PDE4DIP contributes to colorectal cancer growth and chemoresistance through modulation of the NF1/RAS signaling axis
Abstract Phosphodiesterase 4D interacting protein (PDE4DIP) is a centrosome/Golgi protein associated with cyclic nucleotide phosphodiesterases. PDE4DIP is commonly mutated in human cancers, and its alteration in mice leads to a predisposition to intestinal cancer. However, the biological function of...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-06-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05885-y |
| _version_ | 1797795456773783552 |
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| author | Rulu Pan Juji Dai Weicheng Liang Hongxiao Wang Lin Ye Siqi Ye Ziqi Lin Shishun Huang Yan Xiong Li Zhang Liting Lu Ouchen Wang Xian Shen Wanqin Liao Xincheng Lu |
| author_facet | Rulu Pan Juji Dai Weicheng Liang Hongxiao Wang Lin Ye Siqi Ye Ziqi Lin Shishun Huang Yan Xiong Li Zhang Liting Lu Ouchen Wang Xian Shen Wanqin Liao Xincheng Lu |
| author_sort | Rulu Pan |
| collection | DOAJ |
| description | Abstract Phosphodiesterase 4D interacting protein (PDE4DIP) is a centrosome/Golgi protein associated with cyclic nucleotide phosphodiesterases. PDE4DIP is commonly mutated in human cancers, and its alteration in mice leads to a predisposition to intestinal cancer. However, the biological function of PDE4DIP in human cancer remains obscure. Here, we report for the first time the oncogenic role of PDE4DIP in colorectal cancer (CRC) growth and adaptive MEK inhibitor (MEKi) resistance. We show that the expression of PDE4DIP is upregulated in CRC tissues and associated with the clinical characteristics and poor prognosis of CRC patients. Knockdown of PDE4DIP impairs the growth of KRAS-mutant CRC cells by inhibiting the core RAS signaling pathway. PDE4DIP plays an essential role in the full activation of oncogenic RAS/ERK signaling by suppressing the expression of the RAS GTPase-activating protein (RasGAP) neurofibromin (NF1). Mechanistically, PDE4DIP promotes the recruitment of PLCγ/PKCε to the Golgi apparatus, leading to constitutive activation of PKCε, which triggers the degradation of NF1. Upregulation of PDE4DIP results in adaptive MEKi resistance in KRAS-mutant CRC by reactivating the RAS/ERK pathway. Our work reveals a novel functional link between PDE4DIP and NF1/RAS signal transduction and suggests that targeting PDE4DIP is a promising therapeutic strategy for KRAS-mutant CRC. |
| first_indexed | 2024-03-13T03:18:13Z |
| format | Article |
| id | doaj.art-74f1109b36344deda1747e769804eea6 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-13T03:18:13Z |
| publishDate | 2023-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-74f1109b36344deda1747e769804eea62023-06-25T11:30:42ZengNature Publishing GroupCell Death and Disease2041-48892023-06-0114611310.1038/s41419-023-05885-yPDE4DIP contributes to colorectal cancer growth and chemoresistance through modulation of the NF1/RAS signaling axisRulu Pan0Juji Dai1Weicheng Liang2Hongxiao Wang3Lin Ye4Siqi Ye5Ziqi Lin6Shishun Huang7Yan Xiong8Li Zhang9Liting Lu10Ouchen Wang11Xian Shen12Wanqin Liao13Xincheng Lu14School of Basic Medical Sciences, Wenzhou Medical UniversityDepartment of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical UniversitySchool of Basic Medical Sciences, Wenzhou Medical UniversitySchool of Basic Medical Sciences, Wenzhou Medical UniversitySchool of Basic Medical Sciences, Wenzhou Medical UniversitySchool of Basic Medical Sciences, Wenzhou Medical UniversitySchool of Basic Medical Sciences, Wenzhou Medical UniversitySchool of Basic Medical Sciences, Wenzhou Medical UniversitySchool of Basic Medical Sciences, Wenzhou Medical UniversitySchool of Basic Medical Sciences, Wenzhou Medical UniversitySchool of Basic Medical Sciences, Wenzhou Medical UniversityDepartment of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of General Surgery, The First Affiliated Hospital of Wenzhou Medical UniversitySchool of Basic Medical Sciences, Wenzhou Medical UniversitySchool of Basic Medical Sciences, Wenzhou Medical UniversityAbstract Phosphodiesterase 4D interacting protein (PDE4DIP) is a centrosome/Golgi protein associated with cyclic nucleotide phosphodiesterases. PDE4DIP is commonly mutated in human cancers, and its alteration in mice leads to a predisposition to intestinal cancer. However, the biological function of PDE4DIP in human cancer remains obscure. Here, we report for the first time the oncogenic role of PDE4DIP in colorectal cancer (CRC) growth and adaptive MEK inhibitor (MEKi) resistance. We show that the expression of PDE4DIP is upregulated in CRC tissues and associated with the clinical characteristics and poor prognosis of CRC patients. Knockdown of PDE4DIP impairs the growth of KRAS-mutant CRC cells by inhibiting the core RAS signaling pathway. PDE4DIP plays an essential role in the full activation of oncogenic RAS/ERK signaling by suppressing the expression of the RAS GTPase-activating protein (RasGAP) neurofibromin (NF1). Mechanistically, PDE4DIP promotes the recruitment of PLCγ/PKCε to the Golgi apparatus, leading to constitutive activation of PKCε, which triggers the degradation of NF1. Upregulation of PDE4DIP results in adaptive MEKi resistance in KRAS-mutant CRC by reactivating the RAS/ERK pathway. Our work reveals a novel functional link between PDE4DIP and NF1/RAS signal transduction and suggests that targeting PDE4DIP is a promising therapeutic strategy for KRAS-mutant CRC.https://doi.org/10.1038/s41419-023-05885-y |
| spellingShingle | Rulu Pan Juji Dai Weicheng Liang Hongxiao Wang Lin Ye Siqi Ye Ziqi Lin Shishun Huang Yan Xiong Li Zhang Liting Lu Ouchen Wang Xian Shen Wanqin Liao Xincheng Lu PDE4DIP contributes to colorectal cancer growth and chemoresistance through modulation of the NF1/RAS signaling axis Cell Death and Disease |
| title | PDE4DIP contributes to colorectal cancer growth and chemoresistance through modulation of the NF1/RAS signaling axis |
| title_full | PDE4DIP contributes to colorectal cancer growth and chemoresistance through modulation of the NF1/RAS signaling axis |
| title_fullStr | PDE4DIP contributes to colorectal cancer growth and chemoresistance through modulation of the NF1/RAS signaling axis |
| title_full_unstemmed | PDE4DIP contributes to colorectal cancer growth and chemoresistance through modulation of the NF1/RAS signaling axis |
| title_short | PDE4DIP contributes to colorectal cancer growth and chemoresistance through modulation of the NF1/RAS signaling axis |
| title_sort | pde4dip contributes to colorectal cancer growth and chemoresistance through modulation of the nf1 ras signaling axis |
| url | https://doi.org/10.1038/s41419-023-05885-y |
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