Novel SREBP1 inhibitor cinobufotalin suppresses proliferation of hepatocellular carcinoma by targeting lipogenesis
Hepatocellular carcinoma (HCC) is the major type of primary liver cancer and a leading cause of cancer-related deaths worldwide. Cinobufotalin (CBF) is extracted from the skin secretion of the giant toad and clinically used for the treatment of liver cancer, but its molecular mechanism of anti-cance...
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| Veröffentlicht in: | European journal of pharmacology 2021-09, Vol.906, p.174280-174280, Article 174280 |
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| creator | Meng, Huannan Shen, Mengqin Li, Jiajin Zhang, Ruixue Li, Xi Zhao, Li Huang, Gang Liu, Jianjun |
| description | Hepatocellular carcinoma (HCC) is the major type of primary liver cancer and a leading cause of cancer-related deaths worldwide. Cinobufotalin (CBF) is extracted from the skin secretion of the giant toad and clinically used for the treatment of liver cancer, but its molecular mechanism of anti-cancer in HCC has not yet been elucidated. Here, we showed CBF effectively promoted cell apoptosis, induced cell cycle G2-M arrest, inhibited cell proliferation and lipogenesis. Consistently, the lipogenesis ability of xenograft examined by 11C-acetate micro-PET/CT imaging, and the tumor growth rate was notably declined in a centration-dependent manner. The fatty acid profiles showed saturated and mono-unsaturated fatty acid significantly decreased after CBF treatment. Mechanistically, CBF selectively inhibited the expression of SREBP1 and interacted with SREBP1 to prevent it from sterol regulatory elements (SREs), thus inhibiting the expression of lipogenic enzymes. Collectively, our study demonstrates that CBF is a potent native compound that remarkably inhibits HCC lipogenesis and tumorigenesis. CBF may possess this therapeutic potential though interfering with de novo lipid synthesis via SREBP1.
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| doi_str_mv | 10.1016/j.ejphar.2021.174280 |
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[Display omitted]</description><identifier>ISSN: 0014-2999</identifier><identifier>EISSN: 1879-0712</identifier><identifier>DOI: 10.1016/j.ejphar.2021.174280</identifier><identifier>PMID: 34174265</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Animals ; Apoptosis - drug effects ; Apoptosis - genetics ; Bufanolides - pharmacology ; Bufanolides - therapeutic use ; Carcinogenesis - drug effects ; Carcinogenesis - genetics ; Carcinoma, Hepatocellular - drug therapy ; Carcinoma, Hepatocellular - pathology ; CBF ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cell Proliferation - genetics ; G2 Phase Cell Cycle Checkpoints - drug effects ; G2 Phase Cell Cycle Checkpoints - genetics ; Gene Expression Regulation, Neoplastic - drug effects ; Hepatocellular carcinoma ; Humans ; Lipogenesis ; Lipogenesis - drug effects ; Lipogenesis - genetics ; Liver Neoplasms - drug therapy ; Liver Neoplasms - pathology ; Male ; Mice ; Molecular Docking Simulation ; SREBP1 ; Sterol Regulatory Element Binding Protein 1 - antagonists & inhibitors ; Sterol Regulatory Element Binding Protein 1 - metabolism ; Xenograft Model Antitumor Assays</subject><ispartof>European journal of pharmacology, 2021-09, Vol.906, p.174280-174280, Article 174280</ispartof><rights>2021 The Authors</rights><rights>Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c408t-e9f5188448495bccf17725d1ad38af4567ee99263dcfe8c8e9326374627893413</citedby><cites>FETCH-LOGICAL-c408t-e9f5188448495bccf17725d1ad38af4567ee99263dcfe8c8e9326374627893413</cites><orcidid>0000-0002-4707-378X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejphar.2021.174280$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34174265$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Meng, Huannan</creatorcontrib><creatorcontrib>Shen, Mengqin</creatorcontrib><creatorcontrib>Li, Jiajin</creatorcontrib><creatorcontrib>Zhang, Ruixue</creatorcontrib><creatorcontrib>Li, Xi</creatorcontrib><creatorcontrib>Zhao, Li</creatorcontrib><creatorcontrib>Huang, Gang</creatorcontrib><creatorcontrib>Liu, Jianjun</creatorcontrib><title>Novel SREBP1 inhibitor cinobufotalin suppresses proliferation of hepatocellular carcinoma by targeting lipogenesis</title><title>European journal of pharmacology</title><addtitle>Eur J Pharmacol</addtitle><description>Hepatocellular carcinoma (HCC) is the major type of primary liver cancer and a leading cause of cancer-related deaths worldwide. Cinobufotalin (CBF) is extracted from the skin secretion of the giant toad and clinically used for the treatment of liver cancer, but its molecular mechanism of anti-cancer in HCC has not yet been elucidated. Here, we showed CBF effectively promoted cell apoptosis, induced cell cycle G2-M arrest, inhibited cell proliferation and lipogenesis. Consistently, the lipogenesis ability of xenograft examined by 11C-acetate micro-PET/CT imaging, and the tumor growth rate was notably declined in a centration-dependent manner. The fatty acid profiles showed saturated and mono-unsaturated fatty acid significantly decreased after CBF treatment. Mechanistically, CBF selectively inhibited the expression of SREBP1 and interacted with SREBP1 to prevent it from sterol regulatory elements (SREs), thus inhibiting the expression of lipogenic enzymes. Collectively, our study demonstrates that CBF is a potent native compound that remarkably inhibits HCC lipogenesis and tumorigenesis. CBF may possess this therapeutic potential though interfering with de novo lipid synthesis via SREBP1.
[Display omitted]</description><subject>Animals</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - genetics</subject><subject>Bufanolides - pharmacology</subject><subject>Bufanolides - therapeutic use</subject><subject>Carcinogenesis - drug effects</subject><subject>Carcinogenesis - genetics</subject><subject>Carcinoma, Hepatocellular - drug therapy</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>CBF</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Proliferation - genetics</subject><subject>G2 Phase Cell Cycle Checkpoints - drug effects</subject><subject>G2 Phase Cell Cycle Checkpoints - genetics</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Hepatocellular carcinoma</subject><subject>Humans</subject><subject>Lipogenesis</subject><subject>Lipogenesis - drug effects</subject><subject>Lipogenesis - genetics</subject><subject>Liver Neoplasms - drug therapy</subject><subject>Liver Neoplasms - pathology</subject><subject>Male</subject><subject>Mice</subject><subject>Molecular Docking Simulation</subject><subject>SREBP1</subject><subject>Sterol Regulatory Element Binding Protein 1 - antagonists & inhibitors</subject><subject>Sterol Regulatory Element Binding Protein 1 - metabolism</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0014-2999</issn><issn>1879-0712</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM1q3DAURkVpaSZJ36AULbvxRJJlW9oEkpA2gZCWJl0LWb6a0eCxXEkOzNtHxtMss7pcON_9OQh9pWRNCa0vdmvYjVsd1owwuqYNZ4J8QCsqGlmQhrKPaEUI5QWTUp6g0xh3hJBKsuozOin5zNfVCoVH_wI9fvpze_2bYjdsXeuSD9i4wbeT9Un3bsBxGscAMULEY_C9sxB0cn7A3uItjDp5A30_9ToHdZize43bA046bCC5YYN7N_oNDBBdPEefrO4jfDnWM_T3x-3zzV3x8Ovn_c3VQ2E4EakAaSsqBOeCy6o1xtKmYVVHdVcKbXlVNwBSsrrsjAVhBMgyNw2vWSNkfrA8Q9-XufnkfxPEpPYuznfqAfwUFavykOyElRnlC2qCjzGAVWNwex0OihI121Y7tdhWs2212M6xb8cNU7uH7i30X28GLhcA8p8vDoKKxsFgoHMBTFKdd-9veAXnBpP9</recordid><startdate>20210905</startdate><enddate>20210905</enddate><creator>Meng, Huannan</creator><creator>Shen, Mengqin</creator><creator>Li, Jiajin</creator><creator>Zhang, Ruixue</creator><creator>Li, Xi</creator><creator>Zhao, Li</creator><creator>Huang, Gang</creator><creator>Liu, Jianjun</creator><general>Elsevier B.V</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-4707-378X</orcidid></search><sort><creationdate>20210905</creationdate><title>Novel SREBP1 inhibitor cinobufotalin suppresses proliferation of hepatocellular carcinoma by targeting lipogenesis</title><author>Meng, Huannan ; Shen, Mengqin ; Li, Jiajin ; Zhang, Ruixue ; Li, Xi ; Zhao, Li ; Huang, Gang ; Liu, Jianjun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c408t-e9f5188448495bccf17725d1ad38af4567ee99263dcfe8c8e9326374627893413</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis - genetics</topic><topic>Bufanolides - pharmacology</topic><topic>Bufanolides - therapeutic use</topic><topic>Carcinogenesis - drug effects</topic><topic>Carcinogenesis - genetics</topic><topic>Carcinoma, Hepatocellular - drug therapy</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>CBF</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Proliferation - genetics</topic><topic>G2 Phase Cell Cycle Checkpoints - drug effects</topic><topic>G2 Phase Cell Cycle Checkpoints - genetics</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Hepatocellular carcinoma</topic><topic>Humans</topic><topic>Lipogenesis</topic><topic>Lipogenesis - drug effects</topic><topic>Lipogenesis - genetics</topic><topic>Liver Neoplasms - drug therapy</topic><topic>Liver Neoplasms - pathology</topic><topic>Male</topic><topic>Mice</topic><topic>Molecular Docking Simulation</topic><topic>SREBP1</topic><topic>Sterol Regulatory Element Binding Protein 1 - antagonists & inhibitors</topic><topic>Sterol Regulatory Element Binding Protein 1 - metabolism</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Meng, Huannan</creatorcontrib><creatorcontrib>Shen, Mengqin</creatorcontrib><creatorcontrib>Li, Jiajin</creatorcontrib><creatorcontrib>Zhang, Ruixue</creatorcontrib><creatorcontrib>Li, Xi</creatorcontrib><creatorcontrib>Zhao, Li</creatorcontrib><creatorcontrib>Huang, Gang</creatorcontrib><creatorcontrib>Liu, Jianjun</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Meng, Huannan</au><au>Shen, Mengqin</au><au>Li, Jiajin</au><au>Zhang, Ruixue</au><au>Li, Xi</au><au>Zhao, Li</au><au>Huang, Gang</au><au>Liu, Jianjun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel SREBP1 inhibitor cinobufotalin suppresses proliferation of hepatocellular carcinoma by targeting lipogenesis</atitle><jtitle>European journal of pharmacology</jtitle><addtitle>Eur J Pharmacol</addtitle><date>2021-09-05</date><risdate>2021</risdate><volume>906</volume><spage>174280</spage><epage>174280</epage><pages>174280-174280</pages><artnum>174280</artnum><issn>0014-2999</issn><eissn>1879-0712</eissn><abstract>Hepatocellular carcinoma (HCC) is the major type of primary liver cancer and a leading cause of cancer-related deaths worldwide. Cinobufotalin (CBF) is extracted from the skin secretion of the giant toad and clinically used for the treatment of liver cancer, but its molecular mechanism of anti-cancer in HCC has not yet been elucidated. Here, we showed CBF effectively promoted cell apoptosis, induced cell cycle G2-M arrest, inhibited cell proliferation and lipogenesis. Consistently, the lipogenesis ability of xenograft examined by 11C-acetate micro-PET/CT imaging, and the tumor growth rate was notably declined in a centration-dependent manner. The fatty acid profiles showed saturated and mono-unsaturated fatty acid significantly decreased after CBF treatment. Mechanistically, CBF selectively inhibited the expression of SREBP1 and interacted with SREBP1 to prevent it from sterol regulatory elements (SREs), thus inhibiting the expression of lipogenic enzymes. Collectively, our study demonstrates that CBF is a potent native compound that remarkably inhibits HCC lipogenesis and tumorigenesis. CBF may possess this therapeutic potential though interfering with de novo lipid synthesis via SREBP1.
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| subjects | Animals Apoptosis - drug effects Apoptosis - genetics Bufanolides - pharmacology Bufanolides - therapeutic use Carcinogenesis - drug effects Carcinogenesis - genetics Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - pathology CBF Cell Line, Tumor Cell Proliferation - drug effects Cell Proliferation - genetics G2 Phase Cell Cycle Checkpoints - drug effects G2 Phase Cell Cycle Checkpoints - genetics Gene Expression Regulation, Neoplastic - drug effects Hepatocellular carcinoma Humans Lipogenesis Lipogenesis - drug effects Lipogenesis - genetics Liver Neoplasms - drug therapy Liver Neoplasms - pathology Male Mice Molecular Docking Simulation SREBP1 Sterol Regulatory Element Binding Protein 1 - antagonists & inhibitors Sterol Regulatory Element Binding Protein 1 - metabolism Xenograft Model Antitumor Assays |
| title | Novel SREBP1 inhibitor cinobufotalin suppresses proliferation of hepatocellular carcinoma by targeting lipogenesis |
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