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...
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Autor*in:	Chi Zhang [verfasserIn] Yue Zhang [verfasserIn] Yan Dong [verfasserIn] Ruiyang Zi [verfasserIn] Yijie Wang [verfasserIn] Yanrong Chen [verfasserIn] Chengxiang Liu [verfasserIn] Junyi Wang [verfasserIn] Xuesong Wang [verfasserIn] Jianjun Li [verfasserIn] Houjie Liang [verfasserIn] Juanjuan Ou [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2024

Übergeordnetes Werk:	In: Cell Death Discovery - Nature Publishing Group, 2018, 10(2024), 1, Seite 15
Übergeordnetes Werk:	volume:10 ; year:2024 ; number:1 ; pages:15

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1038/s41420-023-01770-x

Katalog-ID:	DOAJ096207531

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520			\|a 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.
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allfields	10.1038/s41420-023-01770-x doi (DE-627)DOAJ096207531 (DE-599)DOAJe06053e593ab4976a59c3eda28e6822d DE-627 ger DE-627 rakwb eng RC254-282 QH573-671 Chi Zhang verfasserin aut Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Neoplasms. Tumors. Oncology. Including cancer and carcinogens Cytology Yue Zhang verfasserin aut Yan Dong verfasserin aut Ruiyang Zi verfasserin aut Yijie Wang verfasserin aut Yanrong Chen verfasserin aut Chengxiang Liu verfasserin aut Junyi Wang verfasserin aut Xuesong Wang verfasserin aut Jianjun Li verfasserin aut Houjie Liang verfasserin aut Juanjuan Ou verfasserin aut In Cell Death Discovery Nature Publishing Group, 2018 10(2024), 1, Seite 15 (DE-627)843856351 (DE-600)2842546-7 20587716 nnns volume:10 year:2024 number:1 pages:15 https://doi.org/10.1038/s41420-023-01770-x kostenfrei https://doaj.org/article/e06053e593ab4976a59c3eda28e6822d kostenfrei https://doi.org/10.1038/s41420-023-01770-x kostenfrei https://doaj.org/toc/2058-7716 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2024 1 15
spelling	10.1038/s41420-023-01770-x doi (DE-627)DOAJ096207531 (DE-599)DOAJe06053e593ab4976a59c3eda28e6822d DE-627 ger DE-627 rakwb eng RC254-282 QH573-671 Chi Zhang verfasserin aut Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Neoplasms. Tumors. Oncology. Including cancer and carcinogens Cytology Yue Zhang verfasserin aut Yan Dong verfasserin aut Ruiyang Zi verfasserin aut Yijie Wang verfasserin aut Yanrong Chen verfasserin aut Chengxiang Liu verfasserin aut Junyi Wang verfasserin aut Xuesong Wang verfasserin aut Jianjun Li verfasserin aut Houjie Liang verfasserin aut Juanjuan Ou verfasserin aut In Cell Death Discovery Nature Publishing Group, 2018 10(2024), 1, Seite 15 (DE-627)843856351 (DE-600)2842546-7 20587716 nnns volume:10 year:2024 number:1 pages:15 https://doi.org/10.1038/s41420-023-01770-x kostenfrei https://doaj.org/article/e06053e593ab4976a59c3eda28e6822d kostenfrei https://doi.org/10.1038/s41420-023-01770-x kostenfrei https://doaj.org/toc/2058-7716 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2024 1 15
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allfieldsSound	10.1038/s41420-023-01770-x doi (DE-627)DOAJ096207531 (DE-599)DOAJe06053e593ab4976a59c3eda28e6822d DE-627 ger DE-627 rakwb eng RC254-282 QH573-671 Chi Zhang verfasserin aut Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Neoplasms. Tumors. Oncology. Including cancer and carcinogens Cytology Yue Zhang verfasserin aut Yan Dong verfasserin aut Ruiyang Zi verfasserin aut Yijie Wang verfasserin aut Yanrong Chen verfasserin aut Chengxiang Liu verfasserin aut Junyi Wang verfasserin aut Xuesong Wang verfasserin aut Jianjun Li verfasserin aut Houjie Liang verfasserin aut Juanjuan Ou verfasserin aut In Cell Death Discovery Nature Publishing Group, 2018 10(2024), 1, Seite 15 (DE-627)843856351 (DE-600)2842546-7 20587716 nnns volume:10 year:2024 number:1 pages:15 https://doi.org/10.1038/s41420-023-01770-x kostenfrei https://doaj.org/article/e06053e593ab4976a59c3eda28e6822d kostenfrei https://doi.org/10.1038/s41420-023-01770-x kostenfrei https://doaj.org/toc/2058-7716 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2024 1 15
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authorswithroles_txt_mv	Chi Zhang @@aut@@ Yue Zhang @@aut@@ Yan Dong @@aut@@ Ruiyang Zi @@aut@@ Yijie Wang @@aut@@ Yanrong Chen @@aut@@ Chengxiang Liu @@aut@@ Junyi Wang @@aut@@ Xuesong Wang @@aut@@ Jianjun Li @@aut@@ Houjie Liang @@aut@@ Juanjuan Ou @@aut@@
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callnumber-first	R - Medicine
author	Chi Zhang
spellingShingle	Chi Zhang misc RC254-282 misc QH573-671 misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens misc Cytology Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation
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topic_title	RC254-282 QH573-671 Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation
topic	misc RC254-282 misc QH573-671 misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens misc Cytology
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title	Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation
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title_full	Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation
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title_sort	non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent egfr palmitoylation
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title_auth	Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation
abstract	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.
abstractGer	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.
abstract_unstemmed	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.
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title_short	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 https://doaj.org/article/e06053e593ab4976a59c3eda28e6822d https://doaj.org/toc/2058-7716
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up_date	2024-07-03T18:53:31.335Z
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Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation

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