Novel fusion protein PK5-RL-Gal-3C inhibits hepatocellular carcinoma via anti-angiogenesis and cytotoxicity
Abstract Background Galectin-3 (Gal-3), the only chimeric β-galactosides-binding lectin, consists of Gal-3N (N-terminal regulatory peptide) and Gal-3C (C-terminal carbohydrate-recognition domain). Interestingly, Gal-3C could specifically inhibit endogenous full-length Gal-3 to exhibit anti-tumor act...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-02-01
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| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12885-023-10608-9 |
| _version_ | 1797840992574898176 |
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| author | Xiaoge Gao Pin Jiang Xiaohuan Wei Wei Zhang Jiwei Zheng Shishuo Sun Hong Yao Xiangye Liu Qing Zhang |
| author_facet | Xiaoge Gao Pin Jiang Xiaohuan Wei Wei Zhang Jiwei Zheng Shishuo Sun Hong Yao Xiangye Liu Qing Zhang |
| author_sort | Xiaoge Gao |
| collection | DOAJ |
| description | Abstract Background Galectin-3 (Gal-3), the only chimeric β-galactosides-binding lectin, consists of Gal-3N (N-terminal regulatory peptide) and Gal-3C (C-terminal carbohydrate-recognition domain). Interestingly, Gal-3C could specifically inhibit endogenous full-length Gal-3 to exhibit anti-tumor activity. Here, we aimed to further improve the anti-tumor activity of Gal-3C via developing novel fusion proteins. Methods PK5 (the fifth kringle domain of plasminogen) was introduced to the N-terminus of Gal-3C via rigid linker (RL) to generate novel fusion protein PK5-RL-Gal-3C. Then, we investigated the anti-tumor activity of PK5-RL-Gal-3C in vivo and in vitro by using several experiments, and figured out their molecular mechanisms in anti-angiogenesis and cytotoxicity to hepatocellular carcinoma (HCC). Results Our results show that PK5-RL-Gal-3C can inhibit HCC both in vivo and in vitro without obvious toxicity, and also significantly prolong the survival time of tumor-bearing mice. Mechanically, we find that PK5-RL-Gal-3C inhibits angiogenesis and show cytotoxicity to HCC. In detail, HUVEC-related and matrigel plug assays indicate that PK5-RL-Gal-3C plays an important role in inhibiting angiogenesis by regulating HIF1α/VEGF and Ang-2 both in vivo and in vitro. Moreover, PK5-RL-Gal-3C induces cell cycle arrest at G1 phase and apoptosis with inhibition of Cyclin D1, Cyclin D3, CDK4, and Bcl-2, but activation of p27, p21, caspase-3, -8 and -9. Conclusion Novel fusion protein PK5-RL-Gal-3C is potent therapeutic agent by inhibiting tumor angiogenesis in HCC and potential antagonist of Gal-3, which provides new strategy for exploring novel antagonist of Gal-3 and promotes their application in clinical treatment. |
| first_indexed | 2024-04-09T16:23:42Z |
| format | Article |
| id | doaj.art-338bac6a0e8b44dc9aff51e8f6d7937b |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-04-09T16:23:42Z |
| publishDate | 2023-02-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-338bac6a0e8b44dc9aff51e8f6d7937b2023-04-23T11:20:21ZengBMCBMC Cancer1471-24072023-02-0123111610.1186/s12885-023-10608-9Novel fusion protein PK5-RL-Gal-3C inhibits hepatocellular carcinoma via anti-angiogenesis and cytotoxicityXiaoge Gao0Pin Jiang1Xiaohuan Wei2Wei Zhang3Jiwei Zheng4Shishuo Sun5Hong Yao6Xiangye Liu7Qing Zhang8Cancer Institute, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityDepartment of Oral Medicine, School of Stomatology, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityDepartment of Pathogenic Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityAbstract Background Galectin-3 (Gal-3), the only chimeric β-galactosides-binding lectin, consists of Gal-3N (N-terminal regulatory peptide) and Gal-3C (C-terminal carbohydrate-recognition domain). Interestingly, Gal-3C could specifically inhibit endogenous full-length Gal-3 to exhibit anti-tumor activity. Here, we aimed to further improve the anti-tumor activity of Gal-3C via developing novel fusion proteins. Methods PK5 (the fifth kringle domain of plasminogen) was introduced to the N-terminus of Gal-3C via rigid linker (RL) to generate novel fusion protein PK5-RL-Gal-3C. Then, we investigated the anti-tumor activity of PK5-RL-Gal-3C in vivo and in vitro by using several experiments, and figured out their molecular mechanisms in anti-angiogenesis and cytotoxicity to hepatocellular carcinoma (HCC). Results Our results show that PK5-RL-Gal-3C can inhibit HCC both in vivo and in vitro without obvious toxicity, and also significantly prolong the survival time of tumor-bearing mice. Mechanically, we find that PK5-RL-Gal-3C inhibits angiogenesis and show cytotoxicity to HCC. In detail, HUVEC-related and matrigel plug assays indicate that PK5-RL-Gal-3C plays an important role in inhibiting angiogenesis by regulating HIF1α/VEGF and Ang-2 both in vivo and in vitro. Moreover, PK5-RL-Gal-3C induces cell cycle arrest at G1 phase and apoptosis with inhibition of Cyclin D1, Cyclin D3, CDK4, and Bcl-2, but activation of p27, p21, caspase-3, -8 and -9. Conclusion Novel fusion protein PK5-RL-Gal-3C is potent therapeutic agent by inhibiting tumor angiogenesis in HCC and potential antagonist of Gal-3, which provides new strategy for exploring novel antagonist of Gal-3 and promotes their application in clinical treatment.https://doi.org/10.1186/s12885-023-10608-9Galectin-3AngiogenesisCarbohydrate-recognition domainFifth kringle of plasminogenHepatocellular carcinoma |
| spellingShingle | Xiaoge Gao Pin Jiang Xiaohuan Wei Wei Zhang Jiwei Zheng Shishuo Sun Hong Yao Xiangye Liu Qing Zhang Novel fusion protein PK5-RL-Gal-3C inhibits hepatocellular carcinoma via anti-angiogenesis and cytotoxicity BMC Cancer Galectin-3 Angiogenesis Carbohydrate-recognition domain Fifth kringle of plasminogen Hepatocellular carcinoma |
| title | Novel fusion protein PK5-RL-Gal-3C inhibits hepatocellular carcinoma via anti-angiogenesis and cytotoxicity |
| title_full | Novel fusion protein PK5-RL-Gal-3C inhibits hepatocellular carcinoma via anti-angiogenesis and cytotoxicity |
| title_fullStr | Novel fusion protein PK5-RL-Gal-3C inhibits hepatocellular carcinoma via anti-angiogenesis and cytotoxicity |
| title_full_unstemmed | Novel fusion protein PK5-RL-Gal-3C inhibits hepatocellular carcinoma via anti-angiogenesis and cytotoxicity |
| title_short | Novel fusion protein PK5-RL-Gal-3C inhibits hepatocellular carcinoma via anti-angiogenesis and cytotoxicity |
| title_sort | novel fusion protein pk5 rl gal 3c inhibits hepatocellular carcinoma via anti angiogenesis and cytotoxicity |
| topic | Galectin-3 Angiogenesis Carbohydrate-recognition domain Fifth kringle of plasminogen Hepatocellular carcinoma |
| url | https://doi.org/10.1186/s12885-023-10608-9 |
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