Glucose restriction induces cell death in parental but not in homeodomain-interacting protein kinase 2-depleted RKO colon cancer cells: molecular mechanisms and implications for tumor therapy
Tumor cell tolerance to nutrient deprivation can be an important factor for tumor progression, and may depend on deregulation of both oncogenes and oncosuppressor proteins. Homeodomain-interacting protein kinase 2 (HIPK2) is an oncosuppressor that, following its activation by several cellular stress...
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creator | Garufi, A Ricci, A Trisciuoglio, D Iorio, E Carpinelli, G Pistritto, G Cirone, M D′Orazi, G |
description | Tumor cell tolerance to nutrient deprivation can be an important factor for tumor progression, and may depend on deregulation of both oncogenes and oncosuppressor proteins. Homeodomain-interacting protein kinase 2 (HIPK2) is an oncosuppressor that, following its activation by several cellular stress, induces cancer cell death via p53-dependent or -independent pathways. Here, we used genetically matched human RKO colon cancer cells harboring wt-HIPK2 (HIPK2
+/+
) or stable HIPK2 siRNA interference (siHIPK2) to investigate
in vitro
whether HIPK2 influenced cell death in glucose restriction. We found that glucose starvation induced cell death, mainly due to c-Jun NH2-terminal kinase activation, in HIPK2
+/+
cells compared with siHIPK2 cells that did not die.
1
H-nuclear magnetic resonance quantitative metabolic analyses showed a marked glycolytic activation in siHIPK2 cells. However, treatment with glycolysis inhibitor 2-deoxy-
D
-glucose induced cell death only in HIPK2
+/+
cells but not in siHIPK2 cells. Similarly, siGlut-1 interference did not re-establish siHIPK2 cell death under glucose restriction, whereas marked cell death was reached only after zinc supplementation, a condition known to reactivate misfolded p53 and inhibit the pseudohypoxic phenotype in this setting. Further siHIPK2 cell death was reached with zinc in combination with autophagy inhibitor. We propose that the metabolic changes acquired by cells after HIPK2 silencing may contribute to induce resistance to cell death in glucose restriction condition, and therefore be directly relevant for tumor progression. Moreover, elimination of such a tolerance might serve as a new strategy for cancer therapy. |
doi_str_mv | 10.1038/cddis.2013.163 |
format | Article |
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+/+
) or stable HIPK2 siRNA interference (siHIPK2) to investigate
in vitro
whether HIPK2 influenced cell death in glucose restriction. We found that glucose starvation induced cell death, mainly due to c-Jun NH2-terminal kinase activation, in HIPK2
+/+
cells compared with siHIPK2 cells that did not die.
1
H-nuclear magnetic resonance quantitative metabolic analyses showed a marked glycolytic activation in siHIPK2 cells. However, treatment with glycolysis inhibitor 2-deoxy-
D
-glucose induced cell death only in HIPK2
+/+
cells but not in siHIPK2 cells. Similarly, siGlut-1 interference did not re-establish siHIPK2 cell death under glucose restriction, whereas marked cell death was reached only after zinc supplementation, a condition known to reactivate misfolded p53 and inhibit the pseudohypoxic phenotype in this setting. Further siHIPK2 cell death was reached with zinc in combination with autophagy inhibitor. We propose that the metabolic changes acquired by cells after HIPK2 silencing may contribute to induce resistance to cell death in glucose restriction condition, and therefore be directly relevant for tumor progression. Moreover, elimination of such a tolerance might serve as a new strategy for cancer therapy.</description><identifier>ISSN: 2041-4889</identifier><identifier>EISSN: 2041-4889</identifier><identifier>DOI: 10.1038/cddis.2013.163</identifier><identifier>PMID: 23703384</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/67/1504/1885/1393 ; 631/67/2327 ; 631/80/82 ; 692/700/565/2072 ; Antibodies ; Apoptosis - drug effects ; Biochemistry ; Biomedical and Life Sciences ; Carrier Proteins - antagonists & inhibitors ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Cell Biology ; Cell Culture ; Cell Line, Tumor ; Colonic Neoplasms - drug therapy ; Colonic Neoplasms - metabolism ; Colonic Neoplasms - pathology ; Deoxyglucose - pharmacology ; Deoxyglucose - therapeutic use ; Glucose Transporter Type 1 - antagonists & inhibitors ; Glucose Transporter Type 1 - genetics ; Glucose Transporter Type 1 - metabolism ; Humans ; Immunology ; JNK Mitogen-Activated Protein Kinases - metabolism ; Life Sciences ; Metabolome ; Original ; original-article ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; RNA Interference ; RNA, Small Interfering - metabolism ; Zinc - pharmacology</subject><ispartof>Cell death & disease, 2013-05, Vol.4 (5), p.e639-e639</ispartof><rights>The Author(s) 2013</rights><rights>Copyright Nature Publishing Group May 2013</rights><rights>Copyright © 2013 Macmillan Publishers Limited 2013 Macmillan Publishers Limited</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c491t-219d59a5fff905326493b6c50d351c2b0c82617aab3d99d3179f4549bf6b890d3</citedby><cites>FETCH-LOGICAL-c491t-219d59a5fff905326493b6c50d351c2b0c82617aab3d99d3179f4549bf6b890d3</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/PMC3674370/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674370/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,41120,42189,51576,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23703384$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Garufi, A</creatorcontrib><creatorcontrib>Ricci, A</creatorcontrib><creatorcontrib>Trisciuoglio, D</creatorcontrib><creatorcontrib>Iorio, E</creatorcontrib><creatorcontrib>Carpinelli, G</creatorcontrib><creatorcontrib>Pistritto, G</creatorcontrib><creatorcontrib>Cirone, M</creatorcontrib><creatorcontrib>D′Orazi, G</creatorcontrib><title>Glucose restriction induces cell death in parental but not in homeodomain-interacting protein kinase 2-depleted RKO colon cancer cells: molecular mechanisms and implications for tumor therapy</title><title>Cell death & disease</title><addtitle>Cell Death Dis</addtitle><addtitle>Cell Death Dis</addtitle><description>Tumor cell tolerance to nutrient deprivation can be an important factor for tumor progression, and may depend on deregulation of both oncogenes and oncosuppressor proteins. Homeodomain-interacting protein kinase 2 (HIPK2) is an oncosuppressor that, following its activation by several cellular stress, induces cancer cell death via p53-dependent or -independent pathways. Here, we used genetically matched human RKO colon cancer cells harboring wt-HIPK2 (HIPK2
+/+
) or stable HIPK2 siRNA interference (siHIPK2) to investigate
in vitro
whether HIPK2 influenced cell death in glucose restriction. We found that glucose starvation induced cell death, mainly due to c-Jun NH2-terminal kinase activation, in HIPK2
+/+
cells compared with siHIPK2 cells that did not die.
1
H-nuclear magnetic resonance quantitative metabolic analyses showed a marked glycolytic activation in siHIPK2 cells. However, treatment with glycolysis inhibitor 2-deoxy-
D
-glucose induced cell death only in HIPK2
+/+
cells but not in siHIPK2 cells. Similarly, siGlut-1 interference did not re-establish siHIPK2 cell death under glucose restriction, whereas marked cell death was reached only after zinc supplementation, a condition known to reactivate misfolded p53 and inhibit the pseudohypoxic phenotype in this setting. Further siHIPK2 cell death was reached with zinc in combination with autophagy inhibitor. We propose that the metabolic changes acquired by cells after HIPK2 silencing may contribute to induce resistance to cell death in glucose restriction condition, and therefore be directly relevant for tumor progression. Moreover, elimination of such a tolerance might serve as a new strategy for cancer therapy.</description><subject>631/67/1504/1885/1393</subject><subject>631/67/2327</subject><subject>631/80/82</subject><subject>692/700/565/2072</subject><subject>Antibodies</subject><subject>Apoptosis - drug effects</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Carrier Proteins - antagonists & inhibitors</subject><subject>Carrier Proteins - genetics</subject><subject>Carrier Proteins - metabolism</subject><subject>Cell Biology</subject><subject>Cell Culture</subject><subject>Cell Line, Tumor</subject><subject>Colonic Neoplasms - drug therapy</subject><subject>Colonic Neoplasms - metabolism</subject><subject>Colonic Neoplasms - pathology</subject><subject>Deoxyglucose - pharmacology</subject><subject>Deoxyglucose - therapeutic use</subject><subject>Glucose Transporter Type 1 - antagonists & inhibitors</subject><subject>Glucose Transporter Type 1 - genetics</subject><subject>Glucose Transporter Type 1 - metabolism</subject><subject>Humans</subject><subject>Immunology</subject><subject>JNK Mitogen-Activated Protein Kinases - metabolism</subject><subject>Life Sciences</subject><subject>Metabolome</subject><subject>Original</subject><subject>original-article</subject><subject>Protein-Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein-Serine-Threonine Kinases - genetics</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>RNA Interference</subject><subject>RNA, Small Interfering - metabolism</subject><subject>Zinc - pharmacology</subject><issn>2041-4889</issn><issn>2041-4889</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNptUstu1DAUtRCIVkO3LJElNmwyteMkE7NAQhUURKVKCNaWYzsTFz-C7VTq1_Fr3HRKNSC88OPe43PuC6GXlGwpYf250trmbU0o29KOPUGnNWlo1fQ9f3p0P0FnOd8QWIyRuu2eo5Oa7eDRN6fo16VbVMwGJ5NLsqrYGLANelEmY2Wcw9rIMoEJzzKZUKTDw1JwiGW1TdGbqKOXNlQ2FJMkMIQ9nlMsBvw_bJBAXlfazM4Uo_HXL9dYRQcqSgZl0r1Ifot9dEYtTibsjZpksNlnLIPG1s_OKrkGlvEYEy6LX_cJxOa7F-jZKF02Zw_nBn3_-OHbxafq6vry88X7q0o1nJaqply3XLbjOHLSsrprOBs61RLNWqrqgai-7uhOyoFpzjWjOz42bcOHsRt6DqgNenfgnZfBG62gEkk6MSfrZboTUVrxtyfYSezjrWDdrlmrvUFvHghS_LlAsYW3ec1dBhOXLECR8I710MgNev0P9CYuKUB6gOo72jNoLaC2B5RKMedkxsdgKBHreIj78RDreAhghQ-vjlN4hP8ZBgCcHwAZXGFv0pHu_yl_A6dUyyo</recordid><startdate>20130501</startdate><enddate>20130501</enddate><creator>Garufi, A</creator><creator>Ricci, A</creator><creator>Trisciuoglio, D</creator><creator>Iorio, E</creator><creator>Carpinelli, G</creator><creator>Pistritto, G</creator><creator>Cirone, M</creator><creator>D′Orazi, G</creator><general>Nature Publishing Group UK</general><general>Springer Nature B.V</general><general>Nature Publishing Group</general><scope>C6C</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</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>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7TO</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20130501</creationdate><title>Glucose restriction induces cell death in parental but not in homeodomain-interacting protein kinase 2-depleted RKO colon cancer cells: molecular mechanisms and implications for tumor therapy</title><author>Garufi, A ; Ricci, A ; Trisciuoglio, D ; Iorio, E ; Carpinelli, G ; Pistritto, G ; Cirone, M ; D′Orazi, G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c491t-219d59a5fff905326493b6c50d351c2b0c82617aab3d99d3179f4549bf6b890d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>631/67/1504/1885/1393</topic><topic>631/67/2327</topic><topic>631/80/82</topic><topic>692/700/565/2072</topic><topic>Antibodies</topic><topic>Apoptosis - drug effects</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Carrier Proteins - antagonists & inhibitors</topic><topic>Carrier Proteins - genetics</topic><topic>Carrier Proteins - metabolism</topic><topic>Cell Biology</topic><topic>Cell Culture</topic><topic>Cell Line, Tumor</topic><topic>Colonic Neoplasms - drug therapy</topic><topic>Colonic Neoplasms - metabolism</topic><topic>Colonic Neoplasms - pathology</topic><topic>Deoxyglucose - pharmacology</topic><topic>Deoxyglucose - therapeutic use</topic><topic>Glucose Transporter Type 1 - antagonists & inhibitors</topic><topic>Glucose Transporter Type 1 - genetics</topic><topic>Glucose Transporter Type 1 - metabolism</topic><topic>Humans</topic><topic>Immunology</topic><topic>JNK Mitogen-Activated Protein Kinases - metabolism</topic><topic>Life Sciences</topic><topic>Metabolome</topic><topic>Original</topic><topic>original-article</topic><topic>Protein-Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Protein-Serine-Threonine Kinases - genetics</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>RNA Interference</topic><topic>RNA, Small Interfering - metabolism</topic><topic>Zinc - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Garufi, A</creatorcontrib><creatorcontrib>Ricci, A</creatorcontrib><creatorcontrib>Trisciuoglio, D</creatorcontrib><creatorcontrib>Iorio, E</creatorcontrib><creatorcontrib>Carpinelli, G</creatorcontrib><creatorcontrib>Pistritto, G</creatorcontrib><creatorcontrib>Cirone, M</creatorcontrib><creatorcontrib>D′Orazi, G</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</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>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Access via ProQuest (Open Access)</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 China</collection><collection>ProQuest Central Basic</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell death & disease</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Garufi, A</au><au>Ricci, A</au><au>Trisciuoglio, D</au><au>Iorio, E</au><au>Carpinelli, G</au><au>Pistritto, G</au><au>Cirone, M</au><au>D′Orazi, G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Glucose restriction induces cell death in parental but not in homeodomain-interacting protein kinase 2-depleted RKO colon cancer cells: molecular mechanisms and implications for tumor therapy</atitle><jtitle>Cell death & disease</jtitle><stitle>Cell Death Dis</stitle><addtitle>Cell Death Dis</addtitle><date>2013-05-01</date><risdate>2013</risdate><volume>4</volume><issue>5</issue><spage>e639</spage><epage>e639</epage><pages>e639-e639</pages><issn>2041-4889</issn><eissn>2041-4889</eissn><abstract>Tumor cell tolerance to nutrient deprivation can be an important factor for tumor progression, and may depend on deregulation of both oncogenes and oncosuppressor proteins. Homeodomain-interacting protein kinase 2 (HIPK2) is an oncosuppressor that, following its activation by several cellular stress, induces cancer cell death via p53-dependent or -independent pathways. Here, we used genetically matched human RKO colon cancer cells harboring wt-HIPK2 (HIPK2
+/+
) or stable HIPK2 siRNA interference (siHIPK2) to investigate
in vitro
whether HIPK2 influenced cell death in glucose restriction. We found that glucose starvation induced cell death, mainly due to c-Jun NH2-terminal kinase activation, in HIPK2
+/+
cells compared with siHIPK2 cells that did not die.
1
H-nuclear magnetic resonance quantitative metabolic analyses showed a marked glycolytic activation in siHIPK2 cells. However, treatment with glycolysis inhibitor 2-deoxy-
D
-glucose induced cell death only in HIPK2
+/+
cells but not in siHIPK2 cells. Similarly, siGlut-1 interference did not re-establish siHIPK2 cell death under glucose restriction, whereas marked cell death was reached only after zinc supplementation, a condition known to reactivate misfolded p53 and inhibit the pseudohypoxic phenotype in this setting. Further siHIPK2 cell death was reached with zinc in combination with autophagy inhibitor. We propose that the metabolic changes acquired by cells after HIPK2 silencing may contribute to induce resistance to cell death in glucose restriction condition, and therefore be directly relevant for tumor progression. Moreover, elimination of such a tolerance might serve as a new strategy for cancer therapy.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>23703384</pmid><doi>10.1038/cddis.2013.163</doi><oa>free_for_read</oa></addata></record> |
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subjects | 631/67/1504/1885/1393 631/67/2327 631/80/82 692/700/565/2072 Antibodies Apoptosis - drug effects Biochemistry Biomedical and Life Sciences Carrier Proteins - antagonists & inhibitors Carrier Proteins - genetics Carrier Proteins - metabolism Cell Biology Cell Culture Cell Line, Tumor Colonic Neoplasms - drug therapy Colonic Neoplasms - metabolism Colonic Neoplasms - pathology Deoxyglucose - pharmacology Deoxyglucose - therapeutic use Glucose Transporter Type 1 - antagonists & inhibitors Glucose Transporter Type 1 - genetics Glucose Transporter Type 1 - metabolism Humans Immunology JNK Mitogen-Activated Protein Kinases - metabolism Life Sciences Metabolome Original original-article Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism RNA Interference RNA, Small Interfering - metabolism Zinc - pharmacology |
title | Glucose restriction induces cell death in parental but not in homeodomain-interacting protein kinase 2-depleted RKO colon cancer cells: molecular mechanisms and implications for tumor therapy |
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