Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis
Abstract Sphingolipid, ceramide for example, plays an essential role in regulating cancer cell death. Defects in the generation and metabolism of ceramide in cancer cells contribute to tumor cell survival and resistance to chemotherapy. Ceramide Transfer Protein (CERT) determines the ratio of cerami...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56520-7 |
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| _version_ | 1823861809453465600 |
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| author | Xiaofan Sun Yue Li Juan Du Fangshu Liu Caiping Wu Weihao Xiao Guopan Yu Xiaowei Chen Robert Peter Gale Hui Zeng |
| author_facet | Xiaofan Sun Yue Li Juan Du Fangshu Liu Caiping Wu Weihao Xiao Guopan Yu Xiaowei Chen Robert Peter Gale Hui Zeng |
| author_sort | Xiaofan Sun |
| collection | DOAJ |
| description | Abstract Sphingolipid, ceramide for example, plays an essential role in regulating cancer cell death. Defects in the generation and metabolism of ceramide in cancer cells contribute to tumor cell survival and resistance to chemotherapy. Ceramide Transfer Protein (CERT) determines the ratio of ceramide and sphingomyelin in cells. Targeting CERT sensitizes solid cancer cells to chemotherapy. However, whether targeting CERT to induce ceramide accumulation thereby improving AML therapy efficiency remains elusive. Here, we show that knocking down CERT inhibits the growth and promotes the apoptosis of AML cells carrying FLT3-ITD mutation. Combining CERT inhibitor with FLT3 inhibitor exhibits synergistic effects on FLT3-ITD mutated acute myeloid leukemia (AML) cells. Additionally, co-treatment of HPA-12 and Crenolanib is effective in FLT3-ITD+ and FLT3-TKD+ AML patients. The synergistic effects are found to be mediated by the endoplasmic reticulum stress-GRP78/ATF6/CHOP axis and mitophagy. Our data provide an effective strategy to enhance the efficacy of FLT3 inhibitors in AML. |
| format | Article |
| id | doaj-art-64e32fc370bc4de29a1f2fe1e21172f6 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-64e32fc370bc4de29a1f2fe1e21172f62025-02-09T12:46:22ZengNature PortfolioNature Communications2041-17232025-02-0116111710.1038/s41467-025-56520-7Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axisXiaofan Sun0Yue Li1Juan Du2Fangshu Liu3Caiping Wu4Weihao Xiao5Guopan Yu6Xiaowei Chen7Robert Peter Gale8Hui Zeng9Department of Hematology, The First Affiliated Hospital, Jinan UniversityDepartment of Hematology, The First Affiliated Hospital, Jinan UniversityDepartment of Hematology, The First Affiliated Hospital, Jinan UniversityDepartment of Hematology, The First Affiliated Hospital, Jinan UniversityDepartment of Hematology, The First Affiliated Hospital, Jinan UniversityDepartment of Hematology, The First Affiliated Hospital, Jinan UniversityDepartment of Hematology, Nanfang Hospital, Southern Medical UniversityDepartment of Hematology, Guangzhou First People’s Hospital, Institute of Blood Transfusion and Hematology, Guangzhou Medical UniversityCentre for Haematology, Department of Immunology and Inflammation, Imperial College of Science, Technology and MedicineDepartment of Hematology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical UniversityAbstract Sphingolipid, ceramide for example, plays an essential role in regulating cancer cell death. Defects in the generation and metabolism of ceramide in cancer cells contribute to tumor cell survival and resistance to chemotherapy. Ceramide Transfer Protein (CERT) determines the ratio of ceramide and sphingomyelin in cells. Targeting CERT sensitizes solid cancer cells to chemotherapy. However, whether targeting CERT to induce ceramide accumulation thereby improving AML therapy efficiency remains elusive. Here, we show that knocking down CERT inhibits the growth and promotes the apoptosis of AML cells carrying FLT3-ITD mutation. Combining CERT inhibitor with FLT3 inhibitor exhibits synergistic effects on FLT3-ITD mutated acute myeloid leukemia (AML) cells. Additionally, co-treatment of HPA-12 and Crenolanib is effective in FLT3-ITD+ and FLT3-TKD+ AML patients. The synergistic effects are found to be mediated by the endoplasmic reticulum stress-GRP78/ATF6/CHOP axis and mitophagy. Our data provide an effective strategy to enhance the efficacy of FLT3 inhibitors in AML.https://doi.org/10.1038/s41467-025-56520-7 |
| spellingShingle | Xiaofan Sun Yue Li Juan Du Fangshu Liu Caiping Wu Weihao Xiao Guopan Yu Xiaowei Chen Robert Peter Gale Hui Zeng Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis Nature Communications |
| title | Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis |
| title_full | Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis |
| title_fullStr | Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis |
| title_full_unstemmed | Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis |
| title_short | Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis |
| title_sort | targeting ceramide transfer protein sensitizes aml to flt3 inhibitors via a grp78 atf6 chop axis |
| url | https://doi.org/10.1038/s41467-025-56520-7 |
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