Molecular mechanism of inhibitory effects of bovine lactoferrin on the growth of oral squamous cell carcinoma
Lactoferrin (LF), a member of the transferrin family, recently has been demonstrated to have anticancer effects on various cancers including oral squamous cell carcinoma (OSCC). However, little is known about the underlying mechanisms of its effects on OSCC. Therefore, we aimed to investigate the me...
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| creator | Chea, Chanbora Miyauchi, Mutsumi Inubushi, Toshihiro Febriyanti Ayuningtyas, Nurina Subarnbhesaj, Ajiravudh Nguyen, Phuong Thao Shrestha, Madhu Haing, Sivmeng Ohta, Kouji Takata, Takashi |
| description | Lactoferrin (LF), a member of the transferrin family, recently has been demonstrated to have anticancer effects on various cancers including oral squamous cell carcinoma (OSCC). However, little is known about the underlying mechanisms of its effects on OSCC. Therefore, we aimed to investigate the mechanism of the suppressive effects of bovine LF (bLF) on the growth of OSCC cells.
In the current study, HSC2, HSC3, HSC4 and normal human oral keratinocytes (RT7) cell lines were tested with bLF 1, 10, and 100 μg/ml. The effects and detail mechanisms of bLF on proliferation and apoptosis of cells were investigated using flow cytometry and western blotting.
We found that bLF (1, 10, and 100 μg/ml) induced activation of p53, a tumor suppressor gene, is associated with the induction of cell cycle arrest in G1/S phase and apoptosis in OSCC. Moreover, bLF downregulated the phosphorylation of Akt and activated suppressor of cytokine signaling 3 (SOCS3), thereby attenuating multiple signaling pathways including mTOR/S6K and JAK/STAT3. Interestingly, we revealed that bLF exerted its effect selectively against HSC3 but not on RT7 via different effects on the phosphorylation status of NF-κB and Akt.
This is the first report showing that bLF selectively suppresses proliferation through mTOR/S6K and JAK/STAT3 pathways and induction of apoptosis in OSCC. This study provides important new findings, which might be useful in the prevention and treatment of OSCC. |
| doi_str_mv | 10.1371/journal.pone.0191683 |
| format | Article |
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In the current study, HSC2, HSC3, HSC4 and normal human oral keratinocytes (RT7) cell lines were tested with bLF 1, 10, and 100 μg/ml. The effects and detail mechanisms of bLF on proliferation and apoptosis of cells were investigated using flow cytometry and western blotting.
We found that bLF (1, 10, and 100 μg/ml) induced activation of p53, a tumor suppressor gene, is associated with the induction of cell cycle arrest in G1/S phase and apoptosis in OSCC. Moreover, bLF downregulated the phosphorylation of Akt and activated suppressor of cytokine signaling 3 (SOCS3), thereby attenuating multiple signaling pathways including mTOR/S6K and JAK/STAT3. Interestingly, we revealed that bLF exerted its effect selectively against HSC3 but not on RT7 via different effects on the phosphorylation status of NF-κB and Akt.
This is the first report showing that bLF selectively suppresses proliferation through mTOR/S6K and JAK/STAT3 pathways and induction of apoptosis in OSCC. This study provides important new findings, which might be useful in the prevention and treatment of OSCC.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0191683</identifier><identifier>PMID: 29381751</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>AKT protein ; Analysis ; Animals ; Anticancer properties ; Antimitotic agents ; Antineoplastic agents ; Apoptosis ; Biology and Life Sciences ; Breast cancer ; Cancer therapies ; Carcinoma, Squamous Cell - pathology ; Care and treatment ; Cattle ; Cell cycle ; Cell Cycle - drug effects ; Cell growth ; Cell Line, Transformed ; Cell proliferation ; Cell Proliferation - drug effects ; Cytokines ; Cytometry ; Diagnosis ; Dosage and administration ; Epithelial cells ; Flow cytometry ; Health sciences ; Humans ; Keratinocytes ; Kinases ; Lactoferrin ; Lactoferrin - pharmacology ; Lactoferrins ; Leukemia ; Mouth Neoplasms - pathology ; NF-κB protein ; Oral cancer ; Oral squamous cell carcinoma ; p53 Protein ; Pathways ; Penicillin ; Phosphorylation ; Proteins ; Rapamycin ; S phase ; Signal transduction ; Signaling ; SOCS-3 protein ; Squamous cell carcinoma ; Stat3 protein ; Studies ; TOR protein ; Transferrin ; Transferrins ; Tumor suppressor genes ; Western blotting</subject><ispartof>PloS one, 2018-01, Vol.13 (1), p.e0191683-e0191683</ispartof><rights>COPYRIGHT 2018 Public Library of Science</rights><rights>2018 Chea et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2018 Chea et al 2018 Chea et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-320c245333903f783428ea02c590a101059d8d6f3ff3ae3c0eaa1be48bf647f53</citedby><cites>FETCH-LOGICAL-c758t-320c245333903f783428ea02c590a101059d8d6f3ff3ae3c0eaa1be48bf647f53</cites><orcidid>0000-0002-5682-4215</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/PMC5790278/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790278/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29381751$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Reddy, Sakamuri V.</contributor><creatorcontrib>Chea, Chanbora</creatorcontrib><creatorcontrib>Miyauchi, Mutsumi</creatorcontrib><creatorcontrib>Inubushi, Toshihiro</creatorcontrib><creatorcontrib>Febriyanti Ayuningtyas, Nurina</creatorcontrib><creatorcontrib>Subarnbhesaj, Ajiravudh</creatorcontrib><creatorcontrib>Nguyen, Phuong Thao</creatorcontrib><creatorcontrib>Shrestha, Madhu</creatorcontrib><creatorcontrib>Haing, Sivmeng</creatorcontrib><creatorcontrib>Ohta, Kouji</creatorcontrib><creatorcontrib>Takata, Takashi</creatorcontrib><title>Molecular mechanism of inhibitory effects of bovine lactoferrin on the growth of oral squamous cell carcinoma</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Lactoferrin (LF), a member of the transferrin family, recently has been demonstrated to have anticancer effects on various cancers including oral squamous cell carcinoma (OSCC). However, little is known about the underlying mechanisms of its effects on OSCC. Therefore, we aimed to investigate the mechanism of the suppressive effects of bovine LF (bLF) on the growth of OSCC cells.
In the current study, HSC2, HSC3, HSC4 and normal human oral keratinocytes (RT7) cell lines were tested with bLF 1, 10, and 100 μg/ml. The effects and detail mechanisms of bLF on proliferation and apoptosis of cells were investigated using flow cytometry and western blotting.
We found that bLF (1, 10, and 100 μg/ml) induced activation of p53, a tumor suppressor gene, is associated with the induction of cell cycle arrest in G1/S phase and apoptosis in OSCC. Moreover, bLF downregulated the phosphorylation of Akt and activated suppressor of cytokine signaling 3 (SOCS3), thereby attenuating multiple signaling pathways including mTOR/S6K and JAK/STAT3. Interestingly, we revealed that bLF exerted its effect selectively against HSC3 but not on RT7 via different effects on the phosphorylation status of NF-κB and Akt.
This is the first report showing that bLF selectively suppresses proliferation through mTOR/S6K and JAK/STAT3 pathways and induction of apoptosis in OSCC. This study provides important new findings, which might be useful in the prevention and treatment of OSCC.</description><subject>AKT protein</subject><subject>Analysis</subject><subject>Animals</subject><subject>Anticancer properties</subject><subject>Antimitotic agents</subject><subject>Antineoplastic agents</subject><subject>Apoptosis</subject><subject>Biology and Life Sciences</subject><subject>Breast cancer</subject><subject>Cancer therapies</subject><subject>Carcinoma, Squamous Cell - pathology</subject><subject>Care and treatment</subject><subject>Cattle</subject><subject>Cell cycle</subject><subject>Cell Cycle - drug effects</subject><subject>Cell growth</subject><subject>Cell Line, Transformed</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Cytokines</subject><subject>Cytometry</subject><subject>Diagnosis</subject><subject>Dosage and administration</subject><subject>Epithelial cells</subject><subject>Flow cytometry</subject><subject>Health sciences</subject><subject>Humans</subject><subject>Keratinocytes</subject><subject>Kinases</subject><subject>Lactoferrin</subject><subject>Lactoferrin - pharmacology</subject><subject>Lactoferrins</subject><subject>Leukemia</subject><subject>Mouth Neoplasms - pathology</subject><subject>NF-κB protein</subject><subject>Oral cancer</subject><subject>Oral squamous cell carcinoma</subject><subject>p53 Protein</subject><subject>Pathways</subject><subject>Penicillin</subject><subject>Phosphorylation</subject><subject>Proteins</subject><subject>Rapamycin</subject><subject>S phase</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>SOCS-3 protein</subject><subject>Squamous cell carcinoma</subject><subject>Stat3 protein</subject><subject>Studies</subject><subject>TOR protein</subject><subject>Transferrin</subject><subject>Transferrins</subject><subject>Tumor suppressor genes</subject><subject>Western 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mechanism of inhibitory effects of bovine lactoferrin on the growth of oral squamous cell carcinoma</title><author>Chea, Chanbora ; Miyauchi, Mutsumi ; Inubushi, Toshihiro ; Febriyanti Ayuningtyas, Nurina ; Subarnbhesaj, Ajiravudh ; Nguyen, Phuong Thao ; Shrestha, Madhu ; Haing, Sivmeng ; Ohta, Kouji ; Takata, Takashi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-320c245333903f783428ea02c590a101059d8d6f3ff3ae3c0eaa1be48bf647f53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>AKT protein</topic><topic>Analysis</topic><topic>Animals</topic><topic>Anticancer properties</topic><topic>Antimitotic agents</topic><topic>Antineoplastic agents</topic><topic>Apoptosis</topic><topic>Biology and Life Sciences</topic><topic>Breast cancer</topic><topic>Cancer therapies</topic><topic>Carcinoma, Squamous Cell - pathology</topic><topic>Care and 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V.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Molecular mechanism of inhibitory effects of bovine lactoferrin on the growth of oral squamous cell carcinoma</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2018-01-30</date><risdate>2018</risdate><volume>13</volume><issue>1</issue><spage>e0191683</spage><epage>e0191683</epage><pages>e0191683-e0191683</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Lactoferrin (LF), a member of the transferrin family, recently has been demonstrated to have anticancer effects on various cancers including oral squamous cell carcinoma (OSCC). However, little is known about the underlying mechanisms of its effects on OSCC. Therefore, we aimed to investigate the mechanism of the suppressive effects of bovine LF (bLF) on the growth of OSCC cells.
In the current study, HSC2, HSC3, HSC4 and normal human oral keratinocytes (RT7) cell lines were tested with bLF 1, 10, and 100 μg/ml. The effects and detail mechanisms of bLF on proliferation and apoptosis of cells were investigated using flow cytometry and western blotting.
We found that bLF (1, 10, and 100 μg/ml) induced activation of p53, a tumor suppressor gene, is associated with the induction of cell cycle arrest in G1/S phase and apoptosis in OSCC. Moreover, bLF downregulated the phosphorylation of Akt and activated suppressor of cytokine signaling 3 (SOCS3), thereby attenuating multiple signaling pathways including mTOR/S6K and JAK/STAT3. Interestingly, we revealed that bLF exerted its effect selectively against HSC3 but not on RT7 via different effects on the phosphorylation status of NF-κB and Akt.
This is the first report showing that bLF selectively suppresses proliferation through mTOR/S6K and JAK/STAT3 pathways and induction of apoptosis in OSCC. This study provides important new findings, which might be useful in the prevention and treatment of OSCC.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>29381751</pmid><doi>10.1371/journal.pone.0191683</doi><tpages>e0191683</tpages><orcidid>https://orcid.org/0000-0002-5682-4215</orcidid><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1992661000 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | AKT protein Analysis Animals Anticancer properties Antimitotic agents Antineoplastic agents Apoptosis Biology and Life Sciences Breast cancer Cancer therapies Carcinoma, Squamous Cell - pathology Care and treatment Cattle Cell cycle Cell Cycle - drug effects Cell growth Cell Line, Transformed Cell proliferation Cell Proliferation - drug effects Cytokines Cytometry Diagnosis Dosage and administration Epithelial cells Flow cytometry Health sciences Humans Keratinocytes Kinases Lactoferrin Lactoferrin - pharmacology Lactoferrins Leukemia Mouth Neoplasms - pathology NF-κB protein Oral cancer Oral squamous cell carcinoma p53 Protein Pathways Penicillin Phosphorylation Proteins Rapamycin S phase Signal transduction Signaling SOCS-3 protein Squamous cell carcinoma Stat3 protein Studies TOR protein Transferrin Transferrins Tumor suppressor genes Western blotting |
| title | Molecular mechanism of inhibitory effects of bovine lactoferrin on the growth of oral squamous cell carcinoma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-31T14%3A53%3A13IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Molecular%20mechanism%20of%20inhibitory%20effects%20of%20bovine%20lactoferrin%20on%20the%20growth%20of%20oral%20squamous%20cell%20carcinoma&rft.jtitle=PloS%20one&rft.au=Chea,%20Chanbora&rft.date=2018-01-30&rft.volume=13&rft.issue=1&rft.spage=e0191683&rft.epage=e0191683&rft.pages=e0191683-e0191683&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0191683&rft_dat=%3Cgale_plos_%3EA525648501%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1992661000&rft_id=info:pmid/29381751&rft_galeid=A525648501&rft_doaj_id=oai_doaj_org_article_cbdfa91dc2604577a2ca9fe6dffcf7fb&rfr_iscdi=true |