GSK-3 and BCL-XL inhibition mitigates the competitive advantage of APC-mutant colorectal cancer cells
Abstract BCL-XL is a crucial anti-apoptotic protein that supports survival of intestinal cells during the progression and in established colorectal cancer (CRC). While targeting BCL-XL with BH3 mimetics is effective, its significant toxicity highlights the need for alternative approaches. Importantl...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-07-01
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| Series: | Oncogenesis |
| Online Access: | https://doi.org/10.1038/s41389-025-00569-y |
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| author | Le Zhang Lidia Atencia Taboada Selami Baglamis Maartje de Kroon Carolien Elshout Prashanthi Ramesh Roxan F.C.P.A Helderman Arezo Torang Kate Cameron Milou S. van Driel Valérie M. Wouters Sanne M. van Neerven Jan Paul Medema |
| author_facet | Le Zhang Lidia Atencia Taboada Selami Baglamis Maartje de Kroon Carolien Elshout Prashanthi Ramesh Roxan F.C.P.A Helderman Arezo Torang Kate Cameron Milou S. van Driel Valérie M. Wouters Sanne M. van Neerven Jan Paul Medema |
| author_sort | Le Zhang |
| collection | DOAJ |
| description | Abstract BCL-XL is a crucial anti-apoptotic protein that supports survival of intestinal cells during the progression and in established colorectal cancer (CRC). While targeting BCL-XL with BH3 mimetics is effective, its significant toxicity highlights the need for alternative approaches. Importantly, the early steps in intestinal transformation are marked by a competition between normal and transformed stem cells in which the mutant cells gain a supercompetitive advantage due to the secretion of WNT inhibitors. Using multiple human and murine CRC models, we revealed that GSK-3 inhibition strongly sensitized to BH3 mimetic-induced killing. As expected, GSK-3 inhibition significantly upregulated the WNT pathway, but also led to marked enhancement of BH3 mimetic-induced apoptosis, as measured by mitochondrial BAX aggregation, Caspase-3 activation and Propidium Iodide exclusion. Furthermore, GSK-3 inhibition provided an advantage to wild-type intestinal organoids in competition with APC-mutant counterparts due to reactivation of the WNT pathway. More strikingly, combining GSK-3 and BCL-XL inhibition profoundly affected the supercompetition APC-mutant intestinal cells exert over the wild-types. In effect, the combination therapy enhanced the competitive fitness of wild-type cells and resulted in the killing of APC-mutant organoids, pointing to a novel combination therapy that can be further exploited in the treatment of adenomas and CRC. |
| format | Article |
| id | doaj-art-676ef2529b3a466682c71faff8eb2dd9 |
| institution | Kabale University |
| issn | 2157-9024 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Oncogenesis |
| spelling | doaj-art-676ef2529b3a466682c71faff8eb2dd92025-08-20T03:43:30ZengNature Publishing GroupOncogenesis2157-90242025-07-011411810.1038/s41389-025-00569-yGSK-3 and BCL-XL inhibition mitigates the competitive advantage of APC-mutant colorectal cancer cellsLe Zhang0Lidia Atencia Taboada1Selami Baglamis2Maartje de Kroon3Carolien Elshout4Prashanthi Ramesh5Roxan F.C.P.A Helderman6Arezo Torang7Kate Cameron8Milou S. van Driel9Valérie M. Wouters10Sanne M. van Neerven11Jan Paul Medema12LEXOR, Center of Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamLEXOR, Center of Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamLEXOR, Center of Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamLEXOR, Center of Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamLEXOR, Center of Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamLEXOR, Center of Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamLEXOR, Center of Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamLEXOR, Center of Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamLEXOR, Center of Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamLEXOR, Center of Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamLEXOR, Center of Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamLEXOR, Center of Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamLEXOR, Center of Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamAbstract BCL-XL is a crucial anti-apoptotic protein that supports survival of intestinal cells during the progression and in established colorectal cancer (CRC). While targeting BCL-XL with BH3 mimetics is effective, its significant toxicity highlights the need for alternative approaches. Importantly, the early steps in intestinal transformation are marked by a competition between normal and transformed stem cells in which the mutant cells gain a supercompetitive advantage due to the secretion of WNT inhibitors. Using multiple human and murine CRC models, we revealed that GSK-3 inhibition strongly sensitized to BH3 mimetic-induced killing. As expected, GSK-3 inhibition significantly upregulated the WNT pathway, but also led to marked enhancement of BH3 mimetic-induced apoptosis, as measured by mitochondrial BAX aggregation, Caspase-3 activation and Propidium Iodide exclusion. Furthermore, GSK-3 inhibition provided an advantage to wild-type intestinal organoids in competition with APC-mutant counterparts due to reactivation of the WNT pathway. More strikingly, combining GSK-3 and BCL-XL inhibition profoundly affected the supercompetition APC-mutant intestinal cells exert over the wild-types. In effect, the combination therapy enhanced the competitive fitness of wild-type cells and resulted in the killing of APC-mutant organoids, pointing to a novel combination therapy that can be further exploited in the treatment of adenomas and CRC.https://doi.org/10.1038/s41389-025-00569-y |
| spellingShingle | Le Zhang Lidia Atencia Taboada Selami Baglamis Maartje de Kroon Carolien Elshout Prashanthi Ramesh Roxan F.C.P.A Helderman Arezo Torang Kate Cameron Milou S. van Driel Valérie M. Wouters Sanne M. van Neerven Jan Paul Medema GSK-3 and BCL-XL inhibition mitigates the competitive advantage of APC-mutant colorectal cancer cells Oncogenesis |
| title | GSK-3 and BCL-XL inhibition mitigates the competitive advantage of APC-mutant colorectal cancer cells |
| title_full | GSK-3 and BCL-XL inhibition mitigates the competitive advantage of APC-mutant colorectal cancer cells |
| title_fullStr | GSK-3 and BCL-XL inhibition mitigates the competitive advantage of APC-mutant colorectal cancer cells |
| title_full_unstemmed | GSK-3 and BCL-XL inhibition mitigates the competitive advantage of APC-mutant colorectal cancer cells |
| title_short | GSK-3 and BCL-XL inhibition mitigates the competitive advantage of APC-mutant colorectal cancer cells |
| title_sort | gsk 3 and bcl xl inhibition mitigates the competitive advantage of apc mutant colorectal cancer cells |
| url | https://doi.org/10.1038/s41389-025-00569-y |
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