Downregulation of the Unfolded Protein Response Links Metformin Treatment to Good Clinical Outcomes in Colorectal Cancer Patients
Type 2 diabetes is a risk factor for colorectal cancer (CRC) development and progression. However, metformin-treated diabetic CRC patients tend to have better clinical outcomes than those managed by other means. To better characterize the molecular underpinnings of metformin’s protective effects, we...
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MDPI AG
2025-02-01
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| Series: | Current Oncology |
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| Online Access: | https://www.mdpi.com/1718-7729/32/3/138 |
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| author | Mary L. Fay Chris Nicol Christine Orr Brooke Wilson David Hurlbut Harriet Feilotter Scott Davey |
| author_facet | Mary L. Fay Chris Nicol Christine Orr Brooke Wilson David Hurlbut Harriet Feilotter Scott Davey |
| author_sort | Mary L. Fay |
| collection | DOAJ |
| description | Type 2 diabetes is a risk factor for colorectal cancer (CRC) development and progression. However, metformin-treated diabetic CRC patients tend to have better clinical outcomes than those managed by other means. To better characterize the molecular underpinnings of metformin’s protective effects, we performed a targeted transcriptomic analysis of primary CRC tissue samples (<i>n</i> = 272). A supervised learning algorithm pinpointed molecular features that discriminate between metformin-treated and diet-controlled diabetic CRC samples, as well as those that discriminated between non-diabetic samples based on their five-year overall survival status. Our results show downregulation of TMEM132 in metformin-treated samples (<i>p</i> = 0.05) and non-diabetics with good clinical outcomes (<i>p</i> = 0.05) relative to diet-controlled and non-diabetics with poor survival, respectively. Furthermore, upregulation of SCNN1A is observed in metformin-treated samples (<i>p</i> = 0.04) and non-diabetics with good clinical outcomes (<i>p</i> = 0.01) relative to diet-controlled samples and those with poor clinical outcomes, respectively. We also show that the antiapoptotic protein sFas is downregulated in metformin-treated samples relative to diet-controlled samples (<i>p</i> = 0.005). These findings suggest a role for the unfolded protein response in mediating metformin-related CRC-protective effects by enhancing apoptosis and suggest the investigation of these proteins as targets for novel CRC therapies. |
| format | Article |
| id | doaj-art-51bbeb68d5094564b2807751ed48a91b |
| institution | Kabale University |
| issn | 1198-0052 1718-7729 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | MDPI AG |
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| series | Current Oncology |
| spelling | doaj-art-51bbeb68d5094564b2807751ed48a91b2025-08-20T03:43:30ZengMDPI AGCurrent Oncology1198-00521718-77292025-02-0132313810.3390/curroncol32030138Downregulation of the Unfolded Protein Response Links Metformin Treatment to Good Clinical Outcomes in Colorectal Cancer PatientsMary L. Fay0Chris Nicol1Christine Orr2Brooke Wilson3David Hurlbut4Harriet Feilotter5Scott Davey6Division of Cancer Biology and Genetics, Sinclair Cancer Research Institute at Queen’s University, Kingston, ON K7L 3N6, CanadaDivision of Cancer Biology and Genetics, Sinclair Cancer Research Institute at Queen’s University, Kingston, ON K7L 3N6, CanadaDepartment of Pathology and Molecular Medicine, Queen’s University, Kingston, ON K7L 3N6, CanadaDepartment of Oncology, Queen’s University, Kingston, ON K7L 3N6, CanadaDepartment of Pathology and Molecular Medicine, Queen’s University, Kingston, ON K7L 3N6, CanadaDepartment of Pathology and Molecular Medicine, Queen’s University, Kingston, ON K7L 3N6, CanadaDivision of Cancer Biology and Genetics, Sinclair Cancer Research Institute at Queen’s University, Kingston, ON K7L 3N6, CanadaType 2 diabetes is a risk factor for colorectal cancer (CRC) development and progression. However, metformin-treated diabetic CRC patients tend to have better clinical outcomes than those managed by other means. To better characterize the molecular underpinnings of metformin’s protective effects, we performed a targeted transcriptomic analysis of primary CRC tissue samples (<i>n</i> = 272). A supervised learning algorithm pinpointed molecular features that discriminate between metformin-treated and diet-controlled diabetic CRC samples, as well as those that discriminated between non-diabetic samples based on their five-year overall survival status. Our results show downregulation of TMEM132 in metformin-treated samples (<i>p</i> = 0.05) and non-diabetics with good clinical outcomes (<i>p</i> = 0.05) relative to diet-controlled and non-diabetics with poor survival, respectively. Furthermore, upregulation of SCNN1A is observed in metformin-treated samples (<i>p</i> = 0.04) and non-diabetics with good clinical outcomes (<i>p</i> = 0.01) relative to diet-controlled samples and those with poor clinical outcomes, respectively. We also show that the antiapoptotic protein sFas is downregulated in metformin-treated samples relative to diet-controlled samples (<i>p</i> = 0.005). These findings suggest a role for the unfolded protein response in mediating metformin-related CRC-protective effects by enhancing apoptosis and suggest the investigation of these proteins as targets for novel CRC therapies.https://www.mdpi.com/1718-7729/32/3/138colorectal cancertype 2 diabetesmetforminunfolded protein response |
| spellingShingle | Mary L. Fay Chris Nicol Christine Orr Brooke Wilson David Hurlbut Harriet Feilotter Scott Davey Downregulation of the Unfolded Protein Response Links Metformin Treatment to Good Clinical Outcomes in Colorectal Cancer Patients Current Oncology colorectal cancer type 2 diabetes metformin unfolded protein response |
| title | Downregulation of the Unfolded Protein Response Links Metformin Treatment to Good Clinical Outcomes in Colorectal Cancer Patients |
| title_full | Downregulation of the Unfolded Protein Response Links Metformin Treatment to Good Clinical Outcomes in Colorectal Cancer Patients |
| title_fullStr | Downregulation of the Unfolded Protein Response Links Metformin Treatment to Good Clinical Outcomes in Colorectal Cancer Patients |
| title_full_unstemmed | Downregulation of the Unfolded Protein Response Links Metformin Treatment to Good Clinical Outcomes in Colorectal Cancer Patients |
| title_short | Downregulation of the Unfolded Protein Response Links Metformin Treatment to Good Clinical Outcomes in Colorectal Cancer Patients |
| title_sort | downregulation of the unfolded protein response links metformin treatment to good clinical outcomes in colorectal cancer patients |
| topic | colorectal cancer type 2 diabetes metformin unfolded protein response |
| url | https://www.mdpi.com/1718-7729/32/3/138 |
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