Activation of β2‐adrenergic receptor signals suppresses mesenchymal phenotypes of oral squamous cell carcinoma cells
Metastasis is a primary reason related to the mortality of oral squamous cell carcinoma (OSCC) patients. A program called epithelial‐mesenchymal transition (EMT) has been shown to play a critical role in promoting metastasis in epithelium‐derived carcinoma. During EMT, epithelial cancer cells acquir...
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| Veröffentlicht in: | Cancer science 2021-01, Vol.112 (1), p.155-167 |
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| creator | Sakakitani, Shintaro Podyma‐Inoue, Katarzyna A. Takayama, Rina Takahashi, Kazuki Ishigami‐Yuasa, Mari Kagechika, Hiroyuki Harada, Hiroyuki Watabe, Tetsuro |
| description | Metastasis is a primary reason related to the mortality of oral squamous cell carcinoma (OSCC) patients. A program called epithelial‐mesenchymal transition (EMT) has been shown to play a critical role in promoting metastasis in epithelium‐derived carcinoma. During EMT, epithelial cancer cells acquire motile mesenchymal phenotypes and detach from primary tumors. Recent lines of evidence have suggested that EMT confers cancer cells with tumor‐initiating ability. Therefore, selective targeting of EMT would lead to the development of effective therapeutic agents. In this study, using a chemical biology approach, we identified isoxsuprine, a β2‐adrenergic receptor (β2‐AR) agonist as a low‐molecular‐weight compound that interferes with the acquisition of mesenchymal phenotypes of oral cancer cells. Treatment of multiple types of oral cancer cells with isoxsuprine led to the downregulation of mesenchymal cell markers that was accompanied by reduced cell motility. Similar inhibitory effects were also observed for isoprenaline, a non‐selective β‐adrenergic receptor (β‐AR) agonist. In addition, inhibition of cell migration upon treatment with isoxsuprine was reverted by a non‐selective β‐AR antagonist, propranolol, and the CRISPR/Cas9 system‐mediated deletion of the β2‐AR gene, suggesting that the effects exerted by isoxsuprine involved signals mediated by β2‐AR. In addition, in a subcutaneous xenograft model of oral cancer cells, the administration of isoxsuprine effectively suppressed primary tumor growth, suggesting β2‐AR signals to be a promising cancer therapeutic target for treatment of OSCC.
In this study we identified isoxsuprine, a β2‐adrenergic receptor agonist as an effective inhibitor of mesenchymal phenotypes and migration of oral squamous cell carcinoma cells suggesting that β2‐adrenergic receptor signal is a new promising therapeutic target for treatment of oral cancer. |
| doi_str_mv | 10.1111/cas.14670 |
| format | Article |
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In this study we identified isoxsuprine, a β2‐adrenergic receptor agonist as an effective inhibitor of mesenchymal phenotypes and migration of oral squamous cell carcinoma cells suggesting that β2‐adrenergic receptor signal is a new promising therapeutic target for treatment of oral cancer.</description><identifier>ISSN: 1347-9032</identifier><identifier>EISSN: 1349-7006</identifier><identifier>DOI: 10.1111/cas.14670</identifier><identifier>PMID: 33007125</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Adrenergic receptors ; Agonists ; Androgen Receptor Antagonists - pharmacology ; Angiogenesis ; Animals ; Carcinoma, Squamous Cell - drug therapy ; Carcinoma, Squamous Cell - metabolism ; Cell adhesion & migration ; Cell growth ; Cell Line, Tumor ; Cell migration ; Cell Movement - drug effects ; Cell Transformation, Neoplastic - drug effects ; Cell Transformation, Neoplastic - metabolism ; Cell, Molecular, and Stem Cell Biology ; CRISPR ; Down-Regulation - drug effects ; Epithelial-Mesenchymal Transition - drug effects ; Epithelium ; Gene deletion ; Genomes ; Growth factors ; Humans ; isoxsuprine ; Kinases ; Male ; Medical prognosis ; Medical research ; Mesenchymal Stem Cells - drug effects ; Mesenchymal Stem Cells - metabolism ; Mesenchyme ; MET (mesenchymal‐epithelial transition) ; Metastases ; Metastasis ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Motility ; Mouth Neoplasms - drug therapy ; Mouth Neoplasms - metabolism ; Oral cancer ; Oral squamous cell carcinoma ; Original ; Phenotype ; Phenotypes ; Plasmids ; Propranolol ; Propranolol - pharmacology ; Proteins ; Receptors, Adrenergic, beta-2 - metabolism ; Signal Transduction - drug effects ; Squamous cell carcinoma ; Therapeutic targets ; tumor growth ; Tumors ; Xenografts ; β2‐adrenergic receptor</subject><ispartof>Cancer science, 2021-01, Vol.112 (1), p.155-167</ispartof><rights>2020 The Authors. published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><rights>2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><rights>2021. This work is published under http://creativecommons.org/licenses/by-nc/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-c6170-f11a2f389b71a12276423dc535f8d3eea8c8106ba8fc26f0dd17a0d85bf9e5ff3</citedby><cites>FETCH-LOGICAL-c6170-f11a2f389b71a12276423dc535f8d3eea8c8106ba8fc26f0dd17a0d85bf9e5ff3</cites><orcidid>0000-0001-5836-1309</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780019/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780019/$$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/33007125$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sakakitani, Shintaro</creatorcontrib><creatorcontrib>Podyma‐Inoue, Katarzyna A.</creatorcontrib><creatorcontrib>Takayama, Rina</creatorcontrib><creatorcontrib>Takahashi, Kazuki</creatorcontrib><creatorcontrib>Ishigami‐Yuasa, Mari</creatorcontrib><creatorcontrib>Kagechika, Hiroyuki</creatorcontrib><creatorcontrib>Harada, Hiroyuki</creatorcontrib><creatorcontrib>Watabe, Tetsuro</creatorcontrib><title>Activation of β2‐adrenergic receptor signals suppresses mesenchymal phenotypes of oral squamous cell carcinoma cells</title><title>Cancer science</title><addtitle>Cancer Sci</addtitle><description>Metastasis is a primary reason related to the mortality of oral squamous cell carcinoma (OSCC) patients. A program called epithelial‐mesenchymal transition (EMT) has been shown to play a critical role in promoting metastasis in epithelium‐derived carcinoma. During EMT, epithelial cancer cells acquire motile mesenchymal phenotypes and detach from primary tumors. Recent lines of evidence have suggested that EMT confers cancer cells with tumor‐initiating ability. Therefore, selective targeting of EMT would lead to the development of effective therapeutic agents. In this study, using a chemical biology approach, we identified isoxsuprine, a β2‐adrenergic receptor (β2‐AR) agonist as a low‐molecular‐weight compound that interferes with the acquisition of mesenchymal phenotypes of oral cancer cells. Treatment of multiple types of oral cancer cells with isoxsuprine led to the downregulation of mesenchymal cell markers that was accompanied by reduced cell motility. Similar inhibitory effects were also observed for isoprenaline, a non‐selective β‐adrenergic receptor (β‐AR) agonist. In addition, inhibition of cell migration upon treatment with isoxsuprine was reverted by a non‐selective β‐AR antagonist, propranolol, and the CRISPR/Cas9 system‐mediated deletion of the β2‐AR gene, suggesting that the effects exerted by isoxsuprine involved signals mediated by β2‐AR. In addition, in a subcutaneous xenograft model of oral cancer cells, the administration of isoxsuprine effectively suppressed primary tumor growth, suggesting β2‐AR signals to be a promising cancer therapeutic target for treatment of OSCC.
In this study we identified isoxsuprine, a β2‐adrenergic receptor agonist as an effective inhibitor of mesenchymal phenotypes and migration of oral squamous cell carcinoma cells suggesting that β2‐adrenergic receptor signal is a new promising therapeutic target for treatment of oral cancer.</description><subject>Adrenergic receptors</subject><subject>Agonists</subject><subject>Androgen Receptor Antagonists - pharmacology</subject><subject>Angiogenesis</subject><subject>Animals</subject><subject>Carcinoma, Squamous Cell - drug therapy</subject><subject>Carcinoma, Squamous Cell - metabolism</subject><subject>Cell adhesion & migration</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell migration</subject><subject>Cell Movement - drug effects</subject><subject>Cell Transformation, Neoplastic - drug effects</subject><subject>Cell Transformation, Neoplastic - metabolism</subject><subject>Cell, Molecular, and Stem Cell Biology</subject><subject>CRISPR</subject><subject>Down-Regulation - drug effects</subject><subject>Epithelial-Mesenchymal Transition - drug effects</subject><subject>Epithelium</subject><subject>Gene deletion</subject><subject>Genomes</subject><subject>Growth factors</subject><subject>Humans</subject><subject>isoxsuprine</subject><subject>Kinases</subject><subject>Male</subject><subject>Medical prognosis</subject><subject>Medical research</subject><subject>Mesenchymal Stem Cells - drug effects</subject><subject>Mesenchymal Stem Cells - metabolism</subject><subject>Mesenchyme</subject><subject>MET (mesenchymal‐epithelial transition)</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Motility</subject><subject>Mouth Neoplasms - drug therapy</subject><subject>Mouth Neoplasms - metabolism</subject><subject>Oral cancer</subject><subject>Oral squamous cell carcinoma</subject><subject>Original</subject><subject>Phenotype</subject><subject>Phenotypes</subject><subject>Plasmids</subject><subject>Propranolol</subject><subject>Propranolol - pharmacology</subject><subject>Proteins</subject><subject>Receptors, Adrenergic, beta-2 - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Squamous cell carcinoma</subject><subject>Therapeutic targets</subject><subject>tumor growth</subject><subject>Tumors</subject><subject>Xenografts</subject><subject>β2‐adrenergic receptor</subject><issn>1347-9032</issn><issn>1349-7006</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</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>eNp1kctKxDAUhoMo3he-gARcuajm0jbtRhgGbyC4UNchk57MRNqmJq0yOx_BZ_FBfAifxDijoguzSXLy8Z1DfoT2KDmicR1rFY5omguygjYpT8tEEJKvLs4iKQlnG2grhHtCeJ6W6Tra4JwQQVm2iZ5GurePqreuxc7gt1f2_vyiKg8t-KnV2IOGrnceBzttVR1wGLrOQwgQcAMBWj2bN6rG3Qxa18-7WI4a52MpPAyqcUPAGuoaa-W1bV2jFtewg9ZM1MHu176N7s5Ob8cXydX1-eV4dJXonAqSGEoVM7woJ4IqypjIU8YrnfHMFBUHUIUuKMknqjCa5YZUFRWKVEU2MSVkxvBtdLL0dsOkgUpD28fZZOdto_xcOmXl35fWzuTUPUohCkJoGQUHXwLvHgYIvbx3g__8CslSkYq8ZEJE6nBJae9C8GB-OlAiPzOSMSO5yCiy-79H-iG_Q4nA8RJ4sjXM_zfJ8ehmqfwACk6g5w</recordid><startdate>202101</startdate><enddate>202101</enddate><creator>Sakakitani, Shintaro</creator><creator>Podyma‐Inoue, Katarzyna A.</creator><creator>Takayama, Rina</creator><creator>Takahashi, Kazuki</creator><creator>Ishigami‐Yuasa, Mari</creator><creator>Kagechika, Hiroyuki</creator><creator>Harada, Hiroyuki</creator><creator>Watabe, Tetsuro</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>AAYXX</scope><scope>CITATION</scope><scope>8FE</scope><scope>8FH</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>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5836-1309</orcidid></search><sort><creationdate>202101</creationdate><title>Activation of β2‐adrenergic receptor signals suppresses mesenchymal phenotypes of oral squamous cell carcinoma cells</title><author>Sakakitani, Shintaro ; Podyma‐Inoue, Katarzyna A. ; Takayama, Rina ; Takahashi, Kazuki ; Ishigami‐Yuasa, Mari ; Kagechika, Hiroyuki ; Harada, Hiroyuki ; Watabe, Tetsuro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6170-f11a2f389b71a12276423dc535f8d3eea8c8106ba8fc26f0dd17a0d85bf9e5ff3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adrenergic receptors</topic><topic>Agonists</topic><topic>Androgen Receptor Antagonists - pharmacology</topic><topic>Angiogenesis</topic><topic>Animals</topic><topic>Carcinoma, Squamous Cell - drug therapy</topic><topic>Carcinoma, Squamous Cell - metabolism</topic><topic>Cell adhesion & migration</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cell migration</topic><topic>Cell Movement - drug effects</topic><topic>Cell Transformation, Neoplastic - drug effects</topic><topic>Cell Transformation, Neoplastic - metabolism</topic><topic>Cell, Molecular, and Stem Cell Biology</topic><topic>CRISPR</topic><topic>Down-Regulation - drug effects</topic><topic>Epithelial-Mesenchymal Transition - drug effects</topic><topic>Epithelium</topic><topic>Gene deletion</topic><topic>Genomes</topic><topic>Growth factors</topic><topic>Humans</topic><topic>isoxsuprine</topic><topic>Kinases</topic><topic>Male</topic><topic>Medical prognosis</topic><topic>Medical research</topic><topic>Mesenchymal Stem Cells - drug effects</topic><topic>Mesenchymal Stem Cells - metabolism</topic><topic>Mesenchyme</topic><topic>MET (mesenchymal‐epithelial transition)</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Motility</topic><topic>Mouth Neoplasms - drug therapy</topic><topic>Mouth Neoplasms - metabolism</topic><topic>Oral cancer</topic><topic>Oral squamous cell carcinoma</topic><topic>Original</topic><topic>Phenotype</topic><topic>Phenotypes</topic><topic>Plasmids</topic><topic>Propranolol</topic><topic>Propranolol - pharmacology</topic><topic>Proteins</topic><topic>Receptors, Adrenergic, beta-2 - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Squamous cell carcinoma</topic><topic>Therapeutic targets</topic><topic>tumor growth</topic><topic>Tumors</topic><topic>Xenografts</topic><topic>β2‐adrenergic receptor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sakakitani, Shintaro</creatorcontrib><creatorcontrib>Podyma‐Inoue, Katarzyna A.</creatorcontrib><creatorcontrib>Takayama, Rina</creatorcontrib><creatorcontrib>Takahashi, Kazuki</creatorcontrib><creatorcontrib>Ishigami‐Yuasa, Mari</creatorcontrib><creatorcontrib>Kagechika, Hiroyuki</creatorcontrib><creatorcontrib>Harada, Hiroyuki</creatorcontrib><creatorcontrib>Watabe, Tetsuro</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library Free Content</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 SciTech Collection</collection><collection>ProQuest Natural Science Collection</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>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Biological Science Database</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>PubMed Central (Full Participant titles)</collection><jtitle>Cancer science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sakakitani, Shintaro</au><au>Podyma‐Inoue, Katarzyna A.</au><au>Takayama, Rina</au><au>Takahashi, Kazuki</au><au>Ishigami‐Yuasa, Mari</au><au>Kagechika, Hiroyuki</au><au>Harada, Hiroyuki</au><au>Watabe, Tetsuro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Activation of β2‐adrenergic receptor signals suppresses mesenchymal phenotypes of oral squamous cell carcinoma cells</atitle><jtitle>Cancer science</jtitle><addtitle>Cancer Sci</addtitle><date>2021-01</date><risdate>2021</risdate><volume>112</volume><issue>1</issue><spage>155</spage><epage>167</epage><pages>155-167</pages><issn>1347-9032</issn><eissn>1349-7006</eissn><abstract>Metastasis is a primary reason related to the mortality of oral squamous cell carcinoma (OSCC) patients. A program called epithelial‐mesenchymal transition (EMT) has been shown to play a critical role in promoting metastasis in epithelium‐derived carcinoma. During EMT, epithelial cancer cells acquire motile mesenchymal phenotypes and detach from primary tumors. Recent lines of evidence have suggested that EMT confers cancer cells with tumor‐initiating ability. Therefore, selective targeting of EMT would lead to the development of effective therapeutic agents. In this study, using a chemical biology approach, we identified isoxsuprine, a β2‐adrenergic receptor (β2‐AR) agonist as a low‐molecular‐weight compound that interferes with the acquisition of mesenchymal phenotypes of oral cancer cells. Treatment of multiple types of oral cancer cells with isoxsuprine led to the downregulation of mesenchymal cell markers that was accompanied by reduced cell motility. Similar inhibitory effects were also observed for isoprenaline, a non‐selective β‐adrenergic receptor (β‐AR) agonist. In addition, inhibition of cell migration upon treatment with isoxsuprine was reverted by a non‐selective β‐AR antagonist, propranolol, and the CRISPR/Cas9 system‐mediated deletion of the β2‐AR gene, suggesting that the effects exerted by isoxsuprine involved signals mediated by β2‐AR. In addition, in a subcutaneous xenograft model of oral cancer cells, the administration of isoxsuprine effectively suppressed primary tumor growth, suggesting β2‐AR signals to be a promising cancer therapeutic target for treatment of OSCC.
In this study we identified isoxsuprine, a β2‐adrenergic receptor agonist as an effective inhibitor of mesenchymal phenotypes and migration of oral squamous cell carcinoma cells suggesting that β2‐adrenergic receptor signal is a new promising therapeutic target for treatment of oral cancer.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>33007125</pmid><doi>10.1111/cas.14670</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0001-5836-1309</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adrenergic receptors Agonists Androgen Receptor Antagonists - pharmacology Angiogenesis Animals Carcinoma, Squamous Cell - drug therapy Carcinoma, Squamous Cell - metabolism Cell adhesion & migration Cell growth Cell Line, Tumor Cell migration Cell Movement - drug effects Cell Transformation, Neoplastic - drug effects Cell Transformation, Neoplastic - metabolism Cell, Molecular, and Stem Cell Biology CRISPR Down-Regulation - drug effects Epithelial-Mesenchymal Transition - drug effects Epithelium Gene deletion Genomes Growth factors Humans isoxsuprine Kinases Male Medical prognosis Medical research Mesenchymal Stem Cells - drug effects Mesenchymal Stem Cells - metabolism Mesenchyme MET (mesenchymal‐epithelial transition) Metastases Metastasis Mice Mice, Inbred BALB C Mice, Nude Motility Mouth Neoplasms - drug therapy Mouth Neoplasms - metabolism Oral cancer Oral squamous cell carcinoma Original Phenotype Phenotypes Plasmids Propranolol Propranolol - pharmacology Proteins Receptors, Adrenergic, beta-2 - metabolism Signal Transduction - drug effects Squamous cell carcinoma Therapeutic targets tumor growth Tumors Xenografts β2‐adrenergic receptor |
| title | Activation of β2‐adrenergic receptor signals suppresses mesenchymal phenotypes of oral squamous cell carcinoma cells |
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