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.
Highlights
The Chinese medicinal herb Tripterygium wilfordii Hook. f. has been used for centuries to treat inflammation, autoimmune diseases, and cancers [1,2]
Tripterygium wilfordii Hook. f. has long been used as a folk medicine to treat cancer in China
Many studies have been carried to elucidate the mode of action of TPL in inducing cancer cell death
Summary
The Chinese medicinal herb Tripterygium wilfordii Hook. f. has been used for centuries to treat inflammation, autoimmune diseases, and cancers [1,2]. Many studies reveal that DNA damage by UV or hydrogen peroxide (H2O2) induces phosphorylation of CTD of Rpb accompanied with ubiquitination and subsequent proteasome degradation. Stalled Pol II needs to be removed from the site of damage in order for the repair machinery to assemble, possibly by phosphorylation-mediated proteolysis [12,17,21] Several kinases such as CDK7, CDK8, CDK9 (a component of P-TEFb), ERK and JNK have been shown to be responsible for the phosphorylation of CTD under different conditions [12,14,22,23,24]. We propose that DNA damage-trigged phosphorylation and degradation of Rpb may be the key for a global transcriptional inhibition by TPL. Our study uncovered a new mechanism of TPL in inducing cancer cell death
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