Abstract
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 adenocarcinomas, implicated in over 30% of all lung cancer cases, we examined the ability of deltarasin to inhibit KRAS-dependent lung cancer cell growth. Here, for the first time, we document 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. Collectively, 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.
Highlights
RAS proto-oncogene encoded oncoproteins were classified as the RAS family of small guanosine triphosphate (GTP)-binding proteins and acted as molecular switches by alternating between an active GTP-bound and an inactive GDP-bound form that activate intracellular signaling pathways to control cell proliferation, differentiation, and apoptosis[1,2]
We have demonstrated that deltarasin can increase intracellular reactive oxygen species (ROS) levels and induce autophagy in lung cancer cells, and we found that autophagy plays a protective role in the process, which weaken the overall anti-cancer effect of deltarasin (Fig. 9)
It has been recently reported that autophagy is an important mechanism for sustaining glycolytic RASmediated oncogenic transformation and KRAS oncogene upregulates basal autophagy to meet tumor cell survival in starvation and tumorigenesis[43,44]
Summary
RAS proto-oncogene encoded oncoproteins were classified as the RAS family of small guanosine triphosphate (GTP)-binding proteins and acted as molecular switches by alternating between an active GTP-bound and an inactive GDP-bound form that activate intracellular signaling pathways to control cell proliferation, differentiation, and apoptosis[1,2]. Of the three RAS isoforms, HRAS, NRAS, and KRAS, KRAS is the most frequently mutated RAS isoform (86%) and is commonly found in more than 30% of all lung adenocarcinoma[4]. Hyperactive KRAS signaling often occurs in common immunological and inflammatory disorders, such as rheumatoid arthritis (RA) and diabetes[5,6,7]. Effective inhibition of activity may establish treatments for those diseases. The KRAS gene is characterized by single base missense mutations, which are predominantly found at codons G12, G13, or Q619.
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