Blockage of glycolysis by targeting PFKFB3 suppresses the development of infantile hemangioma
Abstract Background Infantile hemangioma (IH) is the most common tumor among infants, but the exact pathogenesis of IH is largely unknown. Our previous study revealed that glucose metabolism may play an important role in the pathogenesis of IH and that the inhibition of the glycolytic key enzyme pho...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-02-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-03932-y |
| _version_ | 1811165752668979200 |
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| author | Kaiying Yang Tong Qiu Jiangyuan Zhou Xue Gong Xuepeng Zhang Yuru Lan Zixin Zhang Yi Ji |
| author_facet | Kaiying Yang Tong Qiu Jiangyuan Zhou Xue Gong Xuepeng Zhang Yuru Lan Zixin Zhang Yi Ji |
| author_sort | Kaiying Yang |
| collection | DOAJ |
| description | Abstract Background Infantile hemangioma (IH) is the most common tumor among infants, but the exact pathogenesis of IH is largely unknown. Our previous study revealed that glucose metabolism may play an important role in the pathogenesis of IH and that the inhibition of the glycolytic key enzyme phosphofructokinase-1 suppresses angiogenesis in IH. 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) is a metabolic enzyme that converts fructose-6-bisphosphate to fructose-2,6-bisphosphate (F-2,6-BP), which is the most potent allosteric activator of the rate-limiting enzyme phosphofructokinase-1. This study was performed to explore the role of PFKFB3 in IH. Methods Microarray analysis was performed to screen the differentially expressed genes (DEGs) between proliferating and involuting IH tissues. PFKFB3 expression was examined by western blot and immunohistochemistry analyses. Cell migration, apoptosis and tube formation were analyzed. Metabolic analyses were performed to investigate the effect of PFKFB3 inhibition by PFK15. Mouse models were established to examine the effect of PFKFB3 inhibition in vivo. Results PFKFB3 was identified as one of the most significant DEGs and was more highly expressed in proliferating IH tissues and hemangioma-derived endothelial cells (HemECs) than in involuting IH tissues and human umbilical vein endothelial cells, respectively. PFKFB3 inhibition by PFK15 suppressed HemEC glucose metabolism mainly by affecting glycolytic metabolite metabolism and decreasing the glycolytic flux. Moreover, PFK15 inhibited HemEC angiogenesis and migration and induced apoptosis via activation of the apoptosis pathway. Treatment with the combination of PFK15 with propranolol had a synergistic inhibitory effect on HemECs. Moreover, PFKFB3 knockdown markedly suppressed HemEC angiogenesis. Mechanistically, inhibition of PFKFB3 suppressed the PI3K-Akt signaling pathway and induced apoptotic cell death. More importantly, the suppression of PFKFB3 by PFK15 or shPFKFB3 led to markedly reduced tumor growth in vivo. Conclusions Our findings suggest that PFKFB3 inhibition can suppress IH angiogenesis and induce apoptosis. Thus, targeting PFKFB3 may be a novel therapeutic strategy for IH. |
| first_indexed | 2024-04-10T15:41:41Z |
| format | Article |
| id | doaj.art-13b699f203464797a49a2d386cf3fc65 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-10T15:41:41Z |
| publishDate | 2023-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-13b699f203464797a49a2d386cf3fc652023-02-12T12:20:51ZengBMCJournal of Translational Medicine1479-58762023-02-0121111610.1186/s12967-023-03932-yBlockage of glycolysis by targeting PFKFB3 suppresses the development of infantile hemangiomaKaiying Yang0Tong Qiu1Jiangyuan Zhou2Xue Gong3Xuepeng Zhang4Yuru Lan5Zixin Zhang6Yi Ji7Division of Oncology, Department of Pediatric Surgery, West China Hospital of Sichuan UniversityDivision of Oncology, Department of Pediatric Surgery, West China Hospital of Sichuan UniversityDivision of Oncology, Department of Pediatric Surgery, West China Hospital of Sichuan UniversityDivision of Oncology, Department of Pediatric Surgery, West China Hospital of Sichuan UniversityDivision of Oncology, Department of Pediatric Surgery, West China Hospital of Sichuan UniversityDivision of Oncology, Department of Pediatric Surgery, West China Hospital of Sichuan UniversityDivision of Oncology, Department of Pediatric Surgery, West China Hospital of Sichuan UniversityDivision of Oncology, Department of Pediatric Surgery, West China Hospital of Sichuan UniversityAbstract Background Infantile hemangioma (IH) is the most common tumor among infants, but the exact pathogenesis of IH is largely unknown. Our previous study revealed that glucose metabolism may play an important role in the pathogenesis of IH and that the inhibition of the glycolytic key enzyme phosphofructokinase-1 suppresses angiogenesis in IH. 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) is a metabolic enzyme that converts fructose-6-bisphosphate to fructose-2,6-bisphosphate (F-2,6-BP), which is the most potent allosteric activator of the rate-limiting enzyme phosphofructokinase-1. This study was performed to explore the role of PFKFB3 in IH. Methods Microarray analysis was performed to screen the differentially expressed genes (DEGs) between proliferating and involuting IH tissues. PFKFB3 expression was examined by western blot and immunohistochemistry analyses. Cell migration, apoptosis and tube formation were analyzed. Metabolic analyses were performed to investigate the effect of PFKFB3 inhibition by PFK15. Mouse models were established to examine the effect of PFKFB3 inhibition in vivo. Results PFKFB3 was identified as one of the most significant DEGs and was more highly expressed in proliferating IH tissues and hemangioma-derived endothelial cells (HemECs) than in involuting IH tissues and human umbilical vein endothelial cells, respectively. PFKFB3 inhibition by PFK15 suppressed HemEC glucose metabolism mainly by affecting glycolytic metabolite metabolism and decreasing the glycolytic flux. Moreover, PFK15 inhibited HemEC angiogenesis and migration and induced apoptosis via activation of the apoptosis pathway. Treatment with the combination of PFK15 with propranolol had a synergistic inhibitory effect on HemECs. Moreover, PFKFB3 knockdown markedly suppressed HemEC angiogenesis. Mechanistically, inhibition of PFKFB3 suppressed the PI3K-Akt signaling pathway and induced apoptotic cell death. More importantly, the suppression of PFKFB3 by PFK15 or shPFKFB3 led to markedly reduced tumor growth in vivo. Conclusions Our findings suggest that PFKFB3 inhibition can suppress IH angiogenesis and induce apoptosis. Thus, targeting PFKFB3 may be a novel therapeutic strategy for IH.https://doi.org/10.1186/s12967-023-03932-yInfantile hemangiomaGlycolysis6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3Angiogenesis |
| spellingShingle | Kaiying Yang Tong Qiu Jiangyuan Zhou Xue Gong Xuepeng Zhang Yuru Lan Zixin Zhang Yi Ji Blockage of glycolysis by targeting PFKFB3 suppresses the development of infantile hemangioma Journal of Translational Medicine Infantile hemangioma Glycolysis 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 Angiogenesis |
| title | Blockage of glycolysis by targeting PFKFB3 suppresses the development of infantile hemangioma |
| title_full | Blockage of glycolysis by targeting PFKFB3 suppresses the development of infantile hemangioma |
| title_fullStr | Blockage of glycolysis by targeting PFKFB3 suppresses the development of infantile hemangioma |
| title_full_unstemmed | Blockage of glycolysis by targeting PFKFB3 suppresses the development of infantile hemangioma |
| title_short | Blockage of glycolysis by targeting PFKFB3 suppresses the development of infantile hemangioma |
| title_sort | blockage of glycolysis by targeting pfkfb3 suppresses the development of infantile hemangioma |
| topic | Infantile hemangioma Glycolysis 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 Angiogenesis |
| url | https://doi.org/10.1186/s12967-023-03932-y |
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