Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation
Abstract Liver metastasis is the major reason for most of colorectal cancer (CRC) related deaths. Accumulating evidence indicates that CRC patients with non-alcoholic fatty liver disease (NAFLD) are at a greater risk of developing liver metastasis. With the growing prevalence of NAFLD, a better unde...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-01-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01770-x |
| _version_ | 1797340315609202688 |
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| author | Chi Zhang Yue Zhang Yan Dong Ruiyang Zi Yijie Wang Yanrong Chen Chengxiang Liu Junyi Wang Xuesong Wang Jianjun Li Houjie Liang Juanjuan Ou |
| author_facet | Chi Zhang Yue Zhang Yan Dong Ruiyang Zi Yijie Wang Yanrong Chen Chengxiang Liu Junyi Wang Xuesong Wang Jianjun Li Houjie Liang Juanjuan Ou |
| author_sort | Chi Zhang |
| collection | DOAJ |
| description | Abstract Liver metastasis is the major reason for most of colorectal cancer (CRC) related deaths. Accumulating evidence indicates that CRC patients with non-alcoholic fatty liver disease (NAFLD) are at a greater risk of developing liver metastasis. With the growing prevalence of NAFLD, a better understanding of the molecular mechanism in NAFLD-driven CRC liver metastasis is needed. In this study, we demonstrated that NAFLD facilitated CRC liver metastasis as a metabolic disorder and promoted the stemness of metastatic CRC cells for their colonization and outgrowth in hepatic niches. Metabolically, the lipid-rich microenvironment in NAFLD activated de novo palmitate biosynthesis in metastatic CRC cells via upregulating fatty acid synthase (FASN). Moreover, increased intracellular palmitate bioavailability promoted EGFR palmitoylation to enhance its protein stability and plasma membrane localization. Furthermore, we demonstrated that the FDA-approved FASN inhibitor orlistat could reduce NAFLD-activated endogenous palmitate production, thus inhibiting palmitoylation of EGFR to suppress CRC cell stemness and restrict liver metastasis in synergy with conventional chemotherapy. These findings reveal that the NAFLD metabolic microenvironment boosts endogenous palmitate biosynthesis in metastatic CRC cells and promotes cell stemness via EGFR palmitoylation, and FASN inhibitor orlistat could be a candidate adjuvant drug to suppress liver metastasis in CRC patients with NAFLD. |
| first_indexed | 2024-03-08T10:01:15Z |
| format | Article |
| id | doaj.art-e06053e593ab4976a59c3eda28e6822d |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-03-08T10:01:15Z |
| publishDate | 2024-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-e06053e593ab4976a59c3eda28e6822d2024-01-29T10:58:02ZengNature Publishing GroupCell Death Discovery2058-77162024-01-0110111510.1038/s41420-023-01770-xNon-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylationChi Zhang0Yue Zhang1Yan Dong2Ruiyang Zi3Yijie Wang4Yanrong Chen5Chengxiang Liu6Junyi Wang7Xuesong Wang8Jianjun Li9Houjie Liang10Juanjuan Ou11Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University)Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University)Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University)Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University)Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University)Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University)Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University)Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University)Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University)Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University)Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University)Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University)Abstract Liver metastasis is the major reason for most of colorectal cancer (CRC) related deaths. Accumulating evidence indicates that CRC patients with non-alcoholic fatty liver disease (NAFLD) are at a greater risk of developing liver metastasis. With the growing prevalence of NAFLD, a better understanding of the molecular mechanism in NAFLD-driven CRC liver metastasis is needed. In this study, we demonstrated that NAFLD facilitated CRC liver metastasis as a metabolic disorder and promoted the stemness of metastatic CRC cells for their colonization and outgrowth in hepatic niches. Metabolically, the lipid-rich microenvironment in NAFLD activated de novo palmitate biosynthesis in metastatic CRC cells via upregulating fatty acid synthase (FASN). Moreover, increased intracellular palmitate bioavailability promoted EGFR palmitoylation to enhance its protein stability and plasma membrane localization. Furthermore, we demonstrated that the FDA-approved FASN inhibitor orlistat could reduce NAFLD-activated endogenous palmitate production, thus inhibiting palmitoylation of EGFR to suppress CRC cell stemness and restrict liver metastasis in synergy with conventional chemotherapy. These findings reveal that the NAFLD metabolic microenvironment boosts endogenous palmitate biosynthesis in metastatic CRC cells and promotes cell stemness via EGFR palmitoylation, and FASN inhibitor orlistat could be a candidate adjuvant drug to suppress liver metastasis in CRC patients with NAFLD.https://doi.org/10.1038/s41420-023-01770-x |
| spellingShingle | Chi Zhang Yue Zhang Yan Dong Ruiyang Zi Yijie Wang Yanrong Chen Chengxiang Liu Junyi Wang Xuesong Wang Jianjun Li Houjie Liang Juanjuan Ou Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation Cell Death Discovery |
| title | Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation |
| title_full | Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation |
| title_fullStr | Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation |
| title_full_unstemmed | Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation |
| title_short | Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation |
| title_sort | non alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent egfr palmitoylation |
| url | https://doi.org/10.1038/s41420-023-01770-x |
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