Triptolide (TPL) inhibits global transcription by inducing proteasome-dependent degradation of RNA polymerase II (Pol II)

PLoS One. 2011;6(9):e23993. doi: 10.1371/journal.pone.0023993. Epub 2011 Sep 13.

Abstract

Triptolide (TPL), a key biologically active component of the Chinese medicinal herb Tripterygium wilfordii Hook. f., has potent anti-inflammation and anti-cancer activities. Its anti-proliferative and pro-apoptotic effects have been reported to be related to the inhibition of Nuclear Factor κB (NF-κB) and Nuclear Factor of Activated T-cells (NFAT) mediated transcription and suppression of HSP70 expression. The direct targets and precise mechanisms that are responsible for the gene expression inhibition, however, remain unknown. Here, we report that TPL inhibits global gene transcription by inducing proteasome-dependent degradation of the largest subunit of RNA polymerase II (Rpb1) in cancer cells. In the presence of proteosome inhibitor MG132, TPL treatment causes hyperphosphorylation of Rpb1 by activation of upstream protein kinases such as Positive Transcription Elongation Factor b (P-TEFb) in a time and dose dependent manner. Also, we observe that short time incubation of TPL with cancer cells induces DNA damage. In conclusion, we propose a new mechanism of how TPL works in killing cancer. TPL inhibits global transcription in cancer cells by induction of phosphorylation and subsequent proteasome-dependent degradation of Rpb1 resulting in global gene transcription, which may explain the high potency of TPL in killing cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Death / drug effects
  • DNA Damage
  • Diterpenes / pharmacology*
  • Dose-Response Relationship, Drug
  • Drugs, Chinese Herbal / pharmacology*
  • Enzyme Activation / drug effects
  • Epoxy Compounds / pharmacology
  • HeLa Cells
  • Humans
  • Phenanthrenes / pharmacology*
  • Phosphorylation / drug effects
  • Positive Transcriptional Elongation Factor B / metabolism
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteolysis / drug effects*
  • RNA Polymerase II / metabolism*
  • Time Factors
  • Transcription, Genetic / drug effects*

Substances

  • Diterpenes
  • Drugs, Chinese Herbal
  • Epoxy Compounds
  • Phenanthrenes
  • triptolide
  • Positive Transcriptional Elongation Factor B
  • POLR2J protein, human
  • RNA Polymerase II
  • Proteasome Endopeptidase Complex