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Triptolide-Induced Transcriptional Arrest Is Associated with Changes in Nuclear Substructure

Departments of ¹ Molecular, Cellular, and Developmental Biology, ² Chemistry, and ³ Pharmacology, Yale University, New Haven, Connecticut

Requests for reprints: Craig M. Crews, Department of Molecular, Cellular, and Developmental Biology, Yale University, P. O. Box 208103, New Haven, CT 06520-8103. Phone: 203-432-9364; Fax: 203-432-5713; E-mail: craig.crews{at}yale.edu.

Key Words: triptolide • transcription • NF-B • RNA polymerase

Triptolide, an active component of the medicinal herb lei gong teng, is a potent anticancer and anti-inflammatory therapeutic. It potently inhibits nuclear factor-B transcriptional activation after DNA binding, although a precise mechanism is as yet unknown. Here, we report that triptolide also induces distinct nuclear substructural changes in HeLa cells. These changes in the nucleolus and nuclear speckles are reversible and dependent on both time and concentration. Furthermore, nuclear changes occurred within hours of triptolide treatment and were calcium and caspase independent. Rounding of nuclear speckles, an indication of transcriptional arrest, was evident and was associated with a decrease in RNA polymerase II (RNA Pol II) COOH-terminal domain Ser² phosphorylation. Additionally, the nucleolus disassembled and RNA Pol I activity declined after RNA Pol II inhibition. We therefore conclude that triptolide causes global transcriptional arrest as evidenced by inactivity of RNA Pol I and II and the subsequent alteration in nuclear substructure. [Cancer Res 2008;68(13):5257–66]

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