Lee Hyo-Seon, Safe Stephen, Lee Syng-Ook
Department of Food Science and Technology, Keimyung University, Daegu 42601, Republic of Korea.
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466, USA.
Toxicol Appl Pharmacol. 2017 Oct 1;332:32-39. doi: 10.1016/j.taap.2017.07.017. Epub 2017 Jul 25.
Previous studies have demonstrated that the orphan nuclear receptor NR4A1 is overexpressed in human pancreatic cancer and antagonizing this receptor promotes apoptosis and inhibits pancreatic cancer cells and tumor growth. In the present study, we identified fangchinoline, a bisbenzyltetrahydroisoquinoline alkaloid from Stephania tetrandra, as a new inactivator of nuclear NR4A1 and demonstrated that fangchinoline inhibits cell proliferation and induces apoptosis, in part, via the NR4A1-dependent pro-apoptotic pathways in human pancreatic cancer cells. It decreased expression of the antiapoptotic protein survivin by inhibiting Sp1-mediated transcription and induced oxidative stress-mediated endoplasmic reticulum (ER) stress in pancreatic cancer cells. These results suggest that inhibition of NR4A1-mediated transcriptional activity was involved in the anticancer effects of fangchinoline, and fangchinoline represents a novel class of mechanism-based anticancer agents targeting NR4A1 that is overexpressed in pancreatic cancer.
先前的研究表明，孤儿核受体NR4A1在人类胰腺癌中过表达，拮抗该受体可促进细胞凋亡并抑制胰腺癌细胞和肿瘤生长。在本研究中，我们鉴定出粉防己碱（一种从防己中提取的双苄基四氢异喹啉生物碱）是核NR4A1的一种新型失活剂，并证明粉防己碱部分通过人类胰腺癌细胞中依赖NR4A1的促凋亡途径抑制细胞增殖并诱导细胞凋亡。它通过抑制Sp1介导的转录降低抗凋亡蛋白存活素的表达，并在胰腺癌细胞中诱导氧化应激介导的内质网（ER）应激。这些结果表明，抑制NR4A1介导的转录活性参与了粉防己碱的抗癌作用，并且粉防己碱代表了一类新型的基于机制的抗癌药物，其靶向在胰腺癌中过表达的NR4A1。
