Magnolin promotes autophagy and cell cycle arrest via blocking LIF/Stat3/Mcl-1 axis in human colorectal cancers
Magnolin is a multi-bioactive natural compound that possesses underlying anti-cancer properties. However, the mechanisms underlying remain to be elucidated. Here, we report the role of magnolin in suppressing human colorectal cancer (CRC) cells via activating autophagy and cell cycle arrest in vitro...
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| Veröffentlicht in: | Cell death & disease 2018-06, Vol.9 (6), p.702-13, Article 702 |
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| creator | Yu, Haiyang Yin, Shuangshuang Zhou, Shiyue Shao, Yingying Sun, Jiachen Pang, Xu Han, Lifeng Zhang, Yi Gao, Xiumei Jin, Chengyun Qiu, Yuling Wang, Tao |
| description | Magnolin is a multi-bioactive natural compound that possesses underlying anti-cancer properties. However, the mechanisms underlying remain to be elucidated. Here, we report the role of magnolin in suppressing human colorectal cancer (CRC) cells via activating autophagy and cell cycle arrest in vitro and in vivo. Pre-treatment of cells with specific autophagy inhibitor (3-methyladenine) or knockdown of endogenous LC-3B by siRNA significantly abrogates magnolin-induced cell cycle arrest. Molecular validation mechanistically shows that magnolin-induced autophagy and cell cycle arrest in CRC cells is correlated with decreased transcriptional levels of leukemia inhibitory factor (LIF), and we further find that inhibition of LIF decreases phosphorylation level of Stat3 and represses transcriptional expression of Mcl-1. Furthermore, magnolin-induced autophagy and cell cycle arrest suppress the growth of xenograft colorectal tumors without apparent toxicity. Finally, we evaluate the clinical correlation of LIF/Stat3/Mcl-1 in CRC patient tissues. As expected, LIF, p-Stat3, and Mcl-1 levels are high in CRC tissue but are scarcely found in normal colon tissue. High positive expressions of LIF or Mcl-1 are associated with poor prognosis. Doubly positive cases have shown the worst outcome. Taken together, our results have clarified a novel molecular mechanism whereby magnolin induces autophagy and cell cycle arrest through LIF/Stat3/Mcl-1 pathway in CRCs. Our results also have revealed that magnolin has a promising therapeutic potential in CRCs. |
| doi_str_mv | 10.1038/s41419-018-0660-4 |
| format | Article |
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However, the mechanisms underlying remain to be elucidated. Here, we report the role of magnolin in suppressing human colorectal cancer (CRC) cells via activating autophagy and cell cycle arrest in vitro and in vivo. Pre-treatment of cells with specific autophagy inhibitor (3-methyladenine) or knockdown of endogenous LC-3B by siRNA significantly abrogates magnolin-induced cell cycle arrest. Molecular validation mechanistically shows that magnolin-induced autophagy and cell cycle arrest in CRC cells is correlated with decreased transcriptional levels of leukemia inhibitory factor (LIF), and we further find that inhibition of LIF decreases phosphorylation level of Stat3 and represses transcriptional expression of Mcl-1. Furthermore, magnolin-induced autophagy and cell cycle arrest suppress the growth of xenograft colorectal tumors without apparent toxicity. Finally, we evaluate the clinical correlation of LIF/Stat3/Mcl-1 in CRC patient tissues. As expected, LIF, p-Stat3, and Mcl-1 levels are high in CRC tissue but are scarcely found in normal colon tissue. High positive expressions of LIF or Mcl-1 are associated with poor prognosis. Doubly positive cases have shown the worst outcome. Taken together, our results have clarified a novel molecular mechanism whereby magnolin induces autophagy and cell cycle arrest through LIF/Stat3/Mcl-1 pathway in CRCs. Our results also have revealed that magnolin has a promising therapeutic potential in CRCs.</description><identifier>ISSN: 2041-4889</identifier><identifier>EISSN: 2041-4889</identifier><identifier>DOI: 10.1038/s41419-018-0660-4</identifier><identifier>PMID: 29899555</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>14/19 ; 14/28 ; 38 ; 38/1 ; 38/79 ; 42/109 ; 64/60 ; 82/80 ; 96/31 ; Animals ; Antibodies ; Autophagy ; Autophagy - drug effects ; Biochemistry ; Biomedical and Life Sciences ; Cell Biology ; Cell Culture ; Cell cycle ; Cell Cycle Checkpoints - drug effects ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - metabolism ; Colorectal Neoplasms - pathology ; Colorectal Neoplasms - ultrastructure ; Eukaryotes ; Humans ; Immunology ; Leukemia inhibitory factor ; Leukemia Inhibitory Factor - metabolism ; Life Sciences ; Lignans - chemistry ; Lignans - pharmacology ; Mcl-1 protein ; Mice, Inbred BALB C ; Mice, Nude ; Myeloid Cell Leukemia Sequence 1 Protein - metabolism ; Phagocytosis ; Phosphorylation ; Phosphorylation - drug effects ; Prognosis ; Signal Transduction ; siRNA ; Stat3 protein ; STAT3 Transcription Factor - metabolism ; Toxicity ; Transcription ; Tumors ; Xenograft Model Antitumor Assays ; Xenografts</subject><ispartof>Cell death & disease, 2018-06, Vol.9 (6), p.702-13, Article 702</ispartof><rights>The Author(s) 2018</rights><rights>2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c536t-b6d82d30e70ead601a7463087029b6592bfec676a1b323952a7766b86b18de543</citedby><cites>FETCH-LOGICAL-c536t-b6d82d30e70ead601a7463087029b6592bfec676a1b323952a7766b86b18de543</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999973/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999973/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27923,27924,41119,42188,51575,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29899555$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yu, Haiyang</creatorcontrib><creatorcontrib>Yin, Shuangshuang</creatorcontrib><creatorcontrib>Zhou, Shiyue</creatorcontrib><creatorcontrib>Shao, Yingying</creatorcontrib><creatorcontrib>Sun, Jiachen</creatorcontrib><creatorcontrib>Pang, Xu</creatorcontrib><creatorcontrib>Han, Lifeng</creatorcontrib><creatorcontrib>Zhang, Yi</creatorcontrib><creatorcontrib>Gao, Xiumei</creatorcontrib><creatorcontrib>Jin, Chengyun</creatorcontrib><creatorcontrib>Qiu, Yuling</creatorcontrib><creatorcontrib>Wang, Tao</creatorcontrib><title>Magnolin promotes autophagy and cell cycle arrest via blocking LIF/Stat3/Mcl-1 axis in human colorectal cancers</title><title>Cell death & disease</title><addtitle>Cell Death Dis</addtitle><addtitle>Cell Death Dis</addtitle><description>Magnolin is a multi-bioactive natural compound that possesses underlying anti-cancer properties. However, the mechanisms underlying remain to be elucidated. Here, we report the role of magnolin in suppressing human colorectal cancer (CRC) cells via activating autophagy and cell cycle arrest in vitro and in vivo. Pre-treatment of cells with specific autophagy inhibitor (3-methyladenine) or knockdown of endogenous LC-3B by siRNA significantly abrogates magnolin-induced cell cycle arrest. Molecular validation mechanistically shows that magnolin-induced autophagy and cell cycle arrest in CRC cells is correlated with decreased transcriptional levels of leukemia inhibitory factor (LIF), and we further find that inhibition of LIF decreases phosphorylation level of Stat3 and represses transcriptional expression of Mcl-1. Furthermore, magnolin-induced autophagy and cell cycle arrest suppress the growth of xenograft colorectal tumors without apparent toxicity. Finally, we evaluate the clinical correlation of LIF/Stat3/Mcl-1 in CRC patient tissues. As expected, LIF, p-Stat3, and Mcl-1 levels are high in CRC tissue but are scarcely found in normal colon tissue. High positive expressions of LIF or Mcl-1 are associated with poor prognosis. Doubly positive cases have shown the worst outcome. Taken together, our results have clarified a novel molecular mechanism whereby magnolin induces autophagy and cell cycle arrest through LIF/Stat3/Mcl-1 pathway in CRCs. Our results also have revealed that magnolin has a promising therapeutic potential in CRCs.</description><subject>14/19</subject><subject>14/28</subject><subject>38</subject><subject>38/1</subject><subject>38/79</subject><subject>42/109</subject><subject>64/60</subject><subject>82/80</subject><subject>96/31</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Autophagy</subject><subject>Autophagy - drug effects</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Cell Biology</subject><subject>Cell Culture</subject><subject>Cell cycle</subject><subject>Cell Cycle Checkpoints - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Colorectal Neoplasms - metabolism</subject><subject>Colorectal Neoplasms - pathology</subject><subject>Colorectal Neoplasms - ultrastructure</subject><subject>Eukaryotes</subject><subject>Humans</subject><subject>Immunology</subject><subject>Leukemia inhibitory factor</subject><subject>Leukemia Inhibitory Factor - 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drug effects</topic><topic>Prognosis</topic><topic>Signal Transduction</topic><topic>siRNA</topic><topic>Stat3 protein</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>Toxicity</topic><topic>Transcription</topic><topic>Tumors</topic><topic>Xenograft Model Antitumor Assays</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yu, Haiyang</creatorcontrib><creatorcontrib>Yin, Shuangshuang</creatorcontrib><creatorcontrib>Zhou, Shiyue</creatorcontrib><creatorcontrib>Shao, Yingying</creatorcontrib><creatorcontrib>Sun, Jiachen</creatorcontrib><creatorcontrib>Pang, Xu</creatorcontrib><creatorcontrib>Han, Lifeng</creatorcontrib><creatorcontrib>Zhang, Yi</creatorcontrib><creatorcontrib>Gao, Xiumei</creatorcontrib><creatorcontrib>Jin, Chengyun</creatorcontrib><creatorcontrib>Qiu, Yuling</creatorcontrib><creatorcontrib>Wang, Tao</creatorcontrib><collection>Springer Nature OA/Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell death & disease</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yu, Haiyang</au><au>Yin, Shuangshuang</au><au>Zhou, Shiyue</au><au>Shao, Yingying</au><au>Sun, Jiachen</au><au>Pang, Xu</au><au>Han, Lifeng</au><au>Zhang, Yi</au><au>Gao, Xiumei</au><au>Jin, Chengyun</au><au>Qiu, Yuling</au><au>Wang, Tao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Magnolin promotes autophagy and cell cycle arrest via blocking LIF/Stat3/Mcl-1 axis in human colorectal cancers</atitle><jtitle>Cell death & disease</jtitle><stitle>Cell Death Dis</stitle><addtitle>Cell Death Dis</addtitle><date>2018-06-13</date><risdate>2018</risdate><volume>9</volume><issue>6</issue><spage>702</spage><epage>13</epage><pages>702-13</pages><artnum>702</artnum><issn>2041-4889</issn><eissn>2041-4889</eissn><abstract>Magnolin is a multi-bioactive natural compound that possesses underlying anti-cancer properties. However, the mechanisms underlying remain to be elucidated. Here, we report the role of magnolin in suppressing human colorectal cancer (CRC) cells via activating autophagy and cell cycle arrest in vitro and in vivo. Pre-treatment of cells with specific autophagy inhibitor (3-methyladenine) or knockdown of endogenous LC-3B by siRNA significantly abrogates magnolin-induced cell cycle arrest. Molecular validation mechanistically shows that magnolin-induced autophagy and cell cycle arrest in CRC cells is correlated with decreased transcriptional levels of leukemia inhibitory factor (LIF), and we further find that inhibition of LIF decreases phosphorylation level of Stat3 and represses transcriptional expression of Mcl-1. Furthermore, magnolin-induced autophagy and cell cycle arrest suppress the growth of xenograft colorectal tumors without apparent toxicity. Finally, we evaluate the clinical correlation of LIF/Stat3/Mcl-1 in CRC patient tissues. As expected, LIF, p-Stat3, and Mcl-1 levels are high in CRC tissue but are scarcely found in normal colon tissue. High positive expressions of LIF or Mcl-1 are associated with poor prognosis. Doubly positive cases have shown the worst outcome. Taken together, our results have clarified a novel molecular mechanism whereby magnolin induces autophagy and cell cycle arrest through LIF/Stat3/Mcl-1 pathway in CRCs. Our results also have revealed that magnolin has a promising therapeutic potential in CRCs.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>29899555</pmid><doi>10.1038/s41419-018-0660-4</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 14/19 14/28 38 38/1 38/79 42/109 64/60 82/80 96/31 Animals Antibodies Autophagy Autophagy - drug effects Biochemistry Biomedical and Life Sciences Cell Biology Cell Culture Cell cycle Cell Cycle Checkpoints - drug effects Cell Line, Tumor Cell Proliferation - drug effects Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - metabolism Colorectal Neoplasms - pathology Colorectal Neoplasms - ultrastructure Eukaryotes Humans Immunology Leukemia inhibitory factor Leukemia Inhibitory Factor - metabolism Life Sciences Lignans - chemistry Lignans - pharmacology Mcl-1 protein Mice, Inbred BALB C Mice, Nude Myeloid Cell Leukemia Sequence 1 Protein - metabolism Phagocytosis Phosphorylation Phosphorylation - drug effects Prognosis Signal Transduction siRNA Stat3 protein STAT3 Transcription Factor - metabolism Toxicity Transcription Tumors Xenograft Model Antitumor Assays Xenografts |
| title | Magnolin promotes autophagy and cell cycle arrest via blocking LIF/Stat3/Mcl-1 axis in human colorectal cancers |
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