The Novel Dual GIP and GLP‐1 Receptor Agonist Tirzepatide Attenuates Colon Cancer Development by Regulating Glucose Metabolism
Abstract Colorectal cancer (CRC) is a leading cause of cancer mortality while diabetes is a recognized risk factor for CRC. Here we report that tirzepatide (TZP), a novel polypeptide/glucagon‐like peptide 1 receptor (GIPR/GLP‐1R) agonist for the treatment of diabetes, has a role in attenuating CRC g...
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| Format: | Article |
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Wiley
2025-05-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202411980 |
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| author | Yikai Zhang Yi Xie Shenglong Xia Xinnuo Ge Jiaying Li Fang Liu Fan Jia Shengyao Wang Qiao Zhou Menghan Gao Weihuan Fang Chao Zheng |
| author_facet | Yikai Zhang Yi Xie Shenglong Xia Xinnuo Ge Jiaying Li Fang Liu Fan Jia Shengyao Wang Qiao Zhou Menghan Gao Weihuan Fang Chao Zheng |
| author_sort | Yikai Zhang |
| collection | DOAJ |
| description | Abstract Colorectal cancer (CRC) is a leading cause of cancer mortality while diabetes is a recognized risk factor for CRC. Here we report that tirzepatide (TZP), a novel polypeptide/glucagon‐like peptide 1 receptor (GIPR/GLP‐1R) agonist for the treatment of diabetes, has a role in attenuating CRC growth. TZP significantly inhibited colon cancer cell proliferation promoted apoptosis in vitro and induced durable tumor regression in vivo under hyperglycemic and nonhyperglycemic conditions across multiple murine cancer models. As glucose metabolism is known to critically regulate colon cancer progression, spatial metabolomics results revealed that glucose metabolites are robustly reduced in the colon cancer regions of the TZP‐treated mice. TZP inhibited glucose uptake and destabilized hypoxia‐inducible factor‐1 alpha (HIF‐1α) with reduced expression and activity of the rate‐limiting enzymes 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase 3 (PFKFB3) and phosphofructokinase 1 (PFK‐1). These effects contributed to the downregulation of glycolysis and the tricarboxylic acid (TCA) cycle. TZP also delayed tumor development in a patient‐derived xenograft (PDX) mouse model accompanied by HIF‐1α mediated PFKFB3‐PFK‐1 inhibition. Therefore, the study provides strong evidence that glycolysis‐blocking TZP, besides its application in treating type 2 diabetes, has the potential for preclinical studies as a therapy for colorectal cancer used either as monotherapy or in combination with other anticancer therapies. |
| format | Article |
| id | doaj-art-d51b245cfd5d4a28b5b543b28d02a776 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-d51b245cfd5d4a28b5b543b28d02a7762025-08-20T03:47:33ZengWileyAdvanced Science2198-38442025-05-011219n/an/a10.1002/advs.202411980The Novel Dual GIP and GLP‐1 Receptor Agonist Tirzepatide Attenuates Colon Cancer Development by Regulating Glucose MetabolismYikai Zhang0Yi Xie1Shenglong Xia2Xinnuo Ge3Jiaying Li4Fang Liu5Fan Jia6Shengyao Wang7Qiao Zhou8Menghan Gao9Weihuan Fang10Chao Zheng11Department of Endocrinology The Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou 310009 P. R. ChinaDepartment of Endocrinology The Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou 310009 P. R. ChinaDepartment of Gastroenterology The Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou 310009 P. R. ChinaDepartment of Endocrinology The Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou 310009 P. R. ChinaCenter for Basic and Translational Research The Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou 310009 P. R. ChinaDepartment of Endocrinology The Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou 310009 P. R. ChinaMOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education Department of Polymer Science and Engineering Zhejiang University Hangzhou 310009 P. R. ChinaDepartment of Endocrinology The Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou 310009 P. R. ChinaDepartment of Endocrinology The Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou 310009 P. R. ChinaDepartment of Endocrinology The Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou 310009 P. R. ChinaDepartment of Veterinary Medicine Zhejiang University Hangzhou 310009 P. R. ChinaDepartment of Endocrinology The Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou 310009 P. R. ChinaAbstract Colorectal cancer (CRC) is a leading cause of cancer mortality while diabetes is a recognized risk factor for CRC. Here we report that tirzepatide (TZP), a novel polypeptide/glucagon‐like peptide 1 receptor (GIPR/GLP‐1R) agonist for the treatment of diabetes, has a role in attenuating CRC growth. TZP significantly inhibited colon cancer cell proliferation promoted apoptosis in vitro and induced durable tumor regression in vivo under hyperglycemic and nonhyperglycemic conditions across multiple murine cancer models. As glucose metabolism is known to critically regulate colon cancer progression, spatial metabolomics results revealed that glucose metabolites are robustly reduced in the colon cancer regions of the TZP‐treated mice. TZP inhibited glucose uptake and destabilized hypoxia‐inducible factor‐1 alpha (HIF‐1α) with reduced expression and activity of the rate‐limiting enzymes 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase 3 (PFKFB3) and phosphofructokinase 1 (PFK‐1). These effects contributed to the downregulation of glycolysis and the tricarboxylic acid (TCA) cycle. TZP also delayed tumor development in a patient‐derived xenograft (PDX) mouse model accompanied by HIF‐1α mediated PFKFB3‐PFK‐1 inhibition. Therefore, the study provides strong evidence that glycolysis‐blocking TZP, besides its application in treating type 2 diabetes, has the potential for preclinical studies as a therapy for colorectal cancer used either as monotherapy or in combination with other anticancer therapies.https://doi.org/10.1002/advs.202411980anti‐colorectal cancer effectglucose metabolismtirzepatide |
| spellingShingle | Yikai Zhang Yi Xie Shenglong Xia Xinnuo Ge Jiaying Li Fang Liu Fan Jia Shengyao Wang Qiao Zhou Menghan Gao Weihuan Fang Chao Zheng The Novel Dual GIP and GLP‐1 Receptor Agonist Tirzepatide Attenuates Colon Cancer Development by Regulating Glucose Metabolism Advanced Science anti‐colorectal cancer effect glucose metabolism tirzepatide |
| title | The Novel Dual GIP and GLP‐1 Receptor Agonist Tirzepatide Attenuates Colon Cancer Development by Regulating Glucose Metabolism |
| title_full | The Novel Dual GIP and GLP‐1 Receptor Agonist Tirzepatide Attenuates Colon Cancer Development by Regulating Glucose Metabolism |
| title_fullStr | The Novel Dual GIP and GLP‐1 Receptor Agonist Tirzepatide Attenuates Colon Cancer Development by Regulating Glucose Metabolism |
| title_full_unstemmed | The Novel Dual GIP and GLP‐1 Receptor Agonist Tirzepatide Attenuates Colon Cancer Development by Regulating Glucose Metabolism |
| title_short | The Novel Dual GIP and GLP‐1 Receptor Agonist Tirzepatide Attenuates Colon Cancer Development by Regulating Glucose Metabolism |
| title_sort | novel dual gip and glp 1 receptor agonist tirzepatide attenuates colon cancer development by regulating glucose metabolism |
| topic | anti‐colorectal cancer effect glucose metabolism tirzepatide |
| url | https://doi.org/10.1002/advs.202411980 |
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