。与原发性肿瘤相比，在人类 CRPC 肿瘤中已经记录到几种负责胆固醇合成和转化为下游雄激素的酶的表达增加。基于这些观察结果，有人假设胆固醇及其在细胞中的整体调节发生改变，从而改变了去势肿瘤环境中从头合成雄激素的前体水平。
通过 LC-MS 评估肿瘤类固醇水平。通过 LC-MS 和荧光测定法定量游离胆固醇和酯化胆固醇。通过 RT-PCR 和免疫印迹评估基因和蛋白质表达。
本文通过 Western blot 分析，使用前列腺癌异种移植小鼠模型证明，胆固醇调节蛋白（LDL-r、SR-B1、HMG-CoA 还原酶、ACAT1、2、ABCA1）在疾病进展过程中发生改变，以增加胆固醇的流入和合成，以及从胆固醇酯储存中形成游离胆固醇。反过来，这可以为去势后肿瘤内类固醇生成提供更多的前体。雄激素-睾酮和二氢睾酮-在 CRPC 时巧合地增加到生理相关水平，导致 AR 表达和 PSA 产生的诱导。此外，CRPC 时通过增加胆固醇外排来维持细胞胆固醇稳态，从而使过量的游离胆固醇不会对肿瘤细胞造成毒性。
在进展为 CRPC 期间，细胞胆固醇调节过程发生改变。增加生物合成或摄取的游离胆固醇可能是肿瘤内从头合成雄激素的前体。
