TriptolideAn inhibitor of a disintegrin and metalloproteinase 10(ADAM 10) in cancer cells

摘要

Triptolide, a diterpene triepoxide derived from Trypterygium wilfordii, is documented to have antitumor activity in a broad range of solid tumors and leukemia.The mechanisms that are involved in triptolide-mediated apoptosis or growth inhibition in cancer cells are not fully understood.We identified a disintegrin and metalloproteinase 10 (ADAM 10) as a novel molecular target of triptolide using affinity chromatography and mass spectrometry.The identification was confirmed by western blot analysis using an anti-ADAMIO antibody.The expression of ADAM 10 is enhanced in several tumors including leukemia and is involved in malignant cell growth and cancer progression. ADAM 10 is a type I transmembrane glycoprotein that cleaves several plasma membrane proteins. We show that triptolide, at concentrations in the nM range, resulted in a significant decrease in ADAM 10 expression followed by the appearance of ADAM 10 cleaved product. Furthermore, triptolide reduced the viability of monocytic leukemic U937 cells.Triptolide treatment of MCF-7 breast cancer cells expressing ectopic ADAM 10 or dominant negative ADAM 10 (DN ADAM 10) resulted in a decreased expression of ADAM 10 with a concomitant increase in ADAM 10 cleaved products. Moreover, siRNA-mediated knockdown of ADAM 10 mRNA significantly affected the growth of MCF-7 cells. Interestingly, the combination of siRNA-mediated knockdown of ADAM 10 mRNA expression and triptolide treatment lead to a further reduction in cell growth.Taken together, we provide evidence that ADAM 10 is a novel target of triptolide, presenting a novel strategy to inhibit ADAM 10 activity in tumorigenesis.