Combination of bazedoxifene with chemotherapy and SMAC-mimetics for the treatment of colorectal cancer
Abstract Excessive STAT3 signalling via gp130, the shared receptor subunit for IL-6 and IL-11, contributes to disease progression and poor survival outcomes in patients with colorectal cancer. Here, we provide evidence that bazedoxifene inhibits tumour growth via direct interaction with the gp130 re...
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| Format: | Article |
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Nature Publishing Group
2024-04-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-06631-8 |
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| author | Rhynelle S. Dmello Michelle Palmieri Pathum S. Thilakasiri Larissa Doughty Tracy L. Nero Ashleigh R. Poh Sarah Q. To Erinna F. Lee W. Douglas Fairlie Lisa Mielke Michael W. Parker Ivan K. H. Poon Eduard Batlle Matthias Ernst Ashwini L. Chand |
| author_facet | Rhynelle S. Dmello Michelle Palmieri Pathum S. Thilakasiri Larissa Doughty Tracy L. Nero Ashleigh R. Poh Sarah Q. To Erinna F. Lee W. Douglas Fairlie Lisa Mielke Michael W. Parker Ivan K. H. Poon Eduard Batlle Matthias Ernst Ashwini L. Chand |
| author_sort | Rhynelle S. Dmello |
| collection | DOAJ |
| description | Abstract Excessive STAT3 signalling via gp130, the shared receptor subunit for IL-6 and IL-11, contributes to disease progression and poor survival outcomes in patients with colorectal cancer. Here, we provide evidence that bazedoxifene inhibits tumour growth via direct interaction with the gp130 receptor to suppress IL-6 and IL-11-mediated STAT3 signalling. Additionally, bazedoxifene combined with chemotherapy synergistically reduced cell proliferation and induced apoptosis in patient-derived colon cancer organoids. We elucidated that the primary mechanism of anti-tumour activity conferred by bazedoxifene treatment occurs via pro-apoptotic responses in tumour cells. Co-treatment with bazedoxifene and the SMAC-mimetics, LCL161 or Birinapant, that target the IAP family of proteins, demonstrated increased apoptosis and reduced proliferation in colorectal cancer cells. Our findings provide evidence that bazedoxifene treatment could be combined with SMAC-mimetics and chemotherapy to enhance tumour cell apoptosis in colorectal cancer, where gp130 receptor signalling promotes tumour growth and progression. |
| format | Article |
| id | doaj-art-edd38efeaa4746be83b35dd07210b0bf |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2024-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-edd38efeaa4746be83b35dd07210b0bf2025-08-20T02:25:12ZengNature Publishing GroupCell Death and Disease2041-48892024-04-0115411310.1038/s41419-024-06631-8Combination of bazedoxifene with chemotherapy and SMAC-mimetics for the treatment of colorectal cancerRhynelle S. Dmello0Michelle Palmieri1Pathum S. Thilakasiri2Larissa Doughty3Tracy L. Nero4Ashleigh R. Poh5Sarah Q. To6Erinna F. Lee7W. Douglas Fairlie8Lisa Mielke9Michael W. Parker10Ivan K. H. Poon11Eduard Batlle12Matthias Ernst13Ashwini L. Chand14Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe UniversityWalter and Eliza Hall Institute of Medical Research (WEHI)Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe UniversityDepartment of Biochemistry and Pharmacology, and ACRF Facility for Innovative Cancer Drug Discovery, Bio21 Molecular Science and Biotechnology Institute, The University of MelbourneDepartment of Biochemistry and Pharmacology, and ACRF Facility for Innovative Cancer Drug Discovery, Bio21 Molecular Science and Biotechnology Institute, The University of MelbourneOlivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe UniversityOlivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe UniversityOlivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe UniversityOlivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe UniversityOlivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe UniversityDepartment of Biochemistry and Pharmacology, and ACRF Facility for Innovative Cancer Drug Discovery, Bio21 Molecular Science and Biotechnology Institute, The University of MelbourneDepartment of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe UniversityInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST)Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe UniversityOlivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe UniversityAbstract Excessive STAT3 signalling via gp130, the shared receptor subunit for IL-6 and IL-11, contributes to disease progression and poor survival outcomes in patients with colorectal cancer. Here, we provide evidence that bazedoxifene inhibits tumour growth via direct interaction with the gp130 receptor to suppress IL-6 and IL-11-mediated STAT3 signalling. Additionally, bazedoxifene combined with chemotherapy synergistically reduced cell proliferation and induced apoptosis in patient-derived colon cancer organoids. We elucidated that the primary mechanism of anti-tumour activity conferred by bazedoxifene treatment occurs via pro-apoptotic responses in tumour cells. Co-treatment with bazedoxifene and the SMAC-mimetics, LCL161 or Birinapant, that target the IAP family of proteins, demonstrated increased apoptosis and reduced proliferation in colorectal cancer cells. Our findings provide evidence that bazedoxifene treatment could be combined with SMAC-mimetics and chemotherapy to enhance tumour cell apoptosis in colorectal cancer, where gp130 receptor signalling promotes tumour growth and progression.https://doi.org/10.1038/s41419-024-06631-8 |
| spellingShingle | Rhynelle S. Dmello Michelle Palmieri Pathum S. Thilakasiri Larissa Doughty Tracy L. Nero Ashleigh R. Poh Sarah Q. To Erinna F. Lee W. Douglas Fairlie Lisa Mielke Michael W. Parker Ivan K. H. Poon Eduard Batlle Matthias Ernst Ashwini L. Chand Combination of bazedoxifene with chemotherapy and SMAC-mimetics for the treatment of colorectal cancer Cell Death and Disease |
| title | Combination of bazedoxifene with chemotherapy and SMAC-mimetics for the treatment of colorectal cancer |
| title_full | Combination of bazedoxifene with chemotherapy and SMAC-mimetics for the treatment of colorectal cancer |
| title_fullStr | Combination of bazedoxifene with chemotherapy and SMAC-mimetics for the treatment of colorectal cancer |
| title_full_unstemmed | Combination of bazedoxifene with chemotherapy and SMAC-mimetics for the treatment of colorectal cancer |
| title_short | Combination of bazedoxifene with chemotherapy and SMAC-mimetics for the treatment of colorectal cancer |
| title_sort | combination of bazedoxifene with chemotherapy and smac mimetics for the treatment of colorectal cancer |
| url | https://doi.org/10.1038/s41419-024-06631-8 |
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