Pharmacological targeting of caspase-8/c-FLIPL heterodimer enhances complex II assembly and elimination of pancreatic cancer cells
Abstract Extrinsic apoptotic network is driven by Death Ligand (DL)-mediated activation of procaspase-8. Recently, we have developed the first-in class small molecule, FLIPinB, which specifically targets the key regulator of extrinsic apoptosis, the protein c-FLIPL, in the caspase-8/c-FLIPL heterodi...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-024-07409-6 |
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| author | Corinna König Nikita V. Ivanisenko Vladimir A. Ivanisenko Dagmar Kulms Inna N. Lavrik |
| author_facet | Corinna König Nikita V. Ivanisenko Vladimir A. Ivanisenko Dagmar Kulms Inna N. Lavrik |
| author_sort | Corinna König |
| collection | DOAJ |
| description | Abstract Extrinsic apoptotic network is driven by Death Ligand (DL)-mediated activation of procaspase-8. Recently, we have developed the first-in class small molecule, FLIPinB, which specifically targets the key regulator of extrinsic apoptosis, the protein c-FLIPL, in the caspase-8/c-FLIPL heterodimer. We have shown that FLIPinB enhances DL-induced caspase-8 activity and apoptosis. However, the effects of FLIPinB action in combination with other cell death inducers have only just begun to be elucidated. Here, we show that FLIPinB enhances the cell death in pancreatic cancer cells induced by combinatorial treatment with DL, gemcitabine and Mcl-1 inhibitor S63845. Further, we found that these effects are mediated via an increase in the complex II assembly. Collectively, our study shows that targeting the caspase-8/c-FLIPL heterodimer in combination with the other drugs in pancreatic cancer cells is a promising direction that may provide a basis for further therapeutic strategies. |
| format | Article |
| id | doaj-art-ce6ae12217eb4120a67cff51e4e7e3eb |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-ce6ae12217eb4120a67cff51e4e7e3eb2025-01-05T12:43:14ZengNature PortfolioCommunications Biology2399-36422025-01-018111810.1038/s42003-024-07409-6Pharmacological targeting of caspase-8/c-FLIPL heterodimer enhances complex II assembly and elimination of pancreatic cancer cellsCorinna König0Nikita V. Ivanisenko1Vladimir A. Ivanisenko2Dagmar Kulms3Inna N. Lavrik4Translational Inflammation Research, Medical Faculty, Otto von Guericke University (OvGU), MagdeburgTranslational Inflammation Research, Medical Faculty, Otto von Guericke University (OvGU), MagdeburgInstitute of Cytology and GeneticsExperimental Dermatology, Department of Dermatology, TU-DresdenTranslational Inflammation Research, Medical Faculty, Otto von Guericke University (OvGU), MagdeburgAbstract Extrinsic apoptotic network is driven by Death Ligand (DL)-mediated activation of procaspase-8. Recently, we have developed the first-in class small molecule, FLIPinB, which specifically targets the key regulator of extrinsic apoptosis, the protein c-FLIPL, in the caspase-8/c-FLIPL heterodimer. We have shown that FLIPinB enhances DL-induced caspase-8 activity and apoptosis. However, the effects of FLIPinB action in combination with other cell death inducers have only just begun to be elucidated. Here, we show that FLIPinB enhances the cell death in pancreatic cancer cells induced by combinatorial treatment with DL, gemcitabine and Mcl-1 inhibitor S63845. Further, we found that these effects are mediated via an increase in the complex II assembly. Collectively, our study shows that targeting the caspase-8/c-FLIPL heterodimer in combination with the other drugs in pancreatic cancer cells is a promising direction that may provide a basis for further therapeutic strategies.https://doi.org/10.1038/s42003-024-07409-6 |
| spellingShingle | Corinna König Nikita V. Ivanisenko Vladimir A. Ivanisenko Dagmar Kulms Inna N. Lavrik Pharmacological targeting of caspase-8/c-FLIPL heterodimer enhances complex II assembly and elimination of pancreatic cancer cells Communications Biology |
| title | Pharmacological targeting of caspase-8/c-FLIPL heterodimer enhances complex II assembly and elimination of pancreatic cancer cells |
| title_full | Pharmacological targeting of caspase-8/c-FLIPL heterodimer enhances complex II assembly and elimination of pancreatic cancer cells |
| title_fullStr | Pharmacological targeting of caspase-8/c-FLIPL heterodimer enhances complex II assembly and elimination of pancreatic cancer cells |
| title_full_unstemmed | Pharmacological targeting of caspase-8/c-FLIPL heterodimer enhances complex II assembly and elimination of pancreatic cancer cells |
| title_short | Pharmacological targeting of caspase-8/c-FLIPL heterodimer enhances complex II assembly and elimination of pancreatic cancer cells |
| title_sort | pharmacological targeting of caspase 8 c flipl heterodimer enhances complex ii assembly and elimination of pancreatic cancer cells |
| url | https://doi.org/10.1038/s42003-024-07409-6 |
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