Hypoxia-induced enrichment and mutagenesis of cells that have lost DNA mismatch repair
Loss of DNA mismatch repair (MMR) increases the risk of spontaneous mutations. We sought to determine whether there was an interaction between hypoxia and MMR deficiency that might contribute to the phenomenon of tumor progression. Human colon carcinoma HCT116+ch2 (MMR-deficient) and HCT116+ch3 (MMR...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2001-10, Vol.61 (20), p.7603-7607 |
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| container_title | Cancer research (Chicago, Ill.) |
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| creator | KONDO, Akira SAFAEI, Roohangiz MISHIMA, Misako NIEDNER, Hannes XINJIAN LIN HOWELL, Stephen B |
| description | Loss of DNA mismatch repair (MMR) increases the risk of spontaneous mutations. We sought to determine whether there was an interaction between hypoxia and MMR deficiency that might contribute to the phenomenon of tumor progression. Human colon carcinoma HCT116+ch2 (MMR-deficient) and HCT116+ch3 (MMR-proficient) sublines were exposed for varying periods of time to an environment of |
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We sought to determine whether there was an interaction between hypoxia and MMR deficiency that might contribute to the phenomenon of tumor progression. Human colon carcinoma HCT116+ch2 (MMR-deficient) and HCT116+ch3 (MMR-proficient) sublines were exposed for varying periods of time to an environment of <0.1% O2 and pH as low as 6.1. When a population containing 5% MMR-deficient cells and 95% MMR-proficient cells was subjected to hypoxia for 72 h, the MMR-deficient cells were enriched by a factor of 2-fold in the surviving population, whereas no enrichment was detected in cells maintained under aerobic conditions. The potential of hypoxia to destabilize the genome was determined by measuring the frequency of clones in the surviving population resistant to very high concentrations of 6-thioguanine or cisplatin. A 72-h exposure to hypoxia did not increase the frequency of resistant clones in the MMR-proficient cells but produced a 7.8-fold increase in 6-thioguanine-resistant clones and a 2.5-fold increase in cisplatin-resistant clones in the MMR-deficient cells. Loss of MMR increased the frequency of mutations in a reporter vector sensitive to frameshift mutations in a microsatellite sequence. Exposure to hypoxia for a time period as short as 48 h further increased the number of mutations in both cell types, but the absolute number of mutants was higher in the MMR-deficient cells. These results indicate that hypoxia and its accompanying low pH enrich for MMR-deficient cells and that loss of MMR renders human colon carcinoma cells hypersensitive to the ability of hypoxia to induce microsatellite instability and generate highly drug-resistant clones in the surviving population.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>PMID: 11606400</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>6-thioguanine ; Adenocarcinoma - genetics ; Adenocarcinoma - metabolism ; Base Pair Mismatch - genetics ; Biological and medical sciences ; Cell Hypoxia - genetics ; Cell physiology ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - metabolism ; DNA Repair ; Fundamental and applied biological sciences. Psychology ; Humans ; Hydrogen-Ion Concentration ; Microsatellite Repeats - genetics ; mismatch repair ; Molecular and cellular biology ; Mutagenesis - genetics ; Mutagenesis - physiology ; Tumor Cells, Cultured</subject><ispartof>Cancer research (Chicago, Ill.), 2001-10, Vol.61 (20), p.7603-7607</ispartof><rights>2002 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14106758$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11606400$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>KONDO, Akira</creatorcontrib><creatorcontrib>SAFAEI, Roohangiz</creatorcontrib><creatorcontrib>MISHIMA, Misako</creatorcontrib><creatorcontrib>NIEDNER, Hannes</creatorcontrib><creatorcontrib>XINJIAN LIN</creatorcontrib><creatorcontrib>HOWELL, Stephen B</creatorcontrib><title>Hypoxia-induced enrichment and mutagenesis of cells that have lost DNA mismatch repair</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Loss of DNA mismatch repair (MMR) increases the risk of spontaneous mutations. We sought to determine whether there was an interaction between hypoxia and MMR deficiency that might contribute to the phenomenon of tumor progression. Human colon carcinoma HCT116+ch2 (MMR-deficient) and HCT116+ch3 (MMR-proficient) sublines were exposed for varying periods of time to an environment of <0.1% O2 and pH as low as 6.1. When a population containing 5% MMR-deficient cells and 95% MMR-proficient cells was subjected to hypoxia for 72 h, the MMR-deficient cells were enriched by a factor of 2-fold in the surviving population, whereas no enrichment was detected in cells maintained under aerobic conditions. The potential of hypoxia to destabilize the genome was determined by measuring the frequency of clones in the surviving population resistant to very high concentrations of 6-thioguanine or cisplatin. A 72-h exposure to hypoxia did not increase the frequency of resistant clones in the MMR-proficient cells but produced a 7.8-fold increase in 6-thioguanine-resistant clones and a 2.5-fold increase in cisplatin-resistant clones in the MMR-deficient cells. Loss of MMR increased the frequency of mutations in a reporter vector sensitive to frameshift mutations in a microsatellite sequence. Exposure to hypoxia for a time period as short as 48 h further increased the number of mutations in both cell types, but the absolute number of mutants was higher in the MMR-deficient cells. These results indicate that hypoxia and its accompanying low pH enrich for MMR-deficient cells and that loss of MMR renders human colon carcinoma cells hypersensitive to the ability of hypoxia to induce microsatellite instability and generate highly drug-resistant clones in the surviving population.</description><subject>6-thioguanine</subject><subject>Adenocarcinoma - genetics</subject><subject>Adenocarcinoma - metabolism</subject><subject>Base Pair Mismatch - genetics</subject><subject>Biological and medical sciences</subject><subject>Cell Hypoxia - genetics</subject><subject>Cell physiology</subject><subject>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Colorectal Neoplasms - metabolism</subject><subject>DNA Repair</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>Microsatellite Repeats - genetics</subject><subject>mismatch repair</subject><subject>Molecular and cellular biology</subject><subject>Mutagenesis - genetics</subject><subject>Mutagenesis - physiology</subject><subject>Tumor Cells, Cultured</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpF0EtLAzEUBeAgiq3VvyDZ6G4gz0m6LPVRoehG3Q53kjtOZB51khH77x2x4upy4ONwuEdkzrW0mVFKH5M5Y8xmWhkxI2cxvk9Rc6ZPyYzznOWKsTl53ex3_VeALHR-dOgpdkNwdYtdotB52o4J3rDDGCLtK-qwaSJNNSRawyfSpo-J3jyuaBtiC8nVdMAdhOGcnFTQRLw43AV5ubt9Xm-y7dP9w3q1zWrJRMqWCM5JWyljXS6t4CC1Eww1K6Vnwhrp0NqcgzZSWW1KJyshPPjcqCUrvVyQ69_e3dB_jBhTMQ35GQkd9mMsuBVaK5VP8PIAx7JFX-yG0MKwL_4-MYGrA4DooKkG6FyI_05xlhtt5TdXoGeH</recordid><startdate>20011015</startdate><enddate>20011015</enddate><creator>KONDO, Akira</creator><creator>SAFAEI, Roohangiz</creator><creator>MISHIMA, Misako</creator><creator>NIEDNER, Hannes</creator><creator>XINJIAN LIN</creator><creator>HOWELL, Stephen B</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7TM</scope></search><sort><creationdate>20011015</creationdate><title>Hypoxia-induced enrichment and mutagenesis of cells that have lost DNA mismatch repair</title><author>KONDO, Akira ; SAFAEI, Roohangiz ; MISHIMA, Misako ; NIEDNER, Hannes ; XINJIAN LIN ; HOWELL, Stephen B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h302t-9eacc38f478c63821a35c20e50b3d02873ce8861a5734857bc3f22dad67490bd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>6-thioguanine</topic><topic>Adenocarcinoma - genetics</topic><topic>Adenocarcinoma - metabolism</topic><topic>Base Pair Mismatch - genetics</topic><topic>Biological and medical sciences</topic><topic>Cell Hypoxia - genetics</topic><topic>Cell physiology</topic><topic>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</topic><topic>Colorectal Neoplasms - genetics</topic><topic>Colorectal Neoplasms - metabolism</topic><topic>DNA Repair</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Humans</topic><topic>Hydrogen-Ion Concentration</topic><topic>Microsatellite Repeats - genetics</topic><topic>mismatch repair</topic><topic>Molecular and cellular biology</topic><topic>Mutagenesis - genetics</topic><topic>Mutagenesis - physiology</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>KONDO, Akira</creatorcontrib><creatorcontrib>SAFAEI, Roohangiz</creatorcontrib><creatorcontrib>MISHIMA, Misako</creatorcontrib><creatorcontrib>NIEDNER, Hannes</creatorcontrib><creatorcontrib>XINJIAN LIN</creatorcontrib><creatorcontrib>HOWELL, Stephen B</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Nucleic Acids Abstracts</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>KONDO, Akira</au><au>SAFAEI, Roohangiz</au><au>MISHIMA, Misako</au><au>NIEDNER, Hannes</au><au>XINJIAN LIN</au><au>HOWELL, Stephen B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hypoxia-induced enrichment and mutagenesis of cells that have lost DNA mismatch repair</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2001-10-15</date><risdate>2001</risdate><volume>61</volume><issue>20</issue><spage>7603</spage><epage>7607</epage><pages>7603-7607</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>Loss of DNA mismatch repair (MMR) increases the risk of spontaneous mutations. We sought to determine whether there was an interaction between hypoxia and MMR deficiency that might contribute to the phenomenon of tumor progression. Human colon carcinoma HCT116+ch2 (MMR-deficient) and HCT116+ch3 (MMR-proficient) sublines were exposed for varying periods of time to an environment of <0.1% O2 and pH as low as 6.1. When a population containing 5% MMR-deficient cells and 95% MMR-proficient cells was subjected to hypoxia for 72 h, the MMR-deficient cells were enriched by a factor of 2-fold in the surviving population, whereas no enrichment was detected in cells maintained under aerobic conditions. The potential of hypoxia to destabilize the genome was determined by measuring the frequency of clones in the surviving population resistant to very high concentrations of 6-thioguanine or cisplatin. A 72-h exposure to hypoxia did not increase the frequency of resistant clones in the MMR-proficient cells but produced a 7.8-fold increase in 6-thioguanine-resistant clones and a 2.5-fold increase in cisplatin-resistant clones in the MMR-deficient cells. Loss of MMR increased the frequency of mutations in a reporter vector sensitive to frameshift mutations in a microsatellite sequence. Exposure to hypoxia for a time period as short as 48 h further increased the number of mutations in both cell types, but the absolute number of mutants was higher in the MMR-deficient cells. These results indicate that hypoxia and its accompanying low pH enrich for MMR-deficient cells and that loss of MMR renders human colon carcinoma cells hypersensitive to the ability of hypoxia to induce microsatellite instability and generate highly drug-resistant clones in the surviving population.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>11606400</pmid><tpages>5</tpages></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research |
| subjects | 6-thioguanine Adenocarcinoma - genetics Adenocarcinoma - metabolism Base Pair Mismatch - genetics Biological and medical sciences Cell Hypoxia - genetics Cell physiology Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Colorectal Neoplasms - genetics Colorectal Neoplasms - metabolism DNA Repair Fundamental and applied biological sciences. Psychology Humans Hydrogen-Ion Concentration Microsatellite Repeats - genetics mismatch repair Molecular and cellular biology Mutagenesis - genetics Mutagenesis - physiology Tumor Cells, Cultured |
| title | Hypoxia-induced enrichment and mutagenesis of cells that have lost DNA mismatch repair |
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