Targeted inhibition of ATR or CHEK1 reverses radioresistance in oral squamous cell carcinoma cells with distal chromosome arm 11q loss
Oral squamous cell carcinoma (OSCC), a subset of head and neck squamous cell carcinoma (HNSCC), is the eighth most common cancer in the U.S.. Amplification of chromosomal band 11q13 and its association with poor prognosis has been well established in OSCC. The first step in the breakage‐fusion‐bridg...
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Veröffentlicht in: | Genes chromosomes & cancer 2014-02, Vol.53 (2), p.129-143 |
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description | Oral squamous cell carcinoma (OSCC), a subset of head and neck squamous cell carcinoma (HNSCC), is the eighth most common cancer in the U.S.. Amplification of chromosomal band 11q13 and its association with poor prognosis has been well established in OSCC. The first step in the breakage‐fusion‐bridge (BFB) cycle leading to 11q13 amplification involves breakage and loss of distal 11q. Distal 11q loss marked by copy number loss of the ATM gene is observed in 25% of all Cancer Genome Atlas (TCGA) tumors, including 48% of HNSCC. We showed previously that copy number loss of distal 11q is associated with decreased sensitivity (increased resistance) to ionizing radiation (IR) in OSCC cell lines. We hypothesized that this radioresistance phenotype associated with ATM copy number loss results from upregulation of the compensatory ATR‐CHEK1 pathway, and that knocking down the ATR‐CHEK1 pathway increases the sensitivity to IR of OSCC cells with distal 11q loss. Clonogenic survival assays confirmed the association between reduced sensitivity to IR in OSCC cell lines and distal 11q loss. Gene and protein expression studies revealed upregulation of the ATR‐CHEK1 pathway and flow cytometry showed G2M checkpoint arrest after IR treatment of cell lines with distal 11q loss. Targeted knockdown of the ATR‐CHEK1 pathway using CHEK1 or ATR siRNA or a CHEK1 small molecule inhibitor (SMI, PF‐00477736) resulted in increased sensitivity of the tumor cells to IR. Our results suggest that distal 11q loss is a useful biomarker in OSCC for radioresistance that can be reversed by ATR‐CHEK1 pathway inhibition. © 2013 Wiley Periodicals, Inc. |
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Amplification of chromosomal band 11q13 and its association with poor prognosis has been well established in OSCC. The first step in the breakage‐fusion‐bridge (BFB) cycle leading to 11q13 amplification involves breakage and loss of distal 11q. Distal 11q loss marked by copy number loss of the ATM gene is observed in 25% of all Cancer Genome Atlas (TCGA) tumors, including 48% of HNSCC. We showed previously that copy number loss of distal 11q is associated with decreased sensitivity (increased resistance) to ionizing radiation (IR) in OSCC cell lines. We hypothesized that this radioresistance phenotype associated with ATM copy number loss results from upregulation of the compensatory ATR‐CHEK1 pathway, and that knocking down the ATR‐CHEK1 pathway increases the sensitivity to IR of OSCC cells with distal 11q loss. Clonogenic survival assays confirmed the association between reduced sensitivity to IR in OSCC cell lines and distal 11q loss. Gene and protein expression studies revealed upregulation of the ATR‐CHEK1 pathway and flow cytometry showed G2M checkpoint arrest after IR treatment of cell lines with distal 11q loss. Targeted knockdown of the ATR‐CHEK1 pathway using CHEK1 or ATR siRNA or a CHEK1 small molecule inhibitor (SMI, PF‐00477736) resulted in increased sensitivity of the tumor cells to IR. 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Amplification of chromosomal band 11q13 and its association with poor prognosis has been well established in OSCC. The first step in the breakage‐fusion‐bridge (BFB) cycle leading to 11q13 amplification involves breakage and loss of distal 11q. Distal 11q loss marked by copy number loss of the ATM gene is observed in 25% of all Cancer Genome Atlas (TCGA) tumors, including 48% of HNSCC. We showed previously that copy number loss of distal 11q is associated with decreased sensitivity (increased resistance) to ionizing radiation (IR) in OSCC cell lines. We hypothesized that this radioresistance phenotype associated with ATM copy number loss results from upregulation of the compensatory ATR‐CHEK1 pathway, and that knocking down the ATR‐CHEK1 pathway increases the sensitivity to IR of OSCC cells with distal 11q loss. Clonogenic survival assays confirmed the association between reduced sensitivity to IR in OSCC cell lines and distal 11q loss. Gene and protein expression studies revealed upregulation of the ATR‐CHEK1 pathway and flow cytometry showed G2M checkpoint arrest after IR treatment of cell lines with distal 11q loss. Targeted knockdown of the ATR‐CHEK1 pathway using CHEK1 or ATR siRNA or a CHEK1 small molecule inhibitor (SMI, PF‐00477736) resulted in increased sensitivity of the tumor cells to IR. Our results suggest that distal 11q loss is a useful biomarker in OSCC for radioresistance that can be reversed by ATR‐CHEK1 pathway inhibition. © 2013 Wiley Periodicals, Inc.</description><subject>Ataxia Telangiectasia Mutated Proteins - genetics</subject><subject>Ataxia Telangiectasia Mutated Proteins - metabolism</subject><subject>Carcinoma, Squamous Cell - genetics</subject><subject>Carcinoma, Squamous Cell - radiotherapy</subject><subject>Cell Line, Tumor - radiation effects</subject><subject>Checkpoint Kinase 1</subject><subject>Chromosome Deletion</subject><subject>Chromosome Segregation</subject><subject>Chromosomes, Human, Pair 11 - genetics</subject><subject>DNA Damage</subject><subject>Gene Knockdown Techniques</subject><subject>Humans</subject><subject>M Phase Cell Cycle Checkpoints</subject><subject>Mouth Neoplasms - genetics</subject><subject>Mouth Neoplasms - radiotherapy</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Kinases - genetics</subject><subject>Protein Kinases - metabolism</subject><subject>Radiation Tolerance</subject><subject>Signal Transduction</subject><subject>Up-Regulation</subject><issn>1045-2257</issn><issn>1098-2264</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kd1uEzEQhS0EoiVwwQsgS9yUi7S21_Zmb5CqVZNFVOVHQVxajjObuOyuG3u3Py_Q52bStBEgceWx_c3RnDmEvOXsmDMmTlbOHQvBhXpGDjkrJmMhtHy-raXCWuUH5FVKl4wxnRXqJTkQMhO5kuKQ3M9tXEEPS-q7tV_43oeOhpqezr_TEGlZnX3mNMI1xASJRrv0IULyqbedA-xByDY0bQbbhiFRB01DnY3Od6G1D9dEb3y_psttD_6tY2hDCi1QG1vK-YY2IaXX5EVtmwRvHs8R-TE9m5fV-PzL7FN5ej52iqMXbnVWO7sQUmdaQyFy0Hm-4PguLLeTZS01oMc6m3DBpFNOgFNQM6sKXhcuG5GPO92rYdHC0kHX4_zmKvrWxjsTrDd__3R-bVbh2kjBtSoyFDh6FIhhM0DqTevT1qbtABdguCyE5kpohuj7f9DLMMQO7SGl0YCSqDgiH3aUi7iHCPV-GM7MNl2D6ZqHdJF99-f0e_IpTgROdsCNb-Du_0pmVpZPkuNdB8YDt_sOG38ZnWe5Mj8vZqa6mFbVlH8137Lfcdy-0w</recordid><startdate>201402</startdate><enddate>201402</enddate><creator>Sankunny, Madhav</creator><creator>Parikh, Rahul A.</creator><creator>Lewis, Dale W.</creator><creator>Gooding, William E.</creator><creator>Saunders, William S.</creator><creator>Gollin, Susanne M.</creator><general>Blackwell Publishing Ltd</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</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>7QP</scope><scope>7TM</scope><scope>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>201402</creationdate><title>Targeted inhibition of ATR or CHEK1 reverses radioresistance in oral squamous cell carcinoma cells with distal chromosome arm 11q loss</title><author>Sankunny, Madhav ; Parikh, Rahul A. ; Lewis, Dale W. ; Gooding, William E. ; Saunders, William S. ; Gollin, Susanne M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5145-1a63fcab246366e927e677b11a62a1a8df46e639f381204c5c2ec5ef0a591f9c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Ataxia Telangiectasia Mutated Proteins - genetics</topic><topic>Ataxia Telangiectasia Mutated Proteins - metabolism</topic><topic>Carcinoma, Squamous Cell - genetics</topic><topic>Carcinoma, Squamous Cell - radiotherapy</topic><topic>Cell Line, Tumor - radiation effects</topic><topic>Checkpoint Kinase 1</topic><topic>Chromosome Deletion</topic><topic>Chromosome Segregation</topic><topic>Chromosomes, Human, Pair 11 - genetics</topic><topic>DNA Damage</topic><topic>Gene Knockdown Techniques</topic><topic>Humans</topic><topic>M Phase Cell Cycle Checkpoints</topic><topic>Mouth Neoplasms - genetics</topic><topic>Mouth Neoplasms - radiotherapy</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Kinases - genetics</topic><topic>Protein Kinases - metabolism</topic><topic>Radiation Tolerance</topic><topic>Signal Transduction</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sankunny, Madhav</creatorcontrib><creatorcontrib>Parikh, Rahul A.</creatorcontrib><creatorcontrib>Lewis, Dale W.</creatorcontrib><creatorcontrib>Gooding, William E.</creatorcontrib><creatorcontrib>Saunders, William S.</creatorcontrib><creatorcontrib>Gollin, Susanne M.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Genes chromosomes & cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sankunny, Madhav</au><au>Parikh, Rahul A.</au><au>Lewis, Dale W.</au><au>Gooding, William E.</au><au>Saunders, William S.</au><au>Gollin, Susanne M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeted inhibition of ATR or CHEK1 reverses radioresistance in oral squamous cell carcinoma cells with distal chromosome arm 11q loss</atitle><jtitle>Genes chromosomes & cancer</jtitle><addtitle>Genes Chromosomes Cancer</addtitle><date>2014-02</date><risdate>2014</risdate><volume>53</volume><issue>2</issue><spage>129</spage><epage>143</epage><pages>129-143</pages><issn>1045-2257</issn><eissn>1098-2264</eissn><coden>GCCAES</coden><abstract>Oral squamous cell carcinoma (OSCC), a subset of head and neck squamous cell carcinoma (HNSCC), is the eighth most common cancer in the U.S.. Amplification of chromosomal band 11q13 and its association with poor prognosis has been well established in OSCC. The first step in the breakage‐fusion‐bridge (BFB) cycle leading to 11q13 amplification involves breakage and loss of distal 11q. Distal 11q loss marked by copy number loss of the ATM gene is observed in 25% of all Cancer Genome Atlas (TCGA) tumors, including 48% of HNSCC. We showed previously that copy number loss of distal 11q is associated with decreased sensitivity (increased resistance) to ionizing radiation (IR) in OSCC cell lines. We hypothesized that this radioresistance phenotype associated with ATM copy number loss results from upregulation of the compensatory ATR‐CHEK1 pathway, and that knocking down the ATR‐CHEK1 pathway increases the sensitivity to IR of OSCC cells with distal 11q loss. Clonogenic survival assays confirmed the association between reduced sensitivity to IR in OSCC cell lines and distal 11q loss. Gene and protein expression studies revealed upregulation of the ATR‐CHEK1 pathway and flow cytometry showed G2M checkpoint arrest after IR treatment of cell lines with distal 11q loss. Targeted knockdown of the ATR‐CHEK1 pathway using CHEK1 or ATR siRNA or a CHEK1 small molecule inhibitor (SMI, PF‐00477736) resulted in increased sensitivity of the tumor cells to IR. Our results suggest that distal 11q loss is a useful biomarker in OSCC for radioresistance that can be reversed by ATR‐CHEK1 pathway inhibition. © 2013 Wiley Periodicals, Inc.</abstract><cop>United States</cop><pub>Blackwell Publishing Ltd</pub><pmid>24327542</pmid><doi>10.1002/gcc.22125</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Ataxia Telangiectasia Mutated Proteins - genetics Ataxia Telangiectasia Mutated Proteins - metabolism Carcinoma, Squamous Cell - genetics Carcinoma, Squamous Cell - radiotherapy Cell Line, Tumor - radiation effects Checkpoint Kinase 1 Chromosome Deletion Chromosome Segregation Chromosomes, Human, Pair 11 - genetics DNA Damage Gene Knockdown Techniques Humans M Phase Cell Cycle Checkpoints Mouth Neoplasms - genetics Mouth Neoplasms - radiotherapy Protein Kinase Inhibitors - pharmacology Protein Kinases - genetics Protein Kinases - metabolism Radiation Tolerance Signal Transduction Up-Regulation |
title | Targeted inhibition of ATR or CHEK1 reverses radioresistance in oral squamous cell carcinoma cells with distal chromosome arm 11q loss |
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