Litvinov Ivan V, Vander Griend Donald J, Antony Lizamma, Dalrymple Susan, De Marzo Angelo M, Drake Charles G, Isaacs John T
Chemical Therapeutics Program, Division of Immunology and Hematopoiesis, The Sidney Kimmel Comprehensive Cancer Center, Department of Pathology, and the Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15085-90. doi: 10.1073/pnas.0603057103. Epub 2006 Oct 2.
Androgen receptor (AR) protein expression and function are critical for survival and proliferation of androgen-sensitive (AS) prostate cancer cells. Besides its ability to function as a transcription factor, experimental observations suggest that AR becomes a licensing factor for DNA replication in AS prostate cancer cells and thus must be degraded during each cell cycle in these cells to allow reinitiation of DNA replication in the next cell cycle. This possibility was tested by using the AS human prostate cancer cell lines, LNCaP, CWR22Rv1, and LAPC-4. These studies demonstrated that AR levels fluctuate both within and between various phases of the cell cycle in each of these AS lines. Consistent with its licensing ability, AR is degraded during mitosis via a proteasome-dependent pathway in these AS prostate cancer cells. In contrast, proteasome-dependent degradation of AR during mitosis is not observed in AR-expressing but androgen-insensitive human prostate stromal cells, in which AR does not function as a licensing factor for DNA replication. To evaluate mitotic degradation of AR in vivo, the same series of human AS prostate cancers growing as xenografts in nude mice and malignant tissues obtained directly from prostate cancer patients were evaluated by dual Ki-67 and AR immunohistochemistry for AR expression in mitosis. These results document that AR is also down-regulated during mitosis in vivo. Thus, AS prostate cancer cells do not express AR protein during mitosis, either in vitro or in vivo, consistent with AR functioning as a licensing factor for DNA replication in AS prostate cancer cells.
雄激素受体（AR）蛋白的表达和功能对于雄激素敏感（AS）前列腺癌细胞的存活和增殖至关重要。除了作为转录因子发挥作用的能力外，实验观察表明，AR在AS前列腺癌细胞中成为DNA复制的许可因子，因此在这些细胞的每个细胞周期中都必须被降解，以便在下一个细胞周期重新启动DNA复制。通过使用AS人前列腺癌细胞系LNCaP、CWR22Rv1和LAPC-4对这一可能性进行了测试。这些研究表明，在每个这些AS细胞系中，AR水平在细胞周期的各个阶段内和阶段之间都会波动。与其许可能力一致，在这些AS前列腺癌细胞中，AR在有丝分裂期间通过蛋白酶体依赖性途径被降解。相比之下，在表达AR但对雄激素不敏感的人前列腺基质细胞中未观察到有丝分裂期间AR的蛋白酶体依赖性降解，在这些细胞中AR不作为DNA复制的许可因子。为了评估体内AR的有丝分裂降解，通过双重Ki-67和AR免疫组织化学评估了在裸鼠中作为异种移植生长的同一系列人AS前列腺癌以及直接从前列腺癌患者获得的恶性组织中有丝分裂期的AR表达。这些结果证明，体内有丝分裂期间AR也会下调。因此，AS前列腺癌细胞在有丝分裂期间无论是在体外还是在体内都不表达AR蛋白，这与AR在AS前列腺癌细胞中作为DNA复制的许可因子的功能一致。
