DNA replication stress underpins the vulnerability to oxidative phosphorylation inhibition in colorectal cancer
Abstract Mitochondrial oxidative phosphorylation (OXPHOS) is a therapeutic vulnerability in glycolysis-deficient cancers. Here we show that inhibiting OXPHOS similarly suppresses the proliferation and tumorigenicity of glycolytically competent colorectal cancer (CRC) cells in vitro and in patient-de...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07334-4 |
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| author | Xiao Hong Zhao Man Man Han Qian Qian Yan Yi Meng Yue Kaihong Ye Yuan Yuan Zhang Liu Teng Liang Xu Xiao-Jing Shi Ting La Yu Chen Feng Ran Xu Vinod K. Narayana David P. De Souza Lake-Ee Quek Jeff Holst Tao Liu Mark A. Baker Rick F. Thorne Xu Dong Zhang Lei Jin |
| author_facet | Xiao Hong Zhao Man Man Han Qian Qian Yan Yi Meng Yue Kaihong Ye Yuan Yuan Zhang Liu Teng Liang Xu Xiao-Jing Shi Ting La Yu Chen Feng Ran Xu Vinod K. Narayana David P. De Souza Lake-Ee Quek Jeff Holst Tao Liu Mark A. Baker Rick F. Thorne Xu Dong Zhang Lei Jin |
| author_sort | Xiao Hong Zhao |
| collection | DOAJ |
| description | Abstract Mitochondrial oxidative phosphorylation (OXPHOS) is a therapeutic vulnerability in glycolysis-deficient cancers. Here we show that inhibiting OXPHOS similarly suppresses the proliferation and tumorigenicity of glycolytically competent colorectal cancer (CRC) cells in vitro and in patient-derived CRC xenografts. While the increased glycolytic activity rapidly replenished the ATP pool, it did not restore the reduced production of aspartate upon OXPHOS inhibition. This shortage in aspartate, in turn, caused nucleotide deficiencies, leading to S phase cell cycle arrest, replication fork stalling, and enrichment of the p53 pathway, manifestations of replication stress. The addition of purine nucleobases adenine and guanine along with the pyrimidine nucleoside uridine restored replication fork progression and cell proliferation, whereas the supplementation of exogenous aspartate recovered the nucleotide pool, demonstrating a causal role of the aspartate shortage in OXPHOS inhibition-induced nucleotide deficiencies and consequently replication stress and reductions in proliferation. Moreover, we demonstrate that glutamic-oxaloacetic transaminase 1 (GOT1) is critical for maintaining the minimum aspartate pool when OXPHOS is inhibited, as knockdown of GOT1 further reduced aspartate levels and rendered CRC cells more sensitive to OXPHOS inhibition both in vitro and in vivo. These results propose GOT1 targeting as a potential avenue to sensitize cancer cells to OXPHOS inhibitors, thus lowering the necessary doses to efficiently inhibit cancer growth while alleviating their adverse effects. |
| format | Article |
| id | doaj-art-8ae02858c64a4b869bd91576f8d5b7fb |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-8ae02858c64a4b869bd91576f8d5b7fb2025-01-19T12:40:40ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111210.1038/s41419-025-07334-4DNA replication stress underpins the vulnerability to oxidative phosphorylation inhibition in colorectal cancerXiao Hong Zhao0Man Man Han1Qian Qian Yan2Yi Meng Yue3Kaihong Ye4Yuan Yuan Zhang5Liu Teng6Liang Xu7Xiao-Jing Shi8Ting La9Yu Chen Feng10Ran Xu11Vinod K. Narayana12David P. De Souza13Lake-Ee Quek14Jeff Holst15Tao Liu16Mark A. Baker17Rick F. Thorne18Xu Dong Zhang19Lei Jin20School of Biomedical Sciences and Pharmacy, The University of NewcastleTianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou UniversityTianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou UniversityTianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou UniversitySchool of Biomedical Sciences and Pharmacy, The University of NewcastleSchool of Biomedical Sciences and Pharmacy, The University of NewcastleSchool of Biomedical Sciences and Pharmacy, The University of NewcastleSchool of Biomedical Sciences and Pharmacy, The University of NewcastleTianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou UniversitySchool of Biomedical Sciences and Pharmacy, The University of NewcastleSchool of Medicine and Public Health, The University of NewcastleSchool of Medicine and Public Health, The University of NewcastleBio21 Institute and Department of Biochemistry and Molecular Biology, University of MelbourneBio21 Institute and Department of Biochemistry and Molecular Biology, University of MelbourneSchool of Mathematics and Statistics, The University of SydneySchool of Biomedical Sciences, University of New South WalesTianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou UniversitySchool of Biomedical Sciences and Pharmacy, The University of NewcastleSchool of Biomedical Sciences and Pharmacy, The University of NewcastleSchool of Biomedical Sciences and Pharmacy, The University of NewcastleTianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou UniversityAbstract Mitochondrial oxidative phosphorylation (OXPHOS) is a therapeutic vulnerability in glycolysis-deficient cancers. Here we show that inhibiting OXPHOS similarly suppresses the proliferation and tumorigenicity of glycolytically competent colorectal cancer (CRC) cells in vitro and in patient-derived CRC xenografts. While the increased glycolytic activity rapidly replenished the ATP pool, it did not restore the reduced production of aspartate upon OXPHOS inhibition. This shortage in aspartate, in turn, caused nucleotide deficiencies, leading to S phase cell cycle arrest, replication fork stalling, and enrichment of the p53 pathway, manifestations of replication stress. The addition of purine nucleobases adenine and guanine along with the pyrimidine nucleoside uridine restored replication fork progression and cell proliferation, whereas the supplementation of exogenous aspartate recovered the nucleotide pool, demonstrating a causal role of the aspartate shortage in OXPHOS inhibition-induced nucleotide deficiencies and consequently replication stress and reductions in proliferation. Moreover, we demonstrate that glutamic-oxaloacetic transaminase 1 (GOT1) is critical for maintaining the minimum aspartate pool when OXPHOS is inhibited, as knockdown of GOT1 further reduced aspartate levels and rendered CRC cells more sensitive to OXPHOS inhibition both in vitro and in vivo. These results propose GOT1 targeting as a potential avenue to sensitize cancer cells to OXPHOS inhibitors, thus lowering the necessary doses to efficiently inhibit cancer growth while alleviating their adverse effects.https://doi.org/10.1038/s41419-025-07334-4 |
| spellingShingle | Xiao Hong Zhao Man Man Han Qian Qian Yan Yi Meng Yue Kaihong Ye Yuan Yuan Zhang Liu Teng Liang Xu Xiao-Jing Shi Ting La Yu Chen Feng Ran Xu Vinod K. Narayana David P. De Souza Lake-Ee Quek Jeff Holst Tao Liu Mark A. Baker Rick F. Thorne Xu Dong Zhang Lei Jin DNA replication stress underpins the vulnerability to oxidative phosphorylation inhibition in colorectal cancer Cell Death and Disease |
| title | DNA replication stress underpins the vulnerability to oxidative phosphorylation inhibition in colorectal cancer |
| title_full | DNA replication stress underpins the vulnerability to oxidative phosphorylation inhibition in colorectal cancer |
| title_fullStr | DNA replication stress underpins the vulnerability to oxidative phosphorylation inhibition in colorectal cancer |
| title_full_unstemmed | DNA replication stress underpins the vulnerability to oxidative phosphorylation inhibition in colorectal cancer |
| title_short | DNA replication stress underpins the vulnerability to oxidative phosphorylation inhibition in colorectal cancer |
| title_sort | dna replication stress underpins the vulnerability to oxidative phosphorylation inhibition in colorectal cancer |
| url | https://doi.org/10.1038/s41419-025-07334-4 |
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