SAHA Overcomes 5-FU Resistance in IFIT2-Depleted Oral Squamous Cell Carcinoma Cells
Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) is a member of the interferon-stimulated gene family that contains tetratricopeptide repeats (TPRs), which mediate protein-protein interactions in various biological systems. We previously showed the depletion of IFIT2 enhanced cell...
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| Veröffentlicht in: | Cancers 2020-11, Vol.12 (12), p.3527 |
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| description | Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) is a member of the interferon-stimulated gene family that contains tetratricopeptide repeats (TPRs), which mediate protein-protein interactions in various biological systems. We previously showed the depletion of IFIT2 enhanced cell migration and metastatic activity in oral squamous cell carcinoma (OSCC) cells via the activation of atypical PKC signaling. In this study, we found that IFIT2-knockdown cells displayed higher resistance to 5-fluorouracil (5-FU) than control cells. The comet assay and annexin V analysis showed decreased DNA damage and cell death in IFIT2-knockdown cells compared to control cells treated with 5-FU. Cell cycle progression was also perturbed by 5-FU treatment, with the accumulation of IFIT2-depleted cells in S phase in a time-dependent manner. We further observed the overexpression of thymidylate synthase (TS) and thymidine kinase (TK) in IFIT2-knockdown cells. Inhibition of TS alone or double inhibition of TS and TK1 using the siRNA technique increased susceptibility to 5-FU in IFIT2-knockdown cells. We further identified that suberanilohydroxamic acid (SAHA) treatment decreased the expression of TS in IFIT2-knockdown cells and demonstrated that pretreatment with SAHA sensitized IFIT2-knockdown cells to 5-FU in vitro and in vivo. In conclusion, IFIT2 knockdown enhances TS expression, which mediates 5-FU resistance, and SAHA pretreatment suppresses TS expression and hence sensitizes cells to 5-FU. SAHA will be an effective strategy for the treatment of OSCC patients with 5-FU resistance. |
| doi_str_mv | 10.3390/cancers12123527 |
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We previously showed the depletion of IFIT2 enhanced cell migration and metastatic activity in oral squamous cell carcinoma (OSCC) cells via the activation of atypical PKC signaling. In this study, we found that IFIT2-knockdown cells displayed higher resistance to 5-fluorouracil (5-FU) than control cells. The comet assay and annexin V analysis showed decreased DNA damage and cell death in IFIT2-knockdown cells compared to control cells treated with 5-FU. Cell cycle progression was also perturbed by 5-FU treatment, with the accumulation of IFIT2-depleted cells in S phase in a time-dependent manner. We further observed the overexpression of thymidylate synthase (TS) and thymidine kinase (TK) in IFIT2-knockdown cells. Inhibition of TS alone or double inhibition of TS and TK1 using the siRNA technique increased susceptibility to 5-FU in IFIT2-knockdown cells. We further identified that suberanilohydroxamic acid (SAHA) treatment decreased the expression of TS in IFIT2-knockdown cells and demonstrated that pretreatment with SAHA sensitized IFIT2-knockdown cells to 5-FU in vitro and in vivo. In conclusion, IFIT2 knockdown enhances TS expression, which mediates 5-FU resistance, and SAHA pretreatment suppresses TS expression and hence sensitizes cells to 5-FU. SAHA will be an effective strategy for the treatment of OSCC patients with 5-FU resistance.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers12123527</identifier><identifier>PMID: 33256074</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>5-Fluorouracil ; Angiogenesis ; Annexin V ; Apoptosis ; Biomarkers ; Cancer therapies ; Cell activation ; Cell cycle ; Cell death ; Cell migration ; Chemotherapy ; Clinical trials ; Comet assay ; Cytotoxicity ; Deoxyribonucleic acid ; DNA ; DNA damage ; Drug resistance ; Interferon ; Kinases ; Medical prognosis ; Metastases ; Metastasis ; Oral squamous cell carcinoma ; Population ; Protein interaction ; Protein kinase C ; Proteins ; S phase ; siRNA ; Squamous cell carcinoma ; Thymidine ; Thymidine kinase ; Thymidylate synthase</subject><ispartof>Cancers, 2020-11, Vol.12 (12), p.3527</ispartof><rights>2020. This work is licensed under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 by the authors. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c421t-a1f2862ebb610f1c691ef07a580e93a49234f4c18cc31022b1a5389bbe05c3b53</citedby><cites>FETCH-LOGICAL-c421t-a1f2862ebb610f1c691ef07a580e93a49234f4c18cc31022b1a5389bbe05c3b53</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/PMC7761248/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761248/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33256074$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Regmi, Prabha</creatorcontrib><creatorcontrib>Lai, Kuo-Chu</creatorcontrib><creatorcontrib>Liu, Chung-Ji</creatorcontrib><creatorcontrib>Lee, Te-Chang</creatorcontrib><title>SAHA Overcomes 5-FU Resistance in IFIT2-Depleted Oral Squamous Cell Carcinoma Cells</title><title>Cancers</title><addtitle>Cancers (Basel)</addtitle><description>Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) is a member of the interferon-stimulated gene family that contains tetratricopeptide repeats (TPRs), which mediate protein-protein interactions in various biological systems. We previously showed the depletion of IFIT2 enhanced cell migration and metastatic activity in oral squamous cell carcinoma (OSCC) cells via the activation of atypical PKC signaling. In this study, we found that IFIT2-knockdown cells displayed higher resistance to 5-fluorouracil (5-FU) than control cells. The comet assay and annexin V analysis showed decreased DNA damage and cell death in IFIT2-knockdown cells compared to control cells treated with 5-FU. Cell cycle progression was also perturbed by 5-FU treatment, with the accumulation of IFIT2-depleted cells in S phase in a time-dependent manner. We further observed the overexpression of thymidylate synthase (TS) and thymidine kinase (TK) in IFIT2-knockdown cells. Inhibition of TS alone or double inhibition of TS and TK1 using the siRNA technique increased susceptibility to 5-FU in IFIT2-knockdown cells. We further identified that suberanilohydroxamic acid (SAHA) treatment decreased the expression of TS in IFIT2-knockdown cells and demonstrated that pretreatment with SAHA sensitized IFIT2-knockdown cells to 5-FU in vitro and in vivo. In conclusion, IFIT2 knockdown enhances TS expression, which mediates 5-FU resistance, and SAHA pretreatment suppresses TS expression and hence sensitizes cells to 5-FU. SAHA will be an effective strategy for the treatment of OSCC patients with 5-FU resistance.</description><subject>5-Fluorouracil</subject><subject>Angiogenesis</subject><subject>Annexin V</subject><subject>Apoptosis</subject><subject>Biomarkers</subject><subject>Cancer therapies</subject><subject>Cell activation</subject><subject>Cell cycle</subject><subject>Cell death</subject><subject>Cell migration</subject><subject>Chemotherapy</subject><subject>Clinical trials</subject><subject>Comet assay</subject><subject>Cytotoxicity</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA damage</subject><subject>Drug resistance</subject><subject>Interferon</subject><subject>Kinases</subject><subject>Medical prognosis</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Oral squamous cell carcinoma</subject><subject>Population</subject><subject>Protein interaction</subject><subject>Protein kinase C</subject><subject>Proteins</subject><subject>S phase</subject><subject>siRNA</subject><subject>Squamous cell carcinoma</subject><subject>Thymidine</subject><subject>Thymidine kinase</subject><subject>Thymidylate synthase</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdUU1rwkAQXUpLFeu5t7LQc-p-J7kUxNYqCELV87JZJ20kH7qbCP33jdWK7Vxmhnnz5jEPoXtKnjiPycCa0oLzlFHGJQuvUJeRkAVKxeL6ou6gvvcb0gbnNFThLepwzqQioeiixWI4GeL5HpytCvBYBuMVfgef-frAjrMST8fTJQteYJtDDWs8dybHi11jiqrxeAR5jkfG2aysCvPT-jt0k5rcQ_-Ue2g1fl2OJsFs_jYdDWeBFYzWgaEpixSDJFGUpNSqmEJKQiMjAjE3ImZcpMLSyFpOCWMJNZJHcZIAkZYnkvfQ85F32yQFrC2UdatNb11WGPelK5Ppv5My-9Qf1V6HoaJMRC3B44nAVbsGfK03VePKVrNmQslIsljwFjU4oqyrvHeQni9Qog9G6H9GtBsPl8LO-N-3828KYoOb</recordid><startdate>20201126</startdate><enddate>20201126</enddate><creator>Regmi, Prabha</creator><creator>Lai, Kuo-Chu</creator><creator>Liu, Chung-Ji</creator><creator>Lee, Te-Chang</creator><general>MDPI AG</general><general>MDPI</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</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>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>5PM</scope></search><sort><creationdate>20201126</creationdate><title>SAHA Overcomes 5-FU Resistance in IFIT2-Depleted Oral Squamous Cell Carcinoma Cells</title><author>Regmi, Prabha ; Lai, Kuo-Chu ; Liu, Chung-Ji ; Lee, Te-Chang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c421t-a1f2862ebb610f1c691ef07a580e93a49234f4c18cc31022b1a5389bbe05c3b53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>5-Fluorouracil</topic><topic>Angiogenesis</topic><topic>Annexin V</topic><topic>Apoptosis</topic><topic>Biomarkers</topic><topic>Cancer therapies</topic><topic>Cell activation</topic><topic>Cell cycle</topic><topic>Cell death</topic><topic>Cell migration</topic><topic>Chemotherapy</topic><topic>Clinical trials</topic><topic>Comet assay</topic><topic>Cytotoxicity</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA damage</topic><topic>Drug resistance</topic><topic>Interferon</topic><topic>Kinases</topic><topic>Medical prognosis</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Oral squamous cell carcinoma</topic><topic>Population</topic><topic>Protein interaction</topic><topic>Protein kinase C</topic><topic>Proteins</topic><topic>S phase</topic><topic>siRNA</topic><topic>Squamous cell carcinoma</topic><topic>Thymidine</topic><topic>Thymidine kinase</topic><topic>Thymidylate synthase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Regmi, Prabha</creatorcontrib><creatorcontrib>Lai, Kuo-Chu</creatorcontrib><creatorcontrib>Liu, Chung-Ji</creatorcontrib><creatorcontrib>Lee, Te-Chang</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</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>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</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 Basic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancers</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Regmi, Prabha</au><au>Lai, Kuo-Chu</au><au>Liu, Chung-Ji</au><au>Lee, Te-Chang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>SAHA Overcomes 5-FU Resistance in IFIT2-Depleted Oral Squamous Cell Carcinoma Cells</atitle><jtitle>Cancers</jtitle><addtitle>Cancers (Basel)</addtitle><date>2020-11-26</date><risdate>2020</risdate><volume>12</volume><issue>12</issue><spage>3527</spage><pages>3527-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><abstract>Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) is a member of the interferon-stimulated gene family that contains tetratricopeptide repeats (TPRs), which mediate protein-protein interactions in various biological systems. We previously showed the depletion of IFIT2 enhanced cell migration and metastatic activity in oral squamous cell carcinoma (OSCC) cells via the activation of atypical PKC signaling. In this study, we found that IFIT2-knockdown cells displayed higher resistance to 5-fluorouracil (5-FU) than control cells. The comet assay and annexin V analysis showed decreased DNA damage and cell death in IFIT2-knockdown cells compared to control cells treated with 5-FU. Cell cycle progression was also perturbed by 5-FU treatment, with the accumulation of IFIT2-depleted cells in S phase in a time-dependent manner. We further observed the overexpression of thymidylate synthase (TS) and thymidine kinase (TK) in IFIT2-knockdown cells. Inhibition of TS alone or double inhibition of TS and TK1 using the siRNA technique increased susceptibility to 5-FU in IFIT2-knockdown cells. We further identified that suberanilohydroxamic acid (SAHA) treatment decreased the expression of TS in IFIT2-knockdown cells and demonstrated that pretreatment with SAHA sensitized IFIT2-knockdown cells to 5-FU in vitro and in vivo. In conclusion, IFIT2 knockdown enhances TS expression, which mediates 5-FU resistance, and SAHA pretreatment suppresses TS expression and hence sensitizes cells to 5-FU. SAHA will be an effective strategy for the treatment of OSCC patients with 5-FU resistance.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>33256074</pmid><doi>10.3390/cancers12123527</doi><oa>free_for_read</oa></addata></record> |
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| subjects | 5-Fluorouracil Angiogenesis Annexin V Apoptosis Biomarkers Cancer therapies Cell activation Cell cycle Cell death Cell migration Chemotherapy Clinical trials Comet assay Cytotoxicity Deoxyribonucleic acid DNA DNA damage Drug resistance Interferon Kinases Medical prognosis Metastases Metastasis Oral squamous cell carcinoma Population Protein interaction Protein kinase C Proteins S phase siRNA Squamous cell carcinoma Thymidine Thymidine kinase Thymidylate synthase |
| title | SAHA Overcomes 5-FU Resistance in IFIT2-Depleted Oral Squamous Cell Carcinoma Cells |
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