Triptolide inhibits MDM2 and induces apoptosis in acute lymphoblastic leukemia cells through a p53-independent pathway

摘要

Triptolide, a natural product derived from the Chinese plant Tripterygium wilfordii, is reported to exhibit antitumor effects in a broad range of cancers. The antitumor activity of triptolide is associated with its biological activities, as it inhibits various pro-proliferative or anti-apoptotic factors that are dominantly expressed in given types of cancer cells. Herein, we demonstrate that triptolide induced apoptosis in a subgroup of acute lymphoblastic leukemia (ALL) cells overexpressing the MDM2 oncoprotein, by inhibiting MDM2 expression. More specifically, we found that triptolide inhibited MDM2 at the transcriptional level by suppressing its mRNA synthesis. This MDM2 inhibition led in turn to increased levels of p53 protein; however, p53 functionality was not activated, due to the fact that triptolide-treated cells lacked induction of p21 and PUMA as well as in G1 cell-cycle arrest. Triptolide-mediated downregulation of MDM2 increased inhibition of XIAP, its translational target, in a manner distinct from reactions to cellular stress and DNA-damaging agent ionizing radiation (IR) that induce XIAP due to p53-activated MDM2. These results suggest that increased inhibition of XIAP due to downregulation of MDM2 may play a critical role in triptolide-induced apoptosis in MDM2-overexpressing cancers.