Abstract
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.
Highlights
Tylophorine analogs were first identified and isolated from the herbal medicine Tylophorine indica[1], which was originally used to treat asthma and arthritis in India and China, respectively[2,3]
Considering the levels of hnRNP U bound to biotylated-DCB-3503 in comparison with the beads alone (Fig. 1b), as well as the previous report that hnRNAP A2/B1 is a molecular target of phenanthrene-based tylophorine derivative-1 (PBT-1)[23], we considered heat shock cognate protein 70 (HSC70) and hnRNP U to be potential molecular targets of DCB-3503 and selected HSC70 for further evaluation
This study revealed a functional role for HSC70 in the translation of mRNAs having a specific motif
Summary
Tylophorine analogs were first identified and isolated from the herbal medicine Tylophorine indica[1], which was originally used to treat asthma and arthritis in India and China, respectively[2,3]. DCB3503 allosterically regulates ATPase and chaperone activity of HSC70, inhibiting the translation of cyclin D1 by promoting binding to the AUUUA motif in the 3′–untranslated region (3′UTR) of mRNA. Translation could be regulated by modulating the activities of initiation factors, sequence-specific RNA-binding proteins, and/or microRNAs targeting the 3′UTR of mRNA25.
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