Synthetic Lethality of a Novel Small Molecule Against Mutant KRAS-Expressing Cancer Cells Involves AKT-Dependent ROS Production
© 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 sp...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Journal Article |
| Published: |
Mary Ann Liebert, Inc. Publishers
2016
|
| Online Access: | http://hdl.handle.net/20.500.11937/50816 |
| _version_ | 1848758543002370048 |
|---|---|
| author | Iskandar, K. Rezlan, M. Yadav, S. Foo, C. Sethi, G. Qiang, Y. Bellot, G. Pervaiz, Shazib |
| author_facet | Iskandar, K. Rezlan, M. Yadav, S. Foo, C. Sethi, G. Qiang, Y. Bellot, G. Pervaiz, Shazib |
| author_sort | Iskandar, K. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | © 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. |
| first_indexed | 2025-11-14T09:45:39Z |
| format | Journal Article |
| id | curtin-20.500.11937-50816 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T09:45:39Z |
| publishDate | 2016 |
| publisher | Mary Ann Liebert, Inc. Publishers |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-508162017-09-13T15:34:51Z Synthetic Lethality of a Novel Small Molecule Against Mutant KRAS-Expressing Cancer Cells Involves AKT-Dependent ROS Production Iskandar, K. Rezlan, M. Yadav, S. Foo, C. Sethi, G. Qiang, Y. Bellot, G. Pervaiz, Shazib © 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. 2016 Journal Article http://hdl.handle.net/20.500.11937/50816 10.1089/ars.2015.6362 Mary Ann Liebert, Inc. Publishers restricted |
| spellingShingle | Iskandar, K. Rezlan, M. Yadav, S. Foo, C. Sethi, G. Qiang, Y. Bellot, G. Pervaiz, Shazib Synthetic Lethality of a Novel Small Molecule Against Mutant KRAS-Expressing Cancer Cells Involves AKT-Dependent ROS Production |
| title | Synthetic Lethality of a Novel Small Molecule Against Mutant KRAS-Expressing Cancer Cells Involves AKT-Dependent ROS Production |
| title_full | Synthetic Lethality of a Novel Small Molecule Against Mutant KRAS-Expressing Cancer Cells Involves AKT-Dependent ROS Production |
| title_fullStr | Synthetic Lethality of a Novel Small Molecule Against Mutant KRAS-Expressing Cancer Cells Involves AKT-Dependent ROS Production |
| title_full_unstemmed | Synthetic Lethality of a Novel Small Molecule Against Mutant KRAS-Expressing Cancer Cells Involves AKT-Dependent ROS Production |
| title_short | Synthetic Lethality of a Novel Small Molecule Against Mutant KRAS-Expressing Cancer Cells Involves AKT-Dependent ROS Production |
| title_sort | synthetic lethality of a novel small molecule against mutant kras-expressing cancer cells involves akt-dependent ros production |
| url | http://hdl.handle.net/20.500.11937/50816 |