Selective killing of cancer cells harboring mutant RAS by concomitant inhibition of NADPH oxidase and glutathione biosynthesis
| Autor: | Liang Zhu, Jianjia Ma, Weiqin Lu, Yawei Bi, Eunice Kim, Catherine K. Luo, Dan Wang, Vincent W. Yang, Juntao Ji, Guoqiang Wang, Xiaokun Li, James L. Abbruzzese, Zhao-Shen Li, Haojie Huang, Lianghao Hu, Muyun Liu, Yongde Luo |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Antioxidant Colorectal cancer medicine.medical_treatment medicine.disease_cause chemistry.chemical_compound Methionine Onium Compounds Antineoplastic Combined Chemotherapy Protocols Enzyme Inhibitors Ovarian Neoplasms chemistry.chemical_classification NADPH oxidase Cell Death biology lcsh:Cytology Glutathione Tumor Burden Sulfoxides Colonic Neoplasms Female Carcinoma Pancreatic Ductal Signal Transduction Glutamate-Cysteine Ligase Immunology Mice Nude Mice Transgenic Article Cellular and Molecular Neuroscience medicine Animals Humans Chemotherapy Buthionine sulfoximine lcsh:QH573-671 Reactive oxygen species NADPH Oxidases Cancer Oncogenes Cell Biology Genes p53 HCT116 Cells medicine.disease Xenograft Model Antitumor Assays Pancreatic Neoplasms Oxidative Stress Genes ras chemistry Mutation Cancer cell Cancer research biology.protein Oxidative stress |
| Zdroj: | Cell Death and Disease, Vol 12, Iss 2, Pp 1-15 (2021) Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | Oncogenic RAS is a critical driver for the initiation and progression of several types of cancers. However, effective therapeutic strategies by targeting RAS, in particular RASG12D and RASG12V, and associated downstream pathways have been so far unsuccessful. Treatment of oncogenic RAS-ravaged cancer patients remains a currently unmet clinical need. Consistent with a major role in cancer metabolism, oncogenic RAS activation elevates both reactive oxygen species (ROS)-generating NADPH oxidase (NOX) activity and ROS-scavenging glutathione biosynthesis. At a certain threshold, the heightened oxidative stress and antioxidant capability achieve a higher level of redox balance, on which cancer cells depend to gain a selective advantage on survival and proliferation. However, this prominent metabolic feature may irrevocably render cancer cells vulnerable to concurrent inhibition of both NOX activity and glutathione biosynthesis, which may be exploited as a novel therapeutic strategy. In this report, we test this hypothesis by treating the HRASG12V-transformed ovarian epithelial cells, mutant KRAS-harboring pancreatic and colon cancer cells of mouse and human origins, as well as cancer xenografts, with diphenyleneiodonium (DPI) and buthionine sulfoximine (BSO) combination, which inhibit NOX activity and glutathione biosynthesis, respectively. Our results demonstrate that concomitant targeting of NOX and glutathione biosynthesis induces a highly potent lethality to cancer cells harboring oncogenic RAS. Therefore, our studies provide a novel strategy against RAS-bearing cancers that warrants further mechanistic and translational investigation. |
| Databáze: | OpenAIRE |
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