Cetuximab reverses the Warburg effect by inhibiting HIF-1-regulated LDH-A
Hypoxia-inducible factor-1 (HIF-1) plays a critical role in reprogramming cancer metabolism toward aerobic glycolysis (i.e., the Warburg effect), which is critical to supplying cancer cells with the biomass needed for proliferation. Previous studies have shown that cetuximab, an EGF receptor-blockin...
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Veröffentlicht in: | Molecular cancer therapeutics 2013-10, Vol.12 (10), p.2187-2199 |
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description | Hypoxia-inducible factor-1 (HIF-1) plays a critical role in reprogramming cancer metabolism toward aerobic glycolysis (i.e., the Warburg effect), which is critical to supplying cancer cells with the biomass needed for proliferation. Previous studies have shown that cetuximab, an EGF receptor-blocking monoclonal antibody, downregulates the alpha subunit of HIF-1 (HIF-1α) through the inhibition of EGF receptor downstream cell signaling and that downregulation of HIF-1α is required for cetuximab-induced antiproliferative effects. However, the mechanism underlying these actions has yet to be identified. In this study, we used the Seahorse XF96 extracellular flux analyzer to assess the effect of cetuximab treatment on changes in glycolysis and mitochondrial respiration, the two major energy-producing pathways, in live cells. We found that cetuximab downregulated lactate dehydrogenase A (LDH-A) and inhibited glycolysis in cetuximab-sensitive head and neck squamous cell carcinoma (HNSCC) cells in an HIF-1α downregulation-dependent manner. HNSCC cells with acquired cetuximab resistance expressed a high level of HIF-1α and were highly glycolytic. Overexpression of a HIF-1α mutant (HIF-1α/ΔODD) conferred resistance to cetuximab-induced G1 phase cell-cycle arrest, which could be overcome by knockdown of LDH-A expression. Inhibition of LDH-A activity with oxamate enhanced the response of cetuximab-resistant cells to cetuximab. Cetuximab had no noticeable inhibitory effect on glycolysis in nontransformed cells. These findings provide novel mechanistic insights into cetuximab-induced cell-cycle arrest from the perspective of cancer metabolism and suggest novel strategies for enhancing cetuximab response. |
doi_str_mv | 10.1158/1535-7163.mct-12-1245 |
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Previous studies have shown that cetuximab, an EGF receptor-blocking monoclonal antibody, downregulates the alpha subunit of HIF-1 (HIF-1α) through the inhibition of EGF receptor downstream cell signaling and that downregulation of HIF-1α is required for cetuximab-induced antiproliferative effects. However, the mechanism underlying these actions has yet to be identified. In this study, we used the Seahorse XF96 extracellular flux analyzer to assess the effect of cetuximab treatment on changes in glycolysis and mitochondrial respiration, the two major energy-producing pathways, in live cells. We found that cetuximab downregulated lactate dehydrogenase A (LDH-A) and inhibited glycolysis in cetuximab-sensitive head and neck squamous cell carcinoma (HNSCC) cells in an HIF-1α downregulation-dependent manner. HNSCC cells with acquired cetuximab resistance expressed a high level of HIF-1α and were highly glycolytic. Overexpression of a HIF-1α mutant (HIF-1α/ΔODD) conferred resistance to cetuximab-induced G1 phase cell-cycle arrest, which could be overcome by knockdown of LDH-A expression. Inhibition of LDH-A activity with oxamate enhanced the response of cetuximab-resistant cells to cetuximab. Cetuximab had no noticeable inhibitory effect on glycolysis in nontransformed cells. These findings provide novel mechanistic insights into cetuximab-induced cell-cycle arrest from the perspective of cancer metabolism and suggest novel strategies for enhancing cetuximab response.</description><identifier>ISSN: 1535-7163</identifier><identifier>EISSN: 1538-8514</identifier><identifier>DOI: 10.1158/1535-7163.mct-12-1245</identifier><identifier>PMID: 23920275</identifier><language>eng</language><publisher>United States</publisher><subject>Antibodies, Monoclonal, Humanized - administration & dosage ; Biomarkers, Pharmacological ; Carcinoma, Squamous Cell - drug therapy ; Carcinoma, Squamous Cell - genetics ; Carcinoma, Squamous Cell - pathology ; Cell Cycle Checkpoints - drug effects ; Cell Line, Tumor ; Cell Respiration - drug effects ; Cetuximab ; Gene Expression Regulation, Neoplastic - drug effects ; Glycolysis - drug effects ; Glycolysis - genetics ; Head and Neck Neoplasms - drug therapy ; Head and Neck Neoplasms - genetics ; Head and Neck Neoplasms - pathology ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit - biosynthesis ; Hypoxia-Inducible Factor 1, alpha Subunit - genetics ; Isoenzymes - antagonists & inhibitors ; Isoenzymes - biosynthesis ; Isoenzymes - genetics ; L-Lactate Dehydrogenase - antagonists & inhibitors ; L-Lactate Dehydrogenase - biosynthesis ; L-Lactate Dehydrogenase - genetics ; Mitochondria - drug effects ; Receptor, Epidermal Growth Factor - antagonists & inhibitors</subject><ispartof>Molecular cancer therapeutics, 2013-10, Vol.12 (10), p.2187-2199</ispartof><rights>2013 AACR.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c529t-c4f615d85bc50e39c477b53683f0cc0516dbafb458cb31888e1c4570536e8b503</citedby><cites>FETCH-LOGICAL-c529t-c4f615d85bc50e39c477b53683f0cc0516dbafb458cb31888e1c4570536e8b503</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3356,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23920275$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lu, Haiquan</creatorcontrib><creatorcontrib>Li, Xinqun</creatorcontrib><creatorcontrib>Luo, Zhongguang</creatorcontrib><creatorcontrib>Liu, Jie</creatorcontrib><creatorcontrib>Fan, Zhen</creatorcontrib><title>Cetuximab reverses the Warburg effect by inhibiting HIF-1-regulated LDH-A</title><title>Molecular cancer therapeutics</title><addtitle>Mol Cancer Ther</addtitle><description>Hypoxia-inducible factor-1 (HIF-1) plays a critical role in reprogramming cancer metabolism toward aerobic glycolysis (i.e., the Warburg effect), which is critical to supplying cancer cells with the biomass needed for proliferation. Previous studies have shown that cetuximab, an EGF receptor-blocking monoclonal antibody, downregulates the alpha subunit of HIF-1 (HIF-1α) through the inhibition of EGF receptor downstream cell signaling and that downregulation of HIF-1α is required for cetuximab-induced antiproliferative effects. However, the mechanism underlying these actions has yet to be identified. In this study, we used the Seahorse XF96 extracellular flux analyzer to assess the effect of cetuximab treatment on changes in glycolysis and mitochondrial respiration, the two major energy-producing pathways, in live cells. We found that cetuximab downregulated lactate dehydrogenase A (LDH-A) and inhibited glycolysis in cetuximab-sensitive head and neck squamous cell carcinoma (HNSCC) cells in an HIF-1α downregulation-dependent manner. HNSCC cells with acquired cetuximab resistance expressed a high level of HIF-1α and were highly glycolytic. Overexpression of a HIF-1α mutant (HIF-1α/ΔODD) conferred resistance to cetuximab-induced G1 phase cell-cycle arrest, which could be overcome by knockdown of LDH-A expression. Inhibition of LDH-A activity with oxamate enhanced the response of cetuximab-resistant cells to cetuximab. Cetuximab had no noticeable inhibitory effect on glycolysis in nontransformed cells. These findings provide novel mechanistic insights into cetuximab-induced cell-cycle arrest from the perspective of cancer metabolism and suggest novel strategies for enhancing cetuximab response.</description><subject>Antibodies, Monoclonal, Humanized - administration & dosage</subject><subject>Biomarkers, Pharmacological</subject><subject>Carcinoma, Squamous Cell - drug therapy</subject><subject>Carcinoma, Squamous Cell - genetics</subject><subject>Carcinoma, Squamous Cell - pathology</subject><subject>Cell Cycle Checkpoints - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cell Respiration - drug effects</subject><subject>Cetuximab</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Glycolysis - drug effects</subject><subject>Glycolysis - genetics</subject><subject>Head and Neck Neoplasms - drug therapy</subject><subject>Head and Neck Neoplasms - genetics</subject><subject>Head and Neck Neoplasms - pathology</subject><subject>Humans</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - biosynthesis</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - genetics</subject><subject>Isoenzymes - antagonists & inhibitors</subject><subject>Isoenzymes - biosynthesis</subject><subject>Isoenzymes - genetics</subject><subject>L-Lactate Dehydrogenase - antagonists & inhibitors</subject><subject>L-Lactate Dehydrogenase - biosynthesis</subject><subject>L-Lactate Dehydrogenase - genetics</subject><subject>Mitochondria - drug effects</subject><subject>Receptor, Epidermal Growth Factor - antagonists & inhibitors</subject><issn>1535-7163</issn><issn>1538-8514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkGFLwzAQhoMobk5_gpI_kJlrmjb9Iozq3GDil4kfQ5Neu8rWjTQd7t_bOh0KB3fc3fse9xByC3wMINU9SCFZDJEYb6xnEHQRyjMy7PqKKQnh-Xd93BmQq6b54BxUEsAlGQQiCXgQyyGZp-jbz2qTGepwj67BhvoV0vfMmdaVFIsCrafmQKt6VZnKV3VJZ_MpA-awbNeZx5wuHmdsck0uimzd4M1PHpG36dMynbHF6_M8nSyYlUHimQ2LCGSupLGSo0hsGMdGikiJglvLJUS5yQoTSmWNAKUUgg1lzLsVVEZyMSIPR99dazaYW6y9y9Z657on3EFvs0r_n9TVSpfbvRYKgPO4M5BHA-u2TeOwOGmB656t7rnpnpt-SZcaAt2z7XR3fw-fVL8wxRenbXWm</recordid><startdate>20131001</startdate><enddate>20131001</enddate><creator>Lu, Haiquan</creator><creator>Li, Xinqun</creator><creator>Luo, Zhongguang</creator><creator>Liu, Jie</creator><creator>Fan, Zhen</creator><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>5PM</scope></search><sort><creationdate>20131001</creationdate><title>Cetuximab reverses the Warburg effect by inhibiting HIF-1-regulated LDH-A</title><author>Lu, Haiquan ; Li, Xinqun ; Luo, Zhongguang ; Liu, Jie ; Fan, Zhen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c529t-c4f615d85bc50e39c477b53683f0cc0516dbafb458cb31888e1c4570536e8b503</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Antibodies, Monoclonal, Humanized - administration & dosage</topic><topic>Biomarkers, Pharmacological</topic><topic>Carcinoma, Squamous Cell - drug therapy</topic><topic>Carcinoma, Squamous Cell - genetics</topic><topic>Carcinoma, Squamous Cell - pathology</topic><topic>Cell Cycle Checkpoints - drug effects</topic><topic>Cell Line, Tumor</topic><topic>Cell Respiration - drug effects</topic><topic>Cetuximab</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Glycolysis - drug effects</topic><topic>Glycolysis - genetics</topic><topic>Head and Neck Neoplasms - drug therapy</topic><topic>Head and Neck Neoplasms - genetics</topic><topic>Head and Neck Neoplasms - pathology</topic><topic>Humans</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - biosynthesis</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - genetics</topic><topic>Isoenzymes - antagonists & inhibitors</topic><topic>Isoenzymes - biosynthesis</topic><topic>Isoenzymes - genetics</topic><topic>L-Lactate Dehydrogenase - antagonists & inhibitors</topic><topic>L-Lactate Dehydrogenase - biosynthesis</topic><topic>L-Lactate Dehydrogenase - genetics</topic><topic>Mitochondria - drug effects</topic><topic>Receptor, Epidermal Growth Factor - antagonists & inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lu, Haiquan</creatorcontrib><creatorcontrib>Li, Xinqun</creatorcontrib><creatorcontrib>Luo, Zhongguang</creatorcontrib><creatorcontrib>Liu, Jie</creatorcontrib><creatorcontrib>Fan, Zhen</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular cancer therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lu, Haiquan</au><au>Li, Xinqun</au><au>Luo, Zhongguang</au><au>Liu, Jie</au><au>Fan, Zhen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cetuximab reverses the Warburg effect by inhibiting HIF-1-regulated LDH-A</atitle><jtitle>Molecular cancer therapeutics</jtitle><addtitle>Mol Cancer Ther</addtitle><date>2013-10-01</date><risdate>2013</risdate><volume>12</volume><issue>10</issue><spage>2187</spage><epage>2199</epage><pages>2187-2199</pages><issn>1535-7163</issn><eissn>1538-8514</eissn><abstract>Hypoxia-inducible factor-1 (HIF-1) plays a critical role in reprogramming cancer metabolism toward aerobic glycolysis (i.e., the Warburg effect), which is critical to supplying cancer cells with the biomass needed for proliferation. Previous studies have shown that cetuximab, an EGF receptor-blocking monoclonal antibody, downregulates the alpha subunit of HIF-1 (HIF-1α) through the inhibition of EGF receptor downstream cell signaling and that downregulation of HIF-1α is required for cetuximab-induced antiproliferative effects. However, the mechanism underlying these actions has yet to be identified. In this study, we used the Seahorse XF96 extracellular flux analyzer to assess the effect of cetuximab treatment on changes in glycolysis and mitochondrial respiration, the two major energy-producing pathways, in live cells. We found that cetuximab downregulated lactate dehydrogenase A (LDH-A) and inhibited glycolysis in cetuximab-sensitive head and neck squamous cell carcinoma (HNSCC) cells in an HIF-1α downregulation-dependent manner. HNSCC cells with acquired cetuximab resistance expressed a high level of HIF-1α and were highly glycolytic. Overexpression of a HIF-1α mutant (HIF-1α/ΔODD) conferred resistance to cetuximab-induced G1 phase cell-cycle arrest, which could be overcome by knockdown of LDH-A expression. Inhibition of LDH-A activity with oxamate enhanced the response of cetuximab-resistant cells to cetuximab. Cetuximab had no noticeable inhibitory effect on glycolysis in nontransformed cells. These findings provide novel mechanistic insights into cetuximab-induced cell-cycle arrest from the perspective of cancer metabolism and suggest novel strategies for enhancing cetuximab response.</abstract><cop>United States</cop><pmid>23920275</pmid><doi>10.1158/1535-7163.mct-12-1245</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Antibodies, Monoclonal, Humanized - administration & dosage Biomarkers, Pharmacological Carcinoma, Squamous Cell - drug therapy Carcinoma, Squamous Cell - genetics Carcinoma, Squamous Cell - pathology Cell Cycle Checkpoints - drug effects Cell Line, Tumor Cell Respiration - drug effects Cetuximab Gene Expression Regulation, Neoplastic - drug effects Glycolysis - drug effects Glycolysis - genetics Head and Neck Neoplasms - drug therapy Head and Neck Neoplasms - genetics Head and Neck Neoplasms - pathology Humans Hypoxia-Inducible Factor 1, alpha Subunit - biosynthesis Hypoxia-Inducible Factor 1, alpha Subunit - genetics Isoenzymes - antagonists & inhibitors Isoenzymes - biosynthesis Isoenzymes - genetics L-Lactate Dehydrogenase - antagonists & inhibitors L-Lactate Dehydrogenase - biosynthesis L-Lactate Dehydrogenase - genetics Mitochondria - drug effects Receptor, Epidermal Growth Factor - antagonists & inhibitors |
title | Cetuximab reverses the Warburg effect by inhibiting HIF-1-regulated LDH-A |
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