Department of Biochemistry and Molecular Biology, School of Boonshoft Medical School, Wright State University, Dayton, OH, 45435, United States.
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, United States.
Sci Rep. 2020 Jun 4;10(1):9120. doi: 10.1038/s41598-020-65882-5.
K-Ras must interact primarily with the plasma membrane (PM) for its biological activity. Therefore, disrupting K-Ras PM interaction is a tractable approach to block oncogenic K-Ras activity. Here, we found that avicin G, a family of natural plant-derived triterpenoid saponins from Acacia victoriae, mislocalizes K-Ras from the PM and disrupts PM spatial organization of oncogenic K-Ras and H-Ras by depleting phosphatidylserine (PtdSer) and cholesterol contents, respectively, at the inner PM leaflet. Avicin G also inhibits oncogenic K- and H-Ras signal output and the growth of K-Ras-addicted pancreatic and non-small cell lung cancer cells. We further identified that avicin G perturbs lysosomal activity, and disrupts cellular localization and activity of neutral and acid sphingomyelinases (SMases), resulting in elevated cellular sphingomyelin (SM) levels and altered SM distribution. Moreover, we show that neutral SMase inhibitors disrupt the PM localization of K-Ras and PtdSer and oncogenic K-Ras signaling. In sum, this study identifies avicin G as a new potent anti-Ras inhibitor, and suggests that neutral SMase can be a tractable target for developing anti-K-Ras therapeutics.
K-Ras 必须主要与质膜（PM）相互作用才能发挥其生物学活性。因此，破坏 K-Ras PM 相互作用是阻止致癌 K-Ras 活性的一种可行方法。在这里，我们发现，来自维多利亚相思树的天然植物衍生三萜皂苷家族 avicin G，通过耗尽磷脂酰丝氨酸（PtdSer）和胆固醇含量，分别将 K-Ras 从 PM 中错误定位，并破坏致癌性 K-Ras 和 H-Ras 的 PM 空间组织，位于质膜内层小叶。Avicin G 还抑制致癌性 K-和 H-Ras 信号输出以及对 K-Ras 有依赖性的胰腺和非小细胞肺癌细胞的生长。我们进一步确定，avicin G 扰乱溶酶体活性，并破坏中性和酸性鞘磷脂酶（SMase）的细胞定位和活性，导致细胞鞘磷脂（SM）水平升高和 SM 分布改变。此外，我们表明，中性 SMase 抑制剂破坏了 K-Ras 和 PtdSer 的 PM 定位以及致癌性 K-Ras 信号。总之，这项研究将 avicin G 鉴定为一种新的强效抗 Ras 抑制剂，并表明中性 SMase 可以作为开发抗 K-Ras 治疗药物的可行靶点。
