期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 23, 期 9, 页码 -出版社
MDPI
DOI: 10.3390/ijms23095280
关键词
antagonist; apoptosis; pancreatic cancer; tetrandrine
资金
- National Research Foundation of Korea [NRF-2020R1A2C1005339]
- Keimyung University, Republic of Korea [20190699]
The study demonstrates that tetrandrine (TTD) can act as an NR4A1 antagonist to inhibit proliferation and induce apoptosis in human pancreatic cancer cells by modulating related proapoptotic pathways.
The orphan nuclear receptor 4A1 (NR4A1) is highly expressed in human pancreatic cancer cells and exerts pro-oncogenic activity. In a previous study, we demonstrated that fangchinoline (FCN), a natural inhibitor of nuclear NR4A1, induces NR4A1-dependent apoptosis in human pancreatic cancer cells. In this study, we evaluated FCN and its structural analogs (berbamine, isotetrandrine, tetrandrine, and tubocurarine) for their inhibitory effects on NR4A1 transactivity, and confirmed that tetrandrine (TTD) showed the highest inhibitory effect in pancreatic cancer cells. Moreover, in a tryptophan fluorescence quenching assay, TTD directly bound to the ligand binding domain (LBD) of NR4A1 with a K-D value of 10.60 mu M. Treatment with TTD decreased proliferation and induced apoptosis in Panc-1 human pancreatic cancer cells in part through the reduced expression of the Sp1-dependent anti-apoptotic gene survivin and induction of ROS-mediated endoplasmic reticulum stress, which are the well-known NR4A1-dependent proapoptotic pathways. Furthermore, at a dose of 25 mg/kg/day, TTD reduced tumor growth in an athymic nude mouse xenograft model bearing Panc-1 cells. These data show that TTD is an NR4A1 antagonist and that modulation of the NR4A1-mediated pro-survival pathways is involved in the antitumor effects of TTD.
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