Inhibition of GPR68 induces ferroptosis and radiosensitivity in diverse cancer cell types
Abstract Radioresistance is thought to be a major consequence of tumor milieu acidification resulting from the Warburg effect. Previously, using ogremorphin (OGM), a small molecule inhibitor of GPR68, an extracellular proton sensing receptor, we demonstrated that GPR68 is a key pro-survival pathway...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-02-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-88357-x |
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| author | Leif R. Neitzel Daniela T. Fuller Jessica Cornell Samantha Rea Carolina de Aguiar Ferreira Charles H. Williams Charles C. Hong |
| author_facet | Leif R. Neitzel Daniela T. Fuller Jessica Cornell Samantha Rea Carolina de Aguiar Ferreira Charles H. Williams Charles C. Hong |
| author_sort | Leif R. Neitzel |
| collection | DOAJ |
| description | Abstract Radioresistance is thought to be a major consequence of tumor milieu acidification resulting from the Warburg effect. Previously, using ogremorphin (OGM), a small molecule inhibitor of GPR68, an extracellular proton sensing receptor, we demonstrated that GPR68 is a key pro-survival pathway in glioblastoma cells. Here, we demonstrate that GPR68 inhibition also induces ferroptosis in lung cell carcinoma (A549) and pancreatic ductal adenocarcinoma (Panc02) cells. Moreover, OGM synergized with ionizing radiation to induce lipid peroxidation, a hallmark of ferroptosis, as well as reduce colony size in 2D and 3D cell culture. GPR68 inhibition is not acutely detrimental but increases intracellular free ferrous iron, which is known to trigger reactive oxygen species (ROS) generation. In summary, GPR68 inhibition induces lipid peroxidation in cancer cells and sensitizes them to ionizing radiation in part through the mobilization of intracellular free ferrous iron. Our results suggest that GPR68 is a key mediator of cancer cell radioresistance activated by acidic tumor microenvironment. |
| format | Article |
| id | doaj-art-3ad00e07938a43e7af91aaefe1d547a5 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-3ad00e07938a43e7af91aaefe1d547a52025-02-09T12:30:46ZengNature PortfolioScientific Reports2045-23222025-02-0115111410.1038/s41598-025-88357-xInhibition of GPR68 induces ferroptosis and radiosensitivity in diverse cancer cell typesLeif R. Neitzel0Daniela T. Fuller1Jessica Cornell2Samantha Rea3Carolina de Aguiar Ferreira4Charles H. Williams5Charles C. Hong6Department of Medicine, Michigan State University College of Human MedicineDepartment of Medicine, University of Maryland School of MedicineDepartment of Medicine, University of Maryland School of MedicineDepartment of Medicine, University of Maryland School of MedicineThe Institute for Quantitative Health Science & Engineering, Michigan State UniversityDepartment of Medicine, Michigan State University College of Human MedicineDepartment of Medicine, Michigan State University College of Human MedicineAbstract Radioresistance is thought to be a major consequence of tumor milieu acidification resulting from the Warburg effect. Previously, using ogremorphin (OGM), a small molecule inhibitor of GPR68, an extracellular proton sensing receptor, we demonstrated that GPR68 is a key pro-survival pathway in glioblastoma cells. Here, we demonstrate that GPR68 inhibition also induces ferroptosis in lung cell carcinoma (A549) and pancreatic ductal adenocarcinoma (Panc02) cells. Moreover, OGM synergized with ionizing radiation to induce lipid peroxidation, a hallmark of ferroptosis, as well as reduce colony size in 2D and 3D cell culture. GPR68 inhibition is not acutely detrimental but increases intracellular free ferrous iron, which is known to trigger reactive oxygen species (ROS) generation. In summary, GPR68 inhibition induces lipid peroxidation in cancer cells and sensitizes them to ionizing radiation in part through the mobilization of intracellular free ferrous iron. Our results suggest that GPR68 is a key mediator of cancer cell radioresistance activated by acidic tumor microenvironment.https://doi.org/10.1038/s41598-025-88357-x |
| spellingShingle | Leif R. Neitzel Daniela T. Fuller Jessica Cornell Samantha Rea Carolina de Aguiar Ferreira Charles H. Williams Charles C. Hong Inhibition of GPR68 induces ferroptosis and radiosensitivity in diverse cancer cell types Scientific Reports |
| title | Inhibition of GPR68 induces ferroptosis and radiosensitivity in diverse cancer cell types |
| title_full | Inhibition of GPR68 induces ferroptosis and radiosensitivity in diverse cancer cell types |
| title_fullStr | Inhibition of GPR68 induces ferroptosis and radiosensitivity in diverse cancer cell types |
| title_full_unstemmed | Inhibition of GPR68 induces ferroptosis and radiosensitivity in diverse cancer cell types |
| title_short | Inhibition of GPR68 induces ferroptosis and radiosensitivity in diverse cancer cell types |
| title_sort | inhibition of gpr68 induces ferroptosis and radiosensitivity in diverse cancer cell types |
| url | https://doi.org/10.1038/s41598-025-88357-x |
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