PKM2 is the target of proanthocyanidin B2 during the inhibition of hepatocellular carcinoma
Abstract Background The treatment for advanced primary hepatocellular carcinoma (HCC) is sorafenib (SORA), while HCC has become increasingly drug resistant with enhanced aerobic glycolysis. The present study aimed to examine the chemotherapeutic effects of a flavonoid proanthocyanidin B2 (PB2) on HC...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-05-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-019-1194-z |
| _version_ | 1819103193409257472 |
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| author | Jiao Feng Liwei Wu Jie Ji Kan Chen Qiang Yu Jie Zhang Jiaojiao Chen Yuqing Mao Fan Wang Weiqi Dai Ling Xu Jianye Wu Chuanyong Guo |
| author_facet | Jiao Feng Liwei Wu Jie Ji Kan Chen Qiang Yu Jie Zhang Jiaojiao Chen Yuqing Mao Fan Wang Weiqi Dai Ling Xu Jianye Wu Chuanyong Guo |
| author_sort | Jiao Feng |
| collection | DOAJ |
| description | Abstract Background The treatment for advanced primary hepatocellular carcinoma (HCC) is sorafenib (SORA), while HCC has become increasingly drug resistant with enhanced aerobic glycolysis. The present study aimed to examine the chemotherapeutic effects of a flavonoid proanthocyanidin B2 (PB2) on HCC. Methods Five kinds of HCC cell lines and LO2 were used to test the effect of PB2 on aerobic glycolysis. The proliferation, cell cycle, apoptosis and a xenograft mouse model were analyzed. Lentivirus overexpressed pyruvate kinase M2 (PKM2) or sh-PKM2 was used to verify the target of PB2. The detailed mechanism was investigated by immunofluorescence, co-immunoprecipitation, and western blotting. Results PB2 inhibited the proliferation, induced cell cycle arrest, and triggered apoptosis of HCC cells in vivo and in vitro. PB2 also suppressed glucose uptake and lactate levels via the direct inhibition of the key glycolytic enzyme, PKM2. In addition, PKM2 inhibited the nuclear translocation of PKM2 and co-localization of PKM2/HIF-1α in the nucleus, leading to the inhibition of aerobic glycolysis. Co-treatment with PB2 was also effective in enhancing the chemosensitivity of SORA. Conclusions PB2 inhibited the expression and nuclear translocation of PKM2, therefore disrupting the interaction between PKM2/HSP90/HIF-1α, to suppress aerobic glycolysis and proliferation, and trigger apoptosis in HCC via HIF-1α-mediated transcription suppression. |
| first_indexed | 2024-12-22T01:46:34Z |
| format | Article |
| id | doaj.art-213fe01191a34b5e8b388e9872b37246 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-22T01:46:34Z |
| publishDate | 2019-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-213fe01191a34b5e8b388e9872b372462022-12-21T18:43:02ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662019-05-0138111510.1186/s13046-019-1194-zPKM2 is the target of proanthocyanidin B2 during the inhibition of hepatocellular carcinomaJiao Feng0Liwei Wu1Jie Ji2Kan Chen3Qiang Yu4Jie Zhang5Jiaojiao Chen6Yuqing Mao7Fan Wang8Weiqi Dai9Ling Xu10Jianye Wu11Chuanyong Guo12Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Gerontology, Shanghai General Hospital, Shanghai Jiaotong University School of MedicineDepartment of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of MedicineDepartment of Gastroenterology, Zhongshan Hospital of Fudan UniversityDepartment of Gastroenterology, Shanghai Tongren Hospital, Shanghai Jiaotong University School of MedicineDepartment of Gastroenterology, Putuo People’s Hospital, Tongji University School of MedicineDepartment of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineAbstract Background The treatment for advanced primary hepatocellular carcinoma (HCC) is sorafenib (SORA), while HCC has become increasingly drug resistant with enhanced aerobic glycolysis. The present study aimed to examine the chemotherapeutic effects of a flavonoid proanthocyanidin B2 (PB2) on HCC. Methods Five kinds of HCC cell lines and LO2 were used to test the effect of PB2 on aerobic glycolysis. The proliferation, cell cycle, apoptosis and a xenograft mouse model were analyzed. Lentivirus overexpressed pyruvate kinase M2 (PKM2) or sh-PKM2 was used to verify the target of PB2. The detailed mechanism was investigated by immunofluorescence, co-immunoprecipitation, and western blotting. Results PB2 inhibited the proliferation, induced cell cycle arrest, and triggered apoptosis of HCC cells in vivo and in vitro. PB2 also suppressed glucose uptake and lactate levels via the direct inhibition of the key glycolytic enzyme, PKM2. In addition, PKM2 inhibited the nuclear translocation of PKM2 and co-localization of PKM2/HIF-1α in the nucleus, leading to the inhibition of aerobic glycolysis. Co-treatment with PB2 was also effective in enhancing the chemosensitivity of SORA. Conclusions PB2 inhibited the expression and nuclear translocation of PKM2, therefore disrupting the interaction between PKM2/HSP90/HIF-1α, to suppress aerobic glycolysis and proliferation, and trigger apoptosis in HCC via HIF-1α-mediated transcription suppression.http://link.springer.com/article/10.1186/s13046-019-1194-zProanthocyanidin B2Hepatocellular carcinomaAerobic glycolysisPKM2Sorafenib |
| spellingShingle | Jiao Feng Liwei Wu Jie Ji Kan Chen Qiang Yu Jie Zhang Jiaojiao Chen Yuqing Mao Fan Wang Weiqi Dai Ling Xu Jianye Wu Chuanyong Guo PKM2 is the target of proanthocyanidin B2 during the inhibition of hepatocellular carcinoma Journal of Experimental & Clinical Cancer Research Proanthocyanidin B2 Hepatocellular carcinoma Aerobic glycolysis PKM2 Sorafenib |
| title | PKM2 is the target of proanthocyanidin B2 during the inhibition of hepatocellular carcinoma |
| title_full | PKM2 is the target of proanthocyanidin B2 during the inhibition of hepatocellular carcinoma |
| title_fullStr | PKM2 is the target of proanthocyanidin B2 during the inhibition of hepatocellular carcinoma |
| title_full_unstemmed | PKM2 is the target of proanthocyanidin B2 during the inhibition of hepatocellular carcinoma |
| title_short | PKM2 is the target of proanthocyanidin B2 during the inhibition of hepatocellular carcinoma |
| title_sort | pkm2 is the target of proanthocyanidin b2 during the inhibition of hepatocellular carcinoma |
| topic | Proanthocyanidin B2 Hepatocellular carcinoma Aerobic glycolysis PKM2 Sorafenib |
| url | http://link.springer.com/article/10.1186/s13046-019-1194-z |
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