D-ribose-5-phosphate inactivates YAP and functions as a metabolic checkpoint
Abstract Background Targeting glucose uptake by glucose transporter (GLUT) inhibitors is a therapeutic opportunity, but efforts on GLUT inhibitors have not been successful in the clinic and the underlying mechanism remains unclear. We aim to identify the key metabolic changes responsible for cancer...
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| Language: | English |
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BMC
2025-01-01
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| Series: | Journal of Hematology & Oncology |
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| Online Access: | https://doi.org/10.1186/s13045-024-01655-1 |
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| author | Cheng-E Tu Yong-Feng Liu Hong-Wei Liu Chun-Mei Jiao Quentin Liu Mien-Chie Hung Peng Li Xiang-Bo Wan Xin-Juan Fan Yun-Long Wang |
| author_facet | Cheng-E Tu Yong-Feng Liu Hong-Wei Liu Chun-Mei Jiao Quentin Liu Mien-Chie Hung Peng Li Xiang-Bo Wan Xin-Juan Fan Yun-Long Wang |
| author_sort | Cheng-E Tu |
| collection | DOAJ |
| description | Abstract Background Targeting glucose uptake by glucose transporter (GLUT) inhibitors is a therapeutic opportunity, but efforts on GLUT inhibitors have not been successful in the clinic and the underlying mechanism remains unclear. We aim to identify the key metabolic changes responsible for cancer cell survival from glucose limitation and elucidate its mechanism. Methods The level of phosphorylated YAP was analyzed with Western blotting and Phos-tag immunoblotting. Glucose limitation-induced metabolic changes were analyzed using targeted metabolomics (600MRM). The anti-cancer role of metabolite was examined using colony formation assay and APC min/+ mice. Co-immunoprecipitation, LS-MS, qRT-PCR, and immunofluorescence were performed to explore the underlying mechanisms. Results We found that D-Ribose-5-phosphate (D5P), a product of the pentose phosphate pathway connecting glucose metabolism and nucleotide metabolism, functions as a metabolic checkpoint to activate YAP under glucose limitation to promote cancer cell survival. Mechanistically, in glucose-deprived cancer cells, D5P is decreased, which facilitates the interaction between MYH9 and LATS1, resulting in MYH9-mediated LATS1 aggregation, degradation, and further YAP activation. Interestingly, activated YAP further promotes purine nucleoside phosphorylase (PNP)-mediated breakdown of purine nucleoside to restore D5P in a feedback manner. Importantly, D5P synergistically enhances the tumor-suppressive effect of GLUT inhibitors and inhibits cancer progression in mice. Conclusions Our study identifies D5P as a metabolic checkpoint linking glucose limitation stress and YAP activation, indicating that D5P may be a potential anti-cancer metabolite by enhancing glucose limitation sensitivity. |
| format | Article |
| id | doaj-art-0a960a347acd48219c9586a2b7e46cf6 |
| institution | Kabale University |
| issn | 1756-8722 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Hematology & Oncology |
| spelling | doaj-art-0a960a347acd48219c9586a2b7e46cf62025-08-20T03:43:15ZengBMCJournal of Hematology & Oncology1756-87222025-01-0118112110.1186/s13045-024-01655-1D-ribose-5-phosphate inactivates YAP and functions as a metabolic checkpointCheng-E Tu0Yong-Feng Liu1Hong-Wei Liu2Chun-Mei Jiao3Quentin Liu4Mien-Chie Hung5Peng Li6Xiang-Bo Wan7Xin-Juan Fan8Yun-Long Wang9Department of Radiation Oncology, Henan Provincial Key Laboratory of Radiation Medicine, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Radiation Oncology, Henan Provincial Key Laboratory of Radiation Medicine, The First Affiliated Hospital of Zhengzhou UniversityInstitute of Biology, Hebei Academy of ScienceDepartment of Radiation Oncology, Henan Provincial Key Laboratory of Radiation Medicine, The First Affiliated Hospital of Zhengzhou UniversityInstitute of Cancer Stem Cell, Dalian Medical UniversityGraduate Institute of Biomedical Sciences, Institute of Biochemistry and Molecular Biology, Research Center for Cancer Biology, Cancer Biology and Precision Therapeutics Center, and Center for Molecular Medicine, China Medical UniversityTianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou UniversityDepartment of Radiation Oncology, Henan Provincial Key Laboratory of Radiation Medicine, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Radiation Oncology, Henan Provincial Key Laboratory of Radiation Medicine, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Radiation Oncology, Henan Provincial Key Laboratory of Radiation Medicine, The First Affiliated Hospital of Zhengzhou UniversityAbstract Background Targeting glucose uptake by glucose transporter (GLUT) inhibitors is a therapeutic opportunity, but efforts on GLUT inhibitors have not been successful in the clinic and the underlying mechanism remains unclear. We aim to identify the key metabolic changes responsible for cancer cell survival from glucose limitation and elucidate its mechanism. Methods The level of phosphorylated YAP was analyzed with Western blotting and Phos-tag immunoblotting. Glucose limitation-induced metabolic changes were analyzed using targeted metabolomics (600MRM). The anti-cancer role of metabolite was examined using colony formation assay and APC min/+ mice. Co-immunoprecipitation, LS-MS, qRT-PCR, and immunofluorescence were performed to explore the underlying mechanisms. Results We found that D-Ribose-5-phosphate (D5P), a product of the pentose phosphate pathway connecting glucose metabolism and nucleotide metabolism, functions as a metabolic checkpoint to activate YAP under glucose limitation to promote cancer cell survival. Mechanistically, in glucose-deprived cancer cells, D5P is decreased, which facilitates the interaction between MYH9 and LATS1, resulting in MYH9-mediated LATS1 aggregation, degradation, and further YAP activation. Interestingly, activated YAP further promotes purine nucleoside phosphorylase (PNP)-mediated breakdown of purine nucleoside to restore D5P in a feedback manner. Importantly, D5P synergistically enhances the tumor-suppressive effect of GLUT inhibitors and inhibits cancer progression in mice. Conclusions Our study identifies D5P as a metabolic checkpoint linking glucose limitation stress and YAP activation, indicating that D5P may be a potential anti-cancer metabolite by enhancing glucose limitation sensitivity.https://doi.org/10.1186/s13045-024-01655-1Metabolic stressGlucose deprivationD-ribose-5-phosphateYAPLATS1Purine nucleoside phosphorylase |
| spellingShingle | Cheng-E Tu Yong-Feng Liu Hong-Wei Liu Chun-Mei Jiao Quentin Liu Mien-Chie Hung Peng Li Xiang-Bo Wan Xin-Juan Fan Yun-Long Wang D-ribose-5-phosphate inactivates YAP and functions as a metabolic checkpoint Journal of Hematology & Oncology Metabolic stress Glucose deprivation D-ribose-5-phosphate YAP LATS1 Purine nucleoside phosphorylase |
| title | D-ribose-5-phosphate inactivates YAP and functions as a metabolic checkpoint |
| title_full | D-ribose-5-phosphate inactivates YAP and functions as a metabolic checkpoint |
| title_fullStr | D-ribose-5-phosphate inactivates YAP and functions as a metabolic checkpoint |
| title_full_unstemmed | D-ribose-5-phosphate inactivates YAP and functions as a metabolic checkpoint |
| title_short | D-ribose-5-phosphate inactivates YAP and functions as a metabolic checkpoint |
| title_sort | d ribose 5 phosphate inactivates yap and functions as a metabolic checkpoint |
| topic | Metabolic stress Glucose deprivation D-ribose-5-phosphate YAP LATS1 Purine nucleoside phosphorylase |
| url | https://doi.org/10.1186/s13045-024-01655-1 |
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