Kartini Iskandar1, Majidah Rezlan1, Sanjiv Kumar Yadav1, Chuan Han Jonathan Foo1, Gautam Sethi2, Yu Qiang3, Gregory L Bellot1,4, Shazib Pervaiz1,5,6,7. 1. 1 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore . 2. 2 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore . 3. 3 Genome Institute of Singapore , A*STAR, Singapore, Singapore . 4. 4 Department of Hand and Reconstructive Microsurgery, National University Health System , Singapore, Singapore . 5. 5 NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore , Singapore, Singapore . 6. 6 National University Cancer Institute, National University Health System , Singapore, Singapore . 7. 7 School of Biomedical Sciences, Curtin University , Perth, Australia .
Abstract
AIMS: 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 KRAS(WT/MUT) or KRAS(WT/-) 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. Antioxid. Redox Signal. 24, 781-794.
AIMS: 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 humancancer 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 KRAS(WT/MUT) or KRAS(WT/-) 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. Antioxid. Redox Signal. 24, 781-794.
Authors: K A Heslop; A Rovini; E G Hunt; D Fang; M E Morris; C F Christie; M B Gooz; D N DeHart; Y Dang; J J Lemasters; E N Maldonado Journal: Biochem Pharmacol Date: 2019-11-21 Impact factor: 5.858