MELK promotes HCC carcinogenesis through modulating cuproptosis-related gene DLAT-mediated mitochondrial function
Abstract Cuproptosis caused by copper overload is mediated by a novel regulatory mechanism that differs from previously documented mechanisms regulating cell death. Cells dependent on mitochondrial respiration showed increased sensitivity to a copper ionophore elesclomol that induced cuproptosis. Ma...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-11-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06264-3 |
| _version_ | 1797376756166950912 |
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| author | Zhipeng Li Huaxin Zhou Xiangyu Zhai Lin Gao Mengfan Yang Baokun An Tong Xia Gang Du Xiaoming Li Wei Wang Bin Jin |
| author_facet | Zhipeng Li Huaxin Zhou Xiangyu Zhai Lin Gao Mengfan Yang Baokun An Tong Xia Gang Du Xiaoming Li Wei Wang Bin Jin |
| author_sort | Zhipeng Li |
| collection | DOAJ |
| description | Abstract Cuproptosis caused by copper overload is mediated by a novel regulatory mechanism that differs from previously documented mechanisms regulating cell death. Cells dependent on mitochondrial respiration showed increased sensitivity to a copper ionophore elesclomol that induced cuproptosis. Maternal embryonic leucine zipper kinase(MELK) promotes tumorigenesis and tumor progression through the PI3K/mTOR pathway, which exerts its effects partly by targeting the pyruvate dehydrogenase complex(PDHc) and reprogramming the morphology and function of mitochondria. However, the role of MELK in cuproptosis remains unclear. Here, we validated that elevated MELK expression enhanced the activity of PI3K/mTOR signaling and subsequently promoted Dihydrolipoamide S-Acetyltransferase (DLAT) expression and stabilized mitochondrial function. This regulatory effect helped to improve mitochondrial respiration, eliminate excessive intracellular reactive oxygen species (ROS), reduce intracellular oxidative stress/damage and the possibility of mitochondria-induced cell fate alternations, and ultimately promote the progression of HCC. Meanwhile, elesclomol reduced translocase of outer mitochondrial membrane 20(TOM 20) expression and increased DLAT oligomers. Moreover, the above changes of MELK to HCC were abolished by elesclomol. In conclusion, MELK enhanced the levels of the cuproptosis-related signature(CRS) gene DLAT (especially the proportion of DLAT monomer) by activating the PI3K/mTOR pathway, thereby promoting elesclomol drug resistance, altering mitochondrial function, and ultimately promoting HCC progression. |
| first_indexed | 2024-03-08T19:43:18Z |
| format | Article |
| id | doaj.art-44404c6e97634d8fa4bf210b3ae652de |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-08T19:43:18Z |
| publishDate | 2023-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-44404c6e97634d8fa4bf210b3ae652de2023-12-24T12:30:43ZengNature Publishing GroupCell Death and Disease2041-48892023-11-01141111210.1038/s41419-023-06264-3MELK promotes HCC carcinogenesis through modulating cuproptosis-related gene DLAT-mediated mitochondrial functionZhipeng Li0Huaxin Zhou1Xiangyu Zhai2Lin Gao3Mengfan Yang4Baokun An5Tong Xia6Gang Du7Xiaoming Li8Wei Wang9Bin Jin10Department of Hepatobiliary Surgery, The Second Hospital of Shandong UniversityDepartment of Hepatobiliary Surgery, The Second Hospital of Shandong UniversityDepartment of Hepatobiliary Surgery, The Second Hospital of Shandong UniversityDepartment of Hepatobiliary Surgery, The Second Hospital of Shandong UniversityOrgan Transplant Department, Qilu Hospital of Shandong UniversityDepartment of Hepatobiliary Surgery, The Second Hospital of Shandong UniversityOrgan Transplant Department, Qilu Hospital of Shandong UniversityOrgan Transplant Department, Qilu Hospital of Shandong UniversityDepartment of Hepatobiliary Surgery, The Second Hospital of Shandong UniversityMedical integration and practice center of Shandong UniversityDepartment of Hepatobiliary Surgery, The Second Hospital of Shandong UniversityAbstract Cuproptosis caused by copper overload is mediated by a novel regulatory mechanism that differs from previously documented mechanisms regulating cell death. Cells dependent on mitochondrial respiration showed increased sensitivity to a copper ionophore elesclomol that induced cuproptosis. Maternal embryonic leucine zipper kinase(MELK) promotes tumorigenesis and tumor progression through the PI3K/mTOR pathway, which exerts its effects partly by targeting the pyruvate dehydrogenase complex(PDHc) and reprogramming the morphology and function of mitochondria. However, the role of MELK in cuproptosis remains unclear. Here, we validated that elevated MELK expression enhanced the activity of PI3K/mTOR signaling and subsequently promoted Dihydrolipoamide S-Acetyltransferase (DLAT) expression and stabilized mitochondrial function. This regulatory effect helped to improve mitochondrial respiration, eliminate excessive intracellular reactive oxygen species (ROS), reduce intracellular oxidative stress/damage and the possibility of mitochondria-induced cell fate alternations, and ultimately promote the progression of HCC. Meanwhile, elesclomol reduced translocase of outer mitochondrial membrane 20(TOM 20) expression and increased DLAT oligomers. Moreover, the above changes of MELK to HCC were abolished by elesclomol. In conclusion, MELK enhanced the levels of the cuproptosis-related signature(CRS) gene DLAT (especially the proportion of DLAT monomer) by activating the PI3K/mTOR pathway, thereby promoting elesclomol drug resistance, altering mitochondrial function, and ultimately promoting HCC progression.https://doi.org/10.1038/s41419-023-06264-3 |
| spellingShingle | Zhipeng Li Huaxin Zhou Xiangyu Zhai Lin Gao Mengfan Yang Baokun An Tong Xia Gang Du Xiaoming Li Wei Wang Bin Jin MELK promotes HCC carcinogenesis through modulating cuproptosis-related gene DLAT-mediated mitochondrial function Cell Death and Disease |
| title | MELK promotes HCC carcinogenesis through modulating cuproptosis-related gene DLAT-mediated mitochondrial function |
| title_full | MELK promotes HCC carcinogenesis through modulating cuproptosis-related gene DLAT-mediated mitochondrial function |
| title_fullStr | MELK promotes HCC carcinogenesis through modulating cuproptosis-related gene DLAT-mediated mitochondrial function |
| title_full_unstemmed | MELK promotes HCC carcinogenesis through modulating cuproptosis-related gene DLAT-mediated mitochondrial function |
| title_short | MELK promotes HCC carcinogenesis through modulating cuproptosis-related gene DLAT-mediated mitochondrial function |
| title_sort | melk promotes hcc carcinogenesis through modulating cuproptosis related gene dlat mediated mitochondrial function |
| url | https://doi.org/10.1038/s41419-023-06264-3 |
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