Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao SAR, China.
Sci Rep. 2016 Sep 6;6:32832. doi: 10.1038/srep32832.
Tylophorine analog DCB-3503 is a potential anticancer and immunosuppressive agent that suppresses the translation of cellular regulatory proteins, including cyclin D1, at the elongation step. However, the molecular mechanism underlying this phenomenon remains unknown. This study demonstrates that DCB-3503 preferentially binds to heat shock cognate protein 70 (HSC70), which is a determinant for cyclin D1 translation by binding to the 3'-untranslated region (3' UTR) of its mRNA. DCB-3503 allosterically regulates the ATPase and chaperone activities of HSC70 by promoting ATP hydrolysis in the presence of specific RNA binding motifs (AUUUA) of cyclin D1 mRNA. The suppression of cyclin D1 translation by DCB-3503 is not solely caused by perturbation of the homeostasis of microRNAs, although the microRNA processing complex is dissociated with DCB-3503 treatment. This study highlights a novel regulatory mechanism of protein translation with AUUUA motifs in the 3' UTR of mRNA by HSC70, and its activity can be allosterically modulated by DCB-3503. DCB-3503 may be used to treat malignancies, such as hepatocellular carcinoma or breast cancer with elevated expression of cyclin D1.
蒂洛啡林类似物 DCB-3503 是一种有潜力的抗癌和免疫抑制药物，它在延伸步骤中抑制细胞调节蛋白（包括 cyclin D1）的翻译。然而，这种现象的分子机制尚不清楚。本研究表明，DCB-3503 优先结合热休克同源蛋白 70（HSC70），通过与 cyclin D1 mRNA 的 3'非翻译区（3'UTR）结合，HSC70 决定 cyclin D1 的翻译。DCB-3503 通过促进 cyclin D1 mRNA 上特定的 RNA 结合基序（AUUUA）的 ATP 水解，别构调节 HSC70 的 ATP 酶和伴侣活性。DCB-3503 对 cyclin D1 翻译的抑制作用不仅仅是由于 microRNA 稳态的干扰，尽管 microRNA 加工复合物在 DCB-3503 处理时与 DCB-3503 解离。本研究强调了 HSC70 通过 mRNA 的 3'UTR 上的 AUUUA 基序对蛋白质翻译的新型调节机制，其活性可以通过 DCB-3503 进行别构调节。DCB-3503 可用于治疗恶性肿瘤，如肝细胞癌或乳腺癌，这些肿瘤中 cyclin D1 的表达水平升高。
