隱丹參酮透過泛素蛋白酶體降解多麩醯胺酸雄性激素受體

Cryptotanshinone induces ubiquitin proteasome-dependent degradation of androgen receptor with an explanded poly-glutamine tract

魏國鼎(Ko-Ting Wei)

指導教授 ： 康宏佑

高雄醫學大學/醫學院/醫學研究所碩士班/碩士(2015年)

摘要

隱丹參酮（Cryptotanshinone）是丹參酮的主要成份之一從植物丹參的根所分離，丹參已廣泛運用在中國傳統醫學治療於多種疾病。脊髓延髓肌肉萎縮症Spinal bulbar muscular atrophy（SBMA）是由雄性激素受體基因內CAG（編碼形成胺基酸glutamine，簡稱Q）重複序列延伸所引起的神經肌肉退化性疾病，而調控泛素化作用和蛋白的清除是被牽涉在許多病理變性疾病，特別是蛋白質聚集和包涵體形成的神經變性疾病。我們先前的研究表明隱丹參酮在前列腺癌細胞會減少雄激素受體的轉錄活性。而隱丹參酮對於致病性雄激素受體的詳細機制還不清楚。本研究證明了致病性雄激素受體會增加多泛素化作用是透過泛素中的Lysine-6和Lysine-63泛素鏈。隱丹參酮透過蛋白酶體的降解作用減少突變AR蛋白的表達和聚集是經由轉換泛素Lysine-63到Lysine-48泛素鏈並且緩解由致病性雄激素受體所造成細胞模式的神經元損傷。結果顯示隱丹參酮可望被用來治療脊髓延髓肌肉萎縮症（SBMA）和其他與多麩醯胺酸有關的神經變性疾病。

關鍵字

隱丹參酮 ； 多麩醯胺酸雄性激素受體 ； 泛素蛋白酶體

並列摘要

Cryptotanshinone is one of the major tanshinones isolated from the roots of the plant Salvia miltiorrhiza Bunge (Danshen). Danshen has been widely used in traditional Chinese medicine form treatment of a variety of diseases. Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by the expansion of the CAG triplet repeats within the androgen receptor (AR) gene. Dysregulated ubiquitination and protein clearance has been implicated in a number of pathological conditions, especially neurodegenerative disorders that involve protein aggregation and inclusion body formation. Our recent studies have shown that cryptotanshinone can reduce the AR transcriptional activity in prostate cancer cells, but whether cryptotanshinone has effects on pathogenic AR with an expanded polyglutamine tract remains unclear. Here, we found that polyubiquitination of AR with an expanded polyglutamine tract is significantly increased in the presence of androgen and binds to Lysine-6 and Lysine-63 ubiquitin chains. Cryptotanshinone decreased mutant AR protein expression and aggregates via the induction of proteasomal degradation through switching Lysine-63 to Lysine-48 ubiquitin chains and mitigated pathogenic AR-mediated neuronal damage in SBMA cellular models. These observations suggest that Cryptotanshinone may be used therapeutically to treat SBMA and other polyglutamine-related neurodegenerative diseases.

並列關鍵字

Cryptotanshinone ； poly-Q androgen receptor ； ubiquitin proteasome degradation

參考文獻

參考文獻

Adachi, H., Katsuno, M., Minamiyama, M., Waza, M., Sang, C., Nakagomi, Y., . . . Sobue, G. (2005). Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients. Brain, 128(Pt 3), 659-670.

Adachi, H., Katsuno, M., Waza, M., Minamiyama, M., Tanaka, F., & Sobue, G. (2009). Heat shock proteins in neurodegenerative diseases: pathogenic roles and therapeutic implications. Int J Hyperthermia, 25(8), 647-654.

Adachi, H., Waza, M., Katsuno, M., Tanaka, F., Doyu, M., & Sobue, G. (2007). Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy. Neuropathol Appl Neurobiol, 33(2), 135-151.

Bailey, C. K., Andriola, I. F., Kampinga, H. H., & Merry, D. E. (2002). Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy. Hum Mol Genet, 11(5), 515-523.