Avicin G is a potent sphingomyelinase inhibitor and blocks oncogenic K- and H-Ras signaling

• Published in: Scientific reports Vol. 10; no. 1; p. 9120
• Main Authors: Garrido, Christian M., Henkels, Karen M., Rehl, Kristen M., Liang, Hong, Zhou, Yong, Gutterman, Jordan U., Cho, Kwang-jin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.06.2020; Nature Publishing Group
• Subjects: 631/80/2023/2022; 631/80/86/820; Animals; Biological activity; Cell Line; Cell Membrane - metabolism; Cholesterol; Cholesterol - metabolism; Cricetinae; Dogs; Endocytosis - drug effects; H-Ras protein; Humanities and Social Sciences; Humans; K-Ras protein; Localization; Lung cancer; multidisciplinary; Non-small cell lung carcinoma; Pancreas; Phosphatidylserine; Plants; ras Proteins - metabolism; Saponins; Saponins - chemistry; Saponins - metabolism; Saponins - pharmacology; Science; Science (multidisciplinary); Signal Transduction - drug effects; Small cell lung carcinoma; Sphingomyelin; Sphingomyelin phosphodiesterase; Sphingomyelin Phosphodiesterase - antagonists & inhibitors; Sphingomyelin Phosphodiesterase - metabolism; Sphingomyelins - metabolism
• ISSN: 2045-2322; 2045-2322
• 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.