Triptolide inhibits tumor promoter-induced uPAR expression via blocking NF-kappaB signaling in human gastric AGS cells

Hee J Chang, Mi H Kim, Min K Baek, Jung S Park, Ik J Chung, Boo A Shin, Bong W Ahn, Young D Jung
Anticancer Research 2007, 27 (5): 3411-7
The overexpression of urokinase-type plasminogen activator receptor (uPAR) is closely related to tumor cell invasion. Therefore, strategies for down-regulating uPAR expression may be of clinical utility. This study examined the effects of triptolide, which is a diterpenoid triepoxide extracted from the Chinese herb Tripterygium wilfordii Hook F., on the induction of uPAR in human gastric cancer AGS cells. Triptolide inhibited the phorbol 12-myristate 13-acetate (PMA)-induced uPAR mRNA and protein expression in a dose-dependent manner, and reduced the uPAR transcriptional activity. The stability of the uPAR transcripts was not altered by the triptolide treatment. The signals involved in uPAR induction by PMA were investigated to determine the mechanisms for the triptolide-mediated regulation of uPAR. The inhibitors of extracellular signal-regulated kinases 1 and 2 (Erk-1/2, PD98059), c-Jun N-terminal kinases (JNK, SP600125) and nuclear factor-kappa B (NF-kappaB, Bay11-7082) inhibited the PMA-induced expression of uPAR, which suggests that PMA induces uPAR through multiple signals. Triptolide suppressed the PMA-induced activation of NF-kappaB but not Erk-1/2 and JNKI The inhibitory effect of triptolide on the activation of NF-kappaB was confirmed by an electrophoretic mobility shift assay and NF-kappaB dependent transcription studies. AGS cells treated with PMA showed a remarkably enhanced invasiveness, which was partially abrogated by triptolide and uPAR-neutralizing antibodies. This suggests that triptolide may exert at least part of its anti-invasive effect in gastric cancer by controlling the expression of uPAR through the suppression of NF-kappaB activation.

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