Tanshinone IIA induces apoptosis via inhibition of Wnt/β‑catenin/MGMT signaling in AtT‑20 cells.
Mol Med Rep. 2017 Nov ;16(5):5908-5914. Epub 2017 Aug 22. PMID: 28849207
A strategy to suppress the expression of the DNA repair enzyme O6‑methylguanine‑DNA methyltransferase (MGMT) by inhibition of Wnt/β‑catenin signaling may be useful as a novel treatment for pituitary adenoma. Previous studies have reported that Tanshinone IIA (TSA), a major quinone compound isolated from Salvia miltiorrhiza, had antitumor effects. However,whether TSA has antitumor effects against pituitary adenoma and whether the mechanisms are associated with the Wnt/β‑catenin/MGMT pathway remains to be clarified. In the present study, TSA treatment caused apoptosis in AtT‑20 cells in a concentration‑dependent manner, as demonstrated by cellviability reduction, phophatidylserine externalization detected by Annexin V staining and mitochondrial membrane potential disruption detected by JC‑1 staining, which were associated with activation of caspase‑3 and DNA fragmentation detected by TUNEL in AtT‑20 cells. T‑cell factor (TCF)‑lymphoid‑enhancing factor (LEF) reporter activity was determined by dual luciferase reporter assay and the interaction between β‑catenin and TCF‑4 were detected using a co‑immunoprecipitation kit. The results indicated TSA treatment increased β‑catenin phosphorylation, inhibited β‑catenin nuclear translocation, reduced β‑catenin/TCF‑4 complex formation and TCF‑LEF luciferase reporter activity, and subsequently reduced the expression of cyclin D1 and MGMT. Notably, overexpression of MGMT in β‑catenin knock down AtT‑20 cells abrogated the TSA‑mediated effects in AtT‑20 cells. In conclusion, TSA induced apoptosis via inhibition of Wnt/β‑catenin‑dependent MGMT expression, which may provide novel insights into the understanding of the mechanism of the antitumor effects of Salvia miltiorrhiza.