Targeting Mcl-1 for Radiosensitization of Pancreatic Cancers
In order to identify targets whose inhibition may enhance the efficacy of chemoradiation in pancreatic cancer, we previously conducted an RNAi library screen of 8,800 genes. We identified Mcl-1 (myeloid cell leukemia-1), an anti-apoptotic member of the Bcl-2 family, as a target for sensitizing pancr...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2015-02-01
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| Series: | Translational Oncology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523314001387 |
| _version_ | 1818040209955094528 |
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| author | Dongping Wei Qiang Zhang Jason S. Schreiber Leslie A. Parsels Fardokht A. Abulwerdi Tasneem Kausar Theodore S. Lawrence Yi Sun Zaneta Nikolovska-Coleska Meredith A. Morgan |
| author_facet | Dongping Wei Qiang Zhang Jason S. Schreiber Leslie A. Parsels Fardokht A. Abulwerdi Tasneem Kausar Theodore S. Lawrence Yi Sun Zaneta Nikolovska-Coleska Meredith A. Morgan |
| author_sort | Dongping Wei |
| collection | DOAJ |
| description | In order to identify targets whose inhibition may enhance the efficacy of chemoradiation in pancreatic cancer, we previously conducted an RNAi library screen of 8,800 genes. We identified Mcl-1 (myeloid cell leukemia-1), an anti-apoptotic member of the Bcl-2 family, as a target for sensitizing pancreatic cancer cells to chemoradiation. In the present study we investigated Mcl-1 inhibition by either genetic or pharmacological approaches as a radiosensitizing strategy in pancreatic cancer cells. Mcl-1 depletion by siRNA produced significant radiosensitization in BxPC-3 and Panc-1 cells in association with Caspase-3 activation and PARP cleavage, but only minimal radiosensitization in MiaPaCa-2 cells. We next tested the ability of the recently identified, selective, small molecule inhibitor of Mcl-1, UMI77, to radiosensitize in pancreatic cancer cells. UMI77 caused dissociation of Mcl-1 from the pro-apoptotic protein Bak and produced significant radiosensitization in BxPC-3 and Panc-1 cells, but minimal radiosensitization in MiaPaCa-2 cells. Radiosensitization by UMI77 was associated with Caspase-3 activation and PARP cleavage. Importantly, UMI77 did not radiosensitize normal small intestinal cells. In contrast, ABT-737, an established inhibitor of Bcl-2, Bcl-XL, and Bcl-w, failed to radiosensitize pancreatic cancer cells suggesting the unique importance of Mcl-1 relative to other Bcl-2 family members to radiation survival in pancreatic cancer cells. Taken together, these results validate Mcl-1 as a target for radiosensitization of pancreatic cancer cells and demonstrate the ability of small molecules which bind the canonical BH3 groove of Mcl-1, causing displacement of Mcl-1 from Bak, to selectively radiosensitize pancreatic cancer cells. |
| first_indexed | 2024-12-10T08:10:54Z |
| format | Article |
| id | doaj.art-1288888f068744ae967ef7688a937d90 |
| institution | Directory Open Access Journal |
| issn | 1936-5233 1944-7124 |
| language | English |
| last_indexed | 2024-12-10T08:10:54Z |
| publishDate | 2015-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-1288888f068744ae967ef7688a937d902022-12-22T01:56:35ZengElsevierTranslational Oncology1936-52331944-71242015-02-0181475410.1016/j.tranon.2014.12.004Targeting Mcl-1 for Radiosensitization of Pancreatic CancersDongping Wei0Qiang Zhang1Jason S. Schreiber2Leslie A. Parsels3Fardokht A. Abulwerdi4Tasneem Kausar5Theodore S. Lawrence6Yi Sun7Zaneta Nikolovska-Coleska8Meredith A. Morgan9Department of Radiation Oncology, University of Michigan Medical SchoolDepartment of Radiation Oncology, University of Michigan Medical SchoolDepartment of Radiation Oncology, University of Michigan Medical SchoolDepartment of Pharmacology, University of Michigan Medical SchoolDepartment of Pathology, University of Michigan Medical SchoolDepartment of Radiation Oncology, University of Michigan Medical SchoolDepartment of Radiation Oncology, University of Michigan Medical SchoolDepartment of Radiation Oncology, University of Michigan Medical SchoolDepartment of Pathology, University of Michigan Medical SchoolDepartment of Radiation Oncology, University of Michigan Medical SchoolIn order to identify targets whose inhibition may enhance the efficacy of chemoradiation in pancreatic cancer, we previously conducted an RNAi library screen of 8,800 genes. We identified Mcl-1 (myeloid cell leukemia-1), an anti-apoptotic member of the Bcl-2 family, as a target for sensitizing pancreatic cancer cells to chemoradiation. In the present study we investigated Mcl-1 inhibition by either genetic or pharmacological approaches as a radiosensitizing strategy in pancreatic cancer cells. Mcl-1 depletion by siRNA produced significant radiosensitization in BxPC-3 and Panc-1 cells in association with Caspase-3 activation and PARP cleavage, but only minimal radiosensitization in MiaPaCa-2 cells. We next tested the ability of the recently identified, selective, small molecule inhibitor of Mcl-1, UMI77, to radiosensitize in pancreatic cancer cells. UMI77 caused dissociation of Mcl-1 from the pro-apoptotic protein Bak and produced significant radiosensitization in BxPC-3 and Panc-1 cells, but minimal radiosensitization in MiaPaCa-2 cells. Radiosensitization by UMI77 was associated with Caspase-3 activation and PARP cleavage. Importantly, UMI77 did not radiosensitize normal small intestinal cells. In contrast, ABT-737, an established inhibitor of Bcl-2, Bcl-XL, and Bcl-w, failed to radiosensitize pancreatic cancer cells suggesting the unique importance of Mcl-1 relative to other Bcl-2 family members to radiation survival in pancreatic cancer cells. Taken together, these results validate Mcl-1 as a target for radiosensitization of pancreatic cancer cells and demonstrate the ability of small molecules which bind the canonical BH3 groove of Mcl-1, causing displacement of Mcl-1 from Bak, to selectively radiosensitize pancreatic cancer cells.http://www.sciencedirect.com/science/article/pii/S1936523314001387 |
| spellingShingle | Dongping Wei Qiang Zhang Jason S. Schreiber Leslie A. Parsels Fardokht A. Abulwerdi Tasneem Kausar Theodore S. Lawrence Yi Sun Zaneta Nikolovska-Coleska Meredith A. Morgan Targeting Mcl-1 for Radiosensitization of Pancreatic Cancers Translational Oncology |
| title | Targeting Mcl-1 for Radiosensitization of Pancreatic Cancers |
| title_full | Targeting Mcl-1 for Radiosensitization of Pancreatic Cancers |
| title_fullStr | Targeting Mcl-1 for Radiosensitization of Pancreatic Cancers |
| title_full_unstemmed | Targeting Mcl-1 for Radiosensitization of Pancreatic Cancers |
| title_short | Targeting Mcl-1 for Radiosensitization of Pancreatic Cancers |
| title_sort | targeting mcl 1 for radiosensitization of pancreatic cancers |
| url | http://www.sciencedirect.com/science/article/pii/S1936523314001387 |
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