Interleukin 24 Promotes Mitochondrial Dysfunction, Glucose Regulation, and Apoptosis by Inactivating Glycogen Synthase Kinase 3 Beta in Human Prostate Cancer Cells
Interleukin 24 (IL-24) is a tumor-suppressing protein currently in clinical trials. We previously demonstrated that IL-24 leads to apoptosis in cancer cells through protein kinase A (PKA) activation in human breast cancer cells. To better understand the mechanism by which IL-24 induces apoptosis, we...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-02-01
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| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/14/5/357 |
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| Summary: | Interleukin 24 (IL-24) is a tumor-suppressing protein currently in clinical trials. We previously demonstrated that IL-24 leads to apoptosis in cancer cells through protein kinase A (PKA) activation in human breast cancer cells. To better understand the mechanism by which IL-24 induces apoptosis, we analyzed the role of glycogen synthase kinase-3 beta (GSK3β), a highly conserved serine/threonine kinase in cancer cells and a downstream target of PKA. Our studies show for the first time that GSK3β is inhibited following IL-24 treatment in human prostate cancer cells. We showed that the inhibition of GSK3β is mediated through PKA activation triggered by IL-24. IL-24 decreases the phosphorylation of glycogen synthase, substantially activating glycogen synthase and decreasing intracellular glucose levels. Notably, the expression of a constitutively active form of GSK3β abolishes the effect of IL-24. These results demonstrate a previously unrecognized role of IL-24 in apoptosis mediated through GSK3β regulation and its possible implications for metabolic stress, mitochondria dysfunction, and apoptosis. Future studies should precisely delineate the most effective combinations of IL-24 as a GSK3β inhibitor with cytotoxic agents for prostate and other cancers. GSK3β inhibition disrupts average glucose utilization in cancer cells, potentially creating metabolic stress that could be exploited therapeutically. |
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| ISSN: | 2073-4409 |