Department of Biomedical Sciences, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, South Korea.
Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Mol Oncol. 2018 Jun;12(7):1203-1215. doi: 10.1002/1878-0261.12324. Epub 2018 Jun 11.
Matrine is a natural compound extracted from the herb Sophora flavescens Ait which is widely used in traditional Chinese medicine for treating various diseases. Recently, matrine was reported to have antitumor effects against a variety of cancers without any obvious side effects; however, the molecular mechanisms of its antiproliferative effects on cancer are unclear. Here, we report that matrine inhibits autophagy-mediated energy metabolism, which is necessary for pancreatic cancer growth. We found that matrine significantly reduces pancreatic cancer growth in vitro and in vivo by insufficiently maintaining mitochondrial metabolic function and energy level. We also found that either pyruvate or α-ketoglutarate supplementation markedly rescues pancreatic cancer cell growth following matrine treatment. Inhibition of mitochondrial energy production results from matrine-mediated autophagy inhibition by impairing the function of lysosomal protease. Matrine-mediated autophagy inhibition requires stat3 downregulation. Furthermore, we found that the antitumor effect of matrine on pancreatic cancer growth depends on the mutation of the KRAS oncogene. Together, our data suggest that matrine can suppress the growth of KRAS-mutant pancreatic cancer by inhibiting autophagy-mediated energy metabolism.
苦参碱是从苦参中提取的一种天然化合物，广泛应用于传统中药治疗各种疾病。最近，苦参碱被报道具有抗肿瘤作用，可对抗多种癌症，且无明显副作用；然而，其抑制癌细胞增殖的分子机制尚不清楚。在这里，我们报告苦参碱抑制自噬介导的能量代谢，这对于胰腺癌的生长是必需的。我们发现苦参碱通过不足够维持线粒体代谢功能和能量水平，显著地减少了体外和体内的胰腺癌生长。我们还发现，丙酮酸或α-酮戊二酸的补充明显挽救了苦参碱处理后胰腺癌细胞的生长。线粒体能量产生的抑制是由于苦参碱通过损害溶酶体蛋白酶的功能抑制自噬。苦参碱介导的自噬抑制需要 stat3 下调。此外，我们发现苦参碱对胰腺癌生长的抗肿瘤作用取决于 KRAS 癌基因的突变。总的来说，我们的数据表明，苦参碱可以通过抑制自噬介导的能量代谢来抑制 KRAS 突变型胰腺癌的生长。
