Dec 4 2017
Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity
Dr Elaine Lai Han Leung et al reported that the anti-cancer cell activity of deltarasin can be enhanced by simultaneously blocking “tumor protective” autophagy, but inhibited if combined with an anti-oxidant.
Deltarasin is a recently identified small molecule that can inhibit KRAS-PDEδ interactions by binding to a hydrophobic pocket on PDEδ, resulting in the impairment of cell growth, KRAS activity and RAS/RAF signaling in human pancreatic ductal adenocarcinoma cell lines. Since KRAS mutations are the most common oncogene mutations in lung adeno-carcinomas, implicated in over 30% of all lung cancer cases, the ability of deltarasin to inhibit KRAS-dependent lung cancer cell growth has not yet been explored. Recently, Chair Prof. Liu Liang, Prof David C. Ward, Prof. Yao Xiao-Jun, Dr. Leung Lai Han and their colleagues from the State Key Laboratory of Quality Research in Chinese Medicine (Macau University of Science and Technology, MUST), for the first time, demonstrated that deltarasin produces both apoptosis and autophagy in KRAS-dependent lung cancer cells in vitro and inhibits lung tumor growth in vivo. Deltarasin induces apoptosis by inhibiting the interaction of with PDEδ and its downstream signaling pathways, while it induces autophagy through the AMPK-mTOR signaling pathway. Importantly, the autophagy inhibitor, 3-methyl adenine (3-MA) markedly enhances deltarasin-induced apoptosis via elevation of reactive oxygen species (ROS). In contrast, inhibition of ROS by N-acetylcysteine (NAC) significantly attenuated deltarasin-induced cell death. These observations suggest that the anti-cancer cell activity of deltarasin can be enhanced by simultaneously blocking “tumor protective” autophagy, but inhibited if combined with an anti-oxidant. The significance of the study is providing new theoretical guidance for treating NSCLC patients harboring KRAS mutations. This paper was accepted by the journal cell death and disease of the “Nature Publishing Group” on October 12, 2017. The newly released Impact Factor for cell death and disease is 5.99 (Thomson Reuters, 2017).