Synthetic Lethality of a Novel Small Molecule Against Mutant KRAS-Expressing Cancer Cells Involves AKT-Dependent ROS Production
MetadataShow full item record
© 2016 Mary Ann Liebert, Inc. We recently reported the death-inducing activity of a small-molecule compound, C1, which triggered reactive oxygen species (ROS)-dependent autophagy-associated apoptosis in a variety of human cancer cell lines. In this study, we examine the ability of the compound to specifically target cancer cells harboring mutant KRAS with minimal activity against wild-type (WT) RAS-expressing cells. Results: HCT116 cells expressing mutated KRAS are susceptible, while the WT-expressing HT29 cells are resistant. Interestingly, C1 triggers activation of mutant RAS, which results in the downstream phosphorylation and activation of AKT/PKB. Gene knockdown of KRAS or AKT or their pharmacological inhibition resulted in the abrogation of C1-induced ROS production and rescued tumor colony-forming ability. We also made use of HCT116 mutant KRAS knockout (KO) cells, which express only a single WT KRAS allele. Exposure of KO cells to C1 failed to increase mitochondrial ROS and cell death, unlike the parental cells harboring mutant KRAS. Similarly, mutant KRAS-transformed prostate epithelial cells (RWPE-1-RAS) were more sensitive to the ROS-producing and death-inducing effects of C1 than the vector only expressing RWPE-1 cells. An in vivo model of xenograft tumors generated with HCT116 KRASWT/MUT or KRASWT/- cells showed the efficacy of C1 treatment and its ability to affect the relative mitotic index in tumors harboring KRAS mutant. Innovation and Conclusion: These data indicate a synthetic lethal effect against cells carrying mutant KRAS, which could have therapeutic implications given the paucity of KRAS-specific chemotherapeutic strategies.
Showing items related by title, author, creator and subject.
Stomach-specific activation of oncogenic KRAS and STAT3-dependent inflammation cooperatively promote gastric tumorigenesis in a preclinical modelThiem, S.; Eissmann, M.; Elzer, J.; Jonas, A.; Putoczki, T.; Poh, A.; Nguyen, P.; Preaudet, A.; Flanagan, D.; Vincan, Elizabeth; Waring, P.; Buchert, M.; Jarnicki, A.; Ernst, M. (2016)About 5% to 10% of human gastric tumors harbor oncogenic mutations in the KRAS pathway, but their presence alone is often insufficient for inducing gastric tumorigenesis, suggesting a requirement for additional mutagenic ...
Cheasley, D.; Pereira, L.; Lightowler, S.; Vincan, Elizabeth; Malaterre, J.; Ramsay, R. (2011)Rapid advances have been made in the understanding of how the highly proliferative gastrointestinal tract epithelium is regulated under homeostasis and disease. The identification of putative intestinal stem cell (ISC) ...
Mitochondrial complex II has a key role in mitochondrial-derived reactive oxygen species influence on plant stress gene regulation and defenseGleason, C.; Huang, S.; Thatcher, L.; Foley, R.; Anderson, C.; Carroll, A.; Millar, A.; Singh, Karambir (2011)Mitochondria are both a source of ATP and a site of reactive oxygen species (ROS) production.However, there is little information on the sites of mitochondrial ROS (mROS) production or the biological role of such mROS in ...