Alternol, a natural compound, exerts an anti‐tumour effect on osteosarcoma by modulating of STAT3 and ROS/MAPK signalling pathways
Osteosarcoma (OS) is the most frequent primary malignant bone tumour. Alternol, a novel compound purified from microbial fermentation products exerts anti‐tumour effects across several cancer types. The effect of alternol on human OS remains to be elucidated. We first evaluated the anti‐tumour effec...
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| Veröffentlicht in: | Journal of cellular and molecular medicine 2017-02, Vol.21 (2), p.208-221 |
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| creator | Zuo, Dongqing Zhou, Zifei Wang, Hongsheng Zhang, Tao Zang, Jie Yin, Fei Sun, Wei Chen, Jiepeng Duan, Lili Xu, Jing Wang, Zhuoying Wang, Chongren Lin, Binhui Fu, Zeze Liao, Yuxin Li, Suoyuan Sun, Mengxiong Hua, Yingqi Zheng, Longpo Cai, Zhengdong |
| description | Osteosarcoma (OS) is the most frequent primary malignant bone tumour. Alternol, a novel compound purified from microbial fermentation products exerts anti‐tumour effects across several cancer types. The effect of alternol on human OS remains to be elucidated. We first evaluated the anti‐tumour effect of alternol in several human OS cell lines in vitro and investigated its underlying mechanism. Alternol inhibited OS cell proliferation, migration and induced caspase‐dependent apoptosis, G2/M cell cycle arrest in a dose and time‐dependent manner. Moreover, alternol treatment inhibited signal transducer and activator of transcription‐3 (STAT3) phosphorylation in 143B and MG63 human OS cells, as evaluated using a STAT3‐dependent dual luciferase reporter system. Exposure to alternol resulted in excessive reactive oxygen species (ROS) generation and Jun amino‐terminal kinases (JNK), extracellular signal‐regulated kinases (ERK1/2) and p38 activation. Furthermore, alternol‐induced cell death was significantly restored in the presence of the ROS scavenger, N‐acetyl‐l‐cysteine (NAC) or a caspase inhibitor Z‐VAD‐FMK. NAC also prevented G2/M phase arrest and phosphorylation of mitogen‐activated protein kinases (MAPK), but did not reverse STAT3 inactivation. Finally, alternol suppressed tumour growth in vivo in the nude mouse OS tibia orthotopic model. Immunohistochemistry revealed that alternol treatment resulted in down‐regulation of phosph‐STAT3 Tyr705 and up‐regulation of cleaved caspase‐3 and phosph‐SAPK (Stress‐activated protein kinases)/JNK expression. Taken together, our results reveal that alternol suppresses cell proliferation, migration and induces apoptosis, cell cycle arrest by modulating of ROS‐dependent MAPK and STAT3 signalling pathways in human OS cells. Therefore, alternol is a promising candidate for developing anti‐tumour drugs target OS. |
| doi_str_mv | 10.1111/jcmm.12957 |
| format | Article |
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Alternol, a novel compound purified from microbial fermentation products exerts anti‐tumour effects across several cancer types. The effect of alternol on human OS remains to be elucidated. We first evaluated the anti‐tumour effect of alternol in several human OS cell lines in vitro and investigated its underlying mechanism. Alternol inhibited OS cell proliferation, migration and induced caspase‐dependent apoptosis, G2/M cell cycle arrest in a dose and time‐dependent manner. Moreover, alternol treatment inhibited signal transducer and activator of transcription‐3 (STAT3) phosphorylation in 143B and MG63 human OS cells, as evaluated using a STAT3‐dependent dual luciferase reporter system. Exposure to alternol resulted in excessive reactive oxygen species (ROS) generation and Jun amino‐terminal kinases (JNK), extracellular signal‐regulated kinases (ERK1/2) and p38 activation. Furthermore, alternol‐induced cell death was significantly restored in the presence of the ROS scavenger, N‐acetyl‐l‐cysteine (NAC) or a caspase inhibitor Z‐VAD‐FMK. NAC also prevented G2/M phase arrest and phosphorylation of mitogen‐activated protein kinases (MAPK), but did not reverse STAT3 inactivation. Finally, alternol suppressed tumour growth in vivo in the nude mouse OS tibia orthotopic model. Immunohistochemistry revealed that alternol treatment resulted in down‐regulation of phosph‐STAT3 Tyr705 and up‐regulation of cleaved caspase‐3 and phosph‐SAPK (Stress‐activated protein kinases)/JNK expression. Taken together, our results reveal that alternol suppresses cell proliferation, migration and induces apoptosis, cell cycle arrest by modulating of ROS‐dependent MAPK and STAT3 signalling pathways in human OS cells. Therefore, alternol is a promising candidate for developing anti‐tumour drugs target OS.</description><identifier>ISSN: 1582-1838</identifier><identifier>EISSN: 1582-4934</identifier><identifier>DOI: 10.1111/jcmm.12957</identifier><identifier>PMID: 27624867</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Acetylcysteine ; alternol ; Animals ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Apoptosis ; Apoptosis - drug effects ; Biological Products - pharmacology ; Biological Products - therapeutic use ; Bone cancer ; Bone tumors ; Cancer therapies ; Caspase inhibitors ; Caspases - metabolism ; Cell activation ; Cell cycle ; Cell death ; Cell Line, Tumor ; Cell migration ; Cell Movement - drug effects ; Cell proliferation ; Cell Proliferation - drug effects ; Chemotherapy ; Drug development ; Experiments ; Extracellular signal-regulated kinase ; Fermentation ; G2 Phase Cell Cycle Checkpoints - drug effects ; Gene Expression Regulation, Neoplastic - drug effects ; Heterocyclic Compounds, 4 or More Rings - chemistry ; Heterocyclic Compounds, 4 or More Rings - pharmacology ; Heterocyclic Compounds, 4 or More Rings - therapeutic use ; Homeostasis ; Humans ; Immunohistochemistry ; Inactivation ; Kinases ; MAP kinase ; MAP Kinase Signaling System - drug effects ; MAPKs ; Medical research ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Invasiveness ; Original ; Osteosarcoma ; Osteosarcoma - drug therapy ; Osteosarcoma - enzymology ; Osteosarcoma - pathology ; Phosphorylation ; Prostate cancer ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Research parks ; Sarcoma ; Signal transduction ; STAT3 ; Stat3 protein ; STAT3 Transcription Factor - metabolism ; Tibia ; Time Factors ; Transcription</subject><ispartof>Journal of cellular and molecular medicine, 2017-02, Vol.21 (2), p.208-221</ispartof><rights>2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.</rights><rights>2017. This work is published under https://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></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264147/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264147/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,1417,11562,27924,27925,45574,45575,46052,46476,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27624867$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zuo, Dongqing</creatorcontrib><creatorcontrib>Zhou, Zifei</creatorcontrib><creatorcontrib>Wang, Hongsheng</creatorcontrib><creatorcontrib>Zhang, Tao</creatorcontrib><creatorcontrib>Zang, Jie</creatorcontrib><creatorcontrib>Yin, Fei</creatorcontrib><creatorcontrib>Sun, Wei</creatorcontrib><creatorcontrib>Chen, Jiepeng</creatorcontrib><creatorcontrib>Duan, Lili</creatorcontrib><creatorcontrib>Xu, Jing</creatorcontrib><creatorcontrib>Wang, Zhuoying</creatorcontrib><creatorcontrib>Wang, Chongren</creatorcontrib><creatorcontrib>Lin, Binhui</creatorcontrib><creatorcontrib>Fu, Zeze</creatorcontrib><creatorcontrib>Liao, Yuxin</creatorcontrib><creatorcontrib>Li, Suoyuan</creatorcontrib><creatorcontrib>Sun, Mengxiong</creatorcontrib><creatorcontrib>Hua, Yingqi</creatorcontrib><creatorcontrib>Zheng, Longpo</creatorcontrib><creatorcontrib>Cai, Zhengdong</creatorcontrib><title>Alternol, a natural compound, exerts an anti‐tumour effect on osteosarcoma by modulating of STAT3 and ROS/MAPK signalling pathways</title><title>Journal of cellular and molecular medicine</title><addtitle>J Cell Mol Med</addtitle><description>Osteosarcoma (OS) is the most frequent primary malignant bone tumour. Alternol, a novel compound purified from microbial fermentation products exerts anti‐tumour effects across several cancer types. The effect of alternol on human OS remains to be elucidated. We first evaluated the anti‐tumour effect of alternol in several human OS cell lines in vitro and investigated its underlying mechanism. Alternol inhibited OS cell proliferation, migration and induced caspase‐dependent apoptosis, G2/M cell cycle arrest in a dose and time‐dependent manner. Moreover, alternol treatment inhibited signal transducer and activator of transcription‐3 (STAT3) phosphorylation in 143B and MG63 human OS cells, as evaluated using a STAT3‐dependent dual luciferase reporter system. Exposure to alternol resulted in excessive reactive oxygen species (ROS) generation and Jun amino‐terminal kinases (JNK), extracellular signal‐regulated kinases (ERK1/2) and p38 activation. Furthermore, alternol‐induced cell death was significantly restored in the presence of the ROS scavenger, N‐acetyl‐l‐cysteine (NAC) or a caspase inhibitor Z‐VAD‐FMK. NAC also prevented G2/M phase arrest and phosphorylation of mitogen‐activated protein kinases (MAPK), but did not reverse STAT3 inactivation. Finally, alternol suppressed tumour growth in vivo in the nude mouse OS tibia orthotopic model. Immunohistochemistry revealed that alternol treatment resulted in down‐regulation of phosph‐STAT3 Tyr705 and up‐regulation of cleaved caspase‐3 and phosph‐SAPK (Stress‐activated protein kinases)/JNK expression. Taken together, our results reveal that alternol suppresses cell proliferation, migration and induces apoptosis, cell cycle arrest by modulating of ROS‐dependent MAPK and STAT3 signalling pathways in human OS cells. Therefore, alternol is a promising candidate for developing anti‐tumour drugs target OS.</description><subject>Acetylcysteine</subject><subject>alternol</subject><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Biological Products - pharmacology</subject><subject>Biological Products - therapeutic use</subject><subject>Bone cancer</subject><subject>Bone tumors</subject><subject>Cancer therapies</subject><subject>Caspase inhibitors</subject><subject>Caspases - metabolism</subject><subject>Cell activation</subject><subject>Cell cycle</subject><subject>Cell death</subject><subject>Cell Line, Tumor</subject><subject>Cell migration</subject><subject>Cell Movement - drug effects</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Chemotherapy</subject><subject>Drug development</subject><subject>Experiments</subject><subject>Extracellular signal-regulated kinase</subject><subject>Fermentation</subject><subject>G2 Phase Cell Cycle Checkpoints - drug effects</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Heterocyclic Compounds, 4 or More Rings - chemistry</subject><subject>Heterocyclic Compounds, 4 or More Rings - pharmacology</subject><subject>Heterocyclic Compounds, 4 or More Rings - therapeutic use</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Inactivation</subject><subject>Kinases</subject><subject>MAP kinase</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>MAPKs</subject><subject>Medical research</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Neoplasm Invasiveness</subject><subject>Original</subject><subject>Osteosarcoma</subject><subject>Osteosarcoma - drug therapy</subject><subject>Osteosarcoma - enzymology</subject><subject>Osteosarcoma - pathology</subject><subject>Phosphorylation</subject><subject>Prostate cancer</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Research parks</subject><subject>Sarcoma</subject><subject>Signal transduction</subject><subject>STAT3</subject><subject>Stat3 protein</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Tibia</subject><subject>Time Factors</subject><subject>Transcription</subject><issn>1582-1838</issn><issn>1582-4934</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNpdkc1u1DAQxy0Eoh9w4QGQJS4cum38FccXpNWK8tVVEd27NXGcbVaOncYOZW8ceACekSfB2y4VMLI0I81v_prxH6EXpDglOc42pu9PCVVCPkKHRFR0xhXjj_c1qVh1gI5i3BQFKwlTT9EBlSXlVSkP0Y-5S3b0wZ1gwB7SNILDJvRDmHxzgu03O6aIweeXul_ff6apD9OIbdtak3DwOMRkQ4QxzwCut7gPzeQgdX6NQ4uvVvMVy7MN_nJ5dbacf_6EY7f24NwOGCBd38I2PkNPWnDRPt_nY7Q6f7tavJ9dXL77sJhfzAYmqZyBEGBUbStBWkIZrVoOqqCEFoKr0jJbSWONKBmtOaekqRuwRhXcQCsaWbNj9OZedpjq3jbG-pSv1cPY9TBudYBO_9vx3bVeh69a0JITLrPA673AGG4mG5Puu2isc-BtmKImlVCSUsVERl_9h27yv-XDo85AwUWWY5l6-fdGD6v88ScD5B647ZzdPvRJoXfO653z-s55_XGxXN5V7DfW4KOl</recordid><startdate>201702</startdate><enddate>201702</enddate><creator>Zuo, Dongqing</creator><creator>Zhou, Zifei</creator><creator>Wang, Hongsheng</creator><creator>Zhang, Tao</creator><creator>Zang, Jie</creator><creator>Yin, Fei</creator><creator>Sun, Wei</creator><creator>Chen, Jiepeng</creator><creator>Duan, Lili</creator><creator>Xu, Jing</creator><creator>Wang, Zhuoying</creator><creator>Wang, Chongren</creator><creator>Lin, Binhui</creator><creator>Fu, Zeze</creator><creator>Liao, Yuxin</creator><creator>Li, Suoyuan</creator><creator>Sun, Mengxiong</creator><creator>Hua, Yingqi</creator><creator>Zheng, Longpo</creator><creator>Cai, Zhengdong</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>3V.</scope><scope>7QP</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201702</creationdate><title>Alternol, a natural compound, exerts an anti‐tumour effect on osteosarcoma by modulating of STAT3 and ROS/MAPK signalling pathways</title><author>Zuo, Dongqing ; Zhou, Zifei ; Wang, Hongsheng ; Zhang, Tao ; Zang, Jie ; Yin, Fei ; Sun, Wei ; Chen, Jiepeng ; Duan, Lili ; Xu, Jing ; Wang, Zhuoying ; Wang, Chongren ; Lin, Binhui ; Fu, Zeze ; Liao, Yuxin ; Li, Suoyuan ; Sun, Mengxiong ; Hua, Yingqi ; Zheng, Longpo ; Cai, Zhengdong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p3727-a55ac9be851f12328f4a9021205496e3e87cec5632b4421dbdaec904caf5d7b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Acetylcysteine</topic><topic>alternol</topic><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Biological Products - pharmacology</topic><topic>Biological Products - therapeutic use</topic><topic>Bone cancer</topic><topic>Bone tumors</topic><topic>Cancer therapies</topic><topic>Caspase inhibitors</topic><topic>Caspases - metabolism</topic><topic>Cell activation</topic><topic>Cell cycle</topic><topic>Cell death</topic><topic>Cell Line, Tumor</topic><topic>Cell migration</topic><topic>Cell Movement - drug effects</topic><topic>Cell proliferation</topic><topic>Cell Proliferation - drug effects</topic><topic>Chemotherapy</topic><topic>Drug development</topic><topic>Experiments</topic><topic>Extracellular signal-regulated kinase</topic><topic>Fermentation</topic><topic>G2 Phase Cell Cycle Checkpoints - drug effects</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Heterocyclic Compounds, 4 or More Rings - chemistry</topic><topic>Heterocyclic Compounds, 4 or More Rings - pharmacology</topic><topic>Heterocyclic Compounds, 4 or More Rings - therapeutic use</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Inactivation</topic><topic>Kinases</topic><topic>MAP kinase</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>MAPKs</topic><topic>Medical research</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Neoplasm Invasiveness</topic><topic>Original</topic><topic>Osteosarcoma</topic><topic>Osteosarcoma - drug therapy</topic><topic>Osteosarcoma - enzymology</topic><topic>Osteosarcoma - pathology</topic><topic>Phosphorylation</topic><topic>Prostate cancer</topic><topic>Reactive oxygen species</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Research parks</topic><topic>Sarcoma</topic><topic>Signal transduction</topic><topic>STAT3</topic><topic>Stat3 protein</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>Tibia</topic><topic>Time Factors</topic><topic>Transcription</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zuo, Dongqing</creatorcontrib><creatorcontrib>Zhou, Zifei</creatorcontrib><creatorcontrib>Wang, Hongsheng</creatorcontrib><creatorcontrib>Zhang, Tao</creatorcontrib><creatorcontrib>Zang, Jie</creatorcontrib><creatorcontrib>Yin, Fei</creatorcontrib><creatorcontrib>Sun, Wei</creatorcontrib><creatorcontrib>Chen, Jiepeng</creatorcontrib><creatorcontrib>Duan, Lili</creatorcontrib><creatorcontrib>Xu, Jing</creatorcontrib><creatorcontrib>Wang, Zhuoying</creatorcontrib><creatorcontrib>Wang, Chongren</creatorcontrib><creatorcontrib>Lin, Binhui</creatorcontrib><creatorcontrib>Fu, Zeze</creatorcontrib><creatorcontrib>Liao, Yuxin</creatorcontrib><creatorcontrib>Li, Suoyuan</creatorcontrib><creatorcontrib>Sun, Mengxiong</creatorcontrib><creatorcontrib>Hua, Yingqi</creatorcontrib><creatorcontrib>Zheng, Longpo</creatorcontrib><creatorcontrib>Cai, Zhengdong</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library (Open Access Collection)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</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 (ProQuest)</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</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>Medical Database</collection><collection>Science Database (ProQuest)</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Access via ProQuest (Open Access)</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>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of cellular and molecular medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zuo, Dongqing</au><au>Zhou, Zifei</au><au>Wang, Hongsheng</au><au>Zhang, Tao</au><au>Zang, Jie</au><au>Yin, Fei</au><au>Sun, Wei</au><au>Chen, Jiepeng</au><au>Duan, Lili</au><au>Xu, Jing</au><au>Wang, Zhuoying</au><au>Wang, Chongren</au><au>Lin, Binhui</au><au>Fu, Zeze</au><au>Liao, Yuxin</au><au>Li, Suoyuan</au><au>Sun, Mengxiong</au><au>Hua, Yingqi</au><au>Zheng, Longpo</au><au>Cai, Zhengdong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Alternol, a natural compound, exerts an anti‐tumour effect on osteosarcoma by modulating of STAT3 and ROS/MAPK signalling pathways</atitle><jtitle>Journal of cellular and molecular medicine</jtitle><addtitle>J Cell Mol Med</addtitle><date>2017-02</date><risdate>2017</risdate><volume>21</volume><issue>2</issue><spage>208</spage><epage>221</epage><pages>208-221</pages><issn>1582-1838</issn><eissn>1582-4934</eissn><abstract>Osteosarcoma (OS) is the most frequent primary malignant bone tumour. Alternol, a novel compound purified from microbial fermentation products exerts anti‐tumour effects across several cancer types. The effect of alternol on human OS remains to be elucidated. We first evaluated the anti‐tumour effect of alternol in several human OS cell lines in vitro and investigated its underlying mechanism. Alternol inhibited OS cell proliferation, migration and induced caspase‐dependent apoptosis, G2/M cell cycle arrest in a dose and time‐dependent manner. Moreover, alternol treatment inhibited signal transducer and activator of transcription‐3 (STAT3) phosphorylation in 143B and MG63 human OS cells, as evaluated using a STAT3‐dependent dual luciferase reporter system. Exposure to alternol resulted in excessive reactive oxygen species (ROS) generation and Jun amino‐terminal kinases (JNK), extracellular signal‐regulated kinases (ERK1/2) and p38 activation. Furthermore, alternol‐induced cell death was significantly restored in the presence of the ROS scavenger, N‐acetyl‐l‐cysteine (NAC) or a caspase inhibitor Z‐VAD‐FMK. NAC also prevented G2/M phase arrest and phosphorylation of mitogen‐activated protein kinases (MAPK), but did not reverse STAT3 inactivation. Finally, alternol suppressed tumour growth in vivo in the nude mouse OS tibia orthotopic model. Immunohistochemistry revealed that alternol treatment resulted in down‐regulation of phosph‐STAT3 Tyr705 and up‐regulation of cleaved caspase‐3 and phosph‐SAPK (Stress‐activated protein kinases)/JNK expression. Taken together, our results reveal that alternol suppresses cell proliferation, migration and induces apoptosis, cell cycle arrest by modulating of ROS‐dependent MAPK and STAT3 signalling pathways in human OS cells. Therefore, alternol is a promising candidate for developing anti‐tumour drugs target OS.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>27624867</pmid><doi>10.1111/jcmm.12957</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1582-1838 |
| ispartof | Journal of cellular and molecular medicine, 2017-02, Vol.21 (2), p.208-221 |
| issn | 1582-1838 1582-4934 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5264147 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Access via Wiley Online Library; Wiley Online Library (Open Access Collection); PubMed Central |
| subjects | Acetylcysteine alternol Animals Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Apoptosis Apoptosis - drug effects Biological Products - pharmacology Biological Products - therapeutic use Bone cancer Bone tumors Cancer therapies Caspase inhibitors Caspases - metabolism Cell activation Cell cycle Cell death Cell Line, Tumor Cell migration Cell Movement - drug effects Cell proliferation Cell Proliferation - drug effects Chemotherapy Drug development Experiments Extracellular signal-regulated kinase Fermentation G2 Phase Cell Cycle Checkpoints - drug effects Gene Expression Regulation, Neoplastic - drug effects Heterocyclic Compounds, 4 or More Rings - chemistry Heterocyclic Compounds, 4 or More Rings - pharmacology Heterocyclic Compounds, 4 or More Rings - therapeutic use Homeostasis Humans Immunohistochemistry Inactivation Kinases MAP kinase MAP Kinase Signaling System - drug effects MAPKs Medical research Mice, Inbred BALB C Mice, Nude Neoplasm Invasiveness Original Osteosarcoma Osteosarcoma - drug therapy Osteosarcoma - enzymology Osteosarcoma - pathology Phosphorylation Prostate cancer Reactive oxygen species Reactive Oxygen Species - metabolism Research parks Sarcoma Signal transduction STAT3 Stat3 protein STAT3 Transcription Factor - metabolism Tibia Time Factors Transcription |
| title | Alternol, a natural compound, exerts an anti‐tumour effect on osteosarcoma by modulating of STAT3 and ROS/MAPK signalling pathways |
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