Tetraarsenic hexoxide induces G2/M arrest, apoptosis, and autophagy via PI3K/Akt suppression and p38 MAPK activation in SW620 human colon cancer cells
Tetraarsenic hexoxide (As4O6) has been used in Korean folk medicines for the treatment of cancer, however its anti-cancer mechanisms remain obscured. Here, this study investigated the anti-cancer effect of As4O6 on SW620 human colon cancer cells. As4O6 has showed a dose-dependent inhibition of SW620...
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| Veröffentlicht in: | PloS one 2017-03, Vol.12 (3), p.e0174591-e0174591 |
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| creator | Nagappan, Arulkumar Lee, Won Sup Yun, Jeong Won Lu, Jing Nan Chang, Seong-Hwan Jeong, Jae-Hoon Kim, Gon Sup Jung, Jin-Myung Hong, Soon Chan |
| description | Tetraarsenic hexoxide (As4O6) has been used in Korean folk medicines for the treatment of cancer, however its anti-cancer mechanisms remain obscured. Here, this study investigated the anti-cancer effect of As4O6 on SW620 human colon cancer cells. As4O6 has showed a dose-dependent inhibition of SW620 cells proliferation. As4O6 significantly increased the sub-G1 and G2/M phase population, and Annexin V-positive cells in a dose-dependent manner. G2/M arrest was concomitant with augment of p21 and reduction in cyclin B1, cell division cycle 2 (cdc 2) expressions. Nuclear condensation, cleaved nuclei and poly (adenosine diphosphate‑ribose) polymerase (PARP) activation were also observed in As4O6-treated SW620 cells. As4O6 induced depolarization of mitochondrial membrane potential (MMP, ΔΨm) but not reactive oxygen species (ROS) generation. Further, As4O6 increased death receptor 5 (DR5), not DR4 and suppressed the B‑cell lymphoma‑2 (Bcl-2) and X-linked inhibitor of apoptosis protein (XIAP) family proteins. As4O6 increased the formation of AVOs (lysosomes and autophagolysosomes) and promoted the conversion of microtubule-associated protein 1A/1B-light chain 3 (LC3)-I to LC3-II in a dose- and time- dependent manner. Interestingly, a specific phosphoinositide 3-kinase (PI3K)/Akt inhibitor (LY294002) augmented the As4O6 induced cell death; whereas p38 mitogen-activated protein kinases (p38 MAPK) inhibitor (SB203580) abrogated the cell death. Thus, the present study provides the first evidence that As4O6 induced G2/M arrest, apoptosis and autophagic cell death through PI3K/Akt and p38 MAPK pathways alteration in SW620 cells. |
| doi_str_mv | 10.1371/journal.pone.0174591 |
| format | Article |
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Here, this study investigated the anti-cancer effect of As4O6 on SW620 human colon cancer cells. As4O6 has showed a dose-dependent inhibition of SW620 cells proliferation. As4O6 significantly increased the sub-G1 and G2/M phase population, and Annexin V-positive cells in a dose-dependent manner. G2/M arrest was concomitant with augment of p21 and reduction in cyclin B1, cell division cycle 2 (cdc 2) expressions. Nuclear condensation, cleaved nuclei and poly (adenosine diphosphate‑ribose) polymerase (PARP) activation were also observed in As4O6-treated SW620 cells. As4O6 induced depolarization of mitochondrial membrane potential (MMP, ΔΨm) but not reactive oxygen species (ROS) generation. Further, As4O6 increased death receptor 5 (DR5), not DR4 and suppressed the B‑cell lymphoma‑2 (Bcl-2) and X-linked inhibitor of apoptosis protein (XIAP) family proteins. As4O6 increased the formation of AVOs (lysosomes and autophagolysosomes) and promoted the conversion of microtubule-associated protein 1A/1B-light chain 3 (LC3)-I to LC3-II in a dose- and time- dependent manner. Interestingly, a specific phosphoinositide 3-kinase (PI3K)/Akt inhibitor (LY294002) augmented the As4O6 induced cell death; whereas p38 mitogen-activated protein kinases (p38 MAPK) inhibitor (SB203580) abrogated the cell death. Thus, the present study provides the first evidence that As4O6 induced G2/M arrest, apoptosis and autophagic cell death through PI3K/Akt and p38 MAPK pathways alteration in SW620 cells.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0174591</identifier><identifier>PMID: 28355296</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>1-Phosphatidylinositol 3-kinase ; Adenosine ; Adenosine diphosphate ; AKT protein ; Annexin V ; Anticancer properties ; Antineoplastic Agents - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Arsenicals - pharmacology ; Autophagy ; Autophagy - drug effects ; Bcl protein ; Bcl-2 protein ; Biology and Life Sciences ; Blotting, Western ; Cancer therapies ; CDC2 Protein Kinase ; Cell cycle ; Cell death ; Cell division ; Cell Line, Tumor ; Cell proliferation ; Cell Survival - drug effects ; Chemotherapy ; Colon cancer ; Colonic Neoplasms - metabolism ; Colonic Neoplasms - pathology ; Colorectal cancer ; Cyclin B1 ; Cyclin D1 - metabolism ; Cyclin-Dependent Kinase Inhibitor p21 - metabolism ; Cyclin-Dependent Kinases - metabolism ; Depolarization ; Dose-Response Relationship, Drug ; Enzyme Activation - drug effects ; Enzyme inhibitors ; G2 Phase Cell Cycle Checkpoints - drug effects ; Genetic aspects ; GTP-binding protein ; Health sciences ; Humans ; Immunoglobulins ; Internal medicine ; Kinases ; Leukemia ; Lymphocytes B ; Lymphoma ; Lysosomes ; MAP kinase ; Medical research ; Medicine ; Medicine and Health Sciences ; Membrane potential ; Membrane Potential, Mitochondrial - drug effects ; Microtubule-associated protein 1 ; Mortality ; Oxides - pharmacology ; Oxygen ; p38 Mitogen-Activated Protein Kinases - metabolism ; Phagocytosis ; Phosphatidylinositol 3-Kinases - metabolism ; Physiological aspects ; Poly(ADP-ribose) polymerase ; Protein kinases ; Proteins ; Proto-Oncogene Proteins c-akt - metabolism ; Reactive oxygen species ; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism ; Research and Analysis Methods ; Ribose ; Studies ; Surgery ; Time Factors ; Tumor necrosis factor-TNF</subject><ispartof>PloS one, 2017-03, Vol.12 (3), p.e0174591-e0174591</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Nagappan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Nagappan et al 2017 Nagappan et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-70f84daafecb1ec52da71abaa4fd31d9865e46299734f6d985d33b94e7d211a43</citedby><cites>FETCH-LOGICAL-c692t-70f84daafecb1ec52da71abaa4fd31d9865e46299734f6d985d33b94e7d211a43</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/PMC5371332/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371332/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,2103,2929,23871,27929,27930,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28355296$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Pizzo, Salvatore V.</contributor><creatorcontrib>Nagappan, Arulkumar</creatorcontrib><creatorcontrib>Lee, Won Sup</creatorcontrib><creatorcontrib>Yun, Jeong Won</creatorcontrib><creatorcontrib>Lu, Jing Nan</creatorcontrib><creatorcontrib>Chang, Seong-Hwan</creatorcontrib><creatorcontrib>Jeong, Jae-Hoon</creatorcontrib><creatorcontrib>Kim, Gon Sup</creatorcontrib><creatorcontrib>Jung, Jin-Myung</creatorcontrib><creatorcontrib>Hong, Soon Chan</creatorcontrib><title>Tetraarsenic hexoxide induces G2/M arrest, apoptosis, and autophagy via PI3K/Akt suppression and p38 MAPK activation in SW620 human colon cancer cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Tetraarsenic hexoxide (As4O6) has been used in Korean folk medicines for the treatment of cancer, however its anti-cancer mechanisms remain obscured. Here, this study investigated the anti-cancer effect of As4O6 on SW620 human colon cancer cells. As4O6 has showed a dose-dependent inhibition of SW620 cells proliferation. As4O6 significantly increased the sub-G1 and G2/M phase population, and Annexin V-positive cells in a dose-dependent manner. G2/M arrest was concomitant with augment of p21 and reduction in cyclin B1, cell division cycle 2 (cdc 2) expressions. Nuclear condensation, cleaved nuclei and poly (adenosine diphosphate‑ribose) polymerase (PARP) activation were also observed in As4O6-treated SW620 cells. As4O6 induced depolarization of mitochondrial membrane potential (MMP, ΔΨm) but not reactive oxygen species (ROS) generation. Further, As4O6 increased death receptor 5 (DR5), not DR4 and suppressed the B‑cell lymphoma‑2 (Bcl-2) and X-linked inhibitor of apoptosis protein (XIAP) family proteins. As4O6 increased the formation of AVOs (lysosomes and autophagolysosomes) and promoted the conversion of microtubule-associated protein 1A/1B-light chain 3 (LC3)-I to LC3-II in a dose- and time- dependent manner. Interestingly, a specific phosphoinositide 3-kinase (PI3K)/Akt inhibitor (LY294002) augmented the As4O6 induced cell death; whereas p38 mitogen-activated protein kinases (p38 MAPK) inhibitor (SB203580) abrogated the cell death. Thus, the present study provides the first evidence that As4O6 induced G2/M arrest, apoptosis and autophagic cell death through PI3K/Akt and p38 MAPK pathways alteration in SW620 cells.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>Adenosine</subject><subject>Adenosine diphosphate</subject><subject>AKT protein</subject><subject>Annexin V</subject><subject>Anticancer properties</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Arsenicals - pharmacology</subject><subject>Autophagy</subject><subject>Autophagy - drug effects</subject><subject>Bcl protein</subject><subject>Bcl-2 protein</subject><subject>Biology and Life Sciences</subject><subject>Blotting, Western</subject><subject>Cancer therapies</subject><subject>CDC2 Protein Kinase</subject><subject>Cell cycle</subject><subject>Cell death</subject><subject>Cell division</subject><subject>Cell Line, Tumor</subject><subject>Cell proliferation</subject><subject>Cell Survival - drug effects</subject><subject>Chemotherapy</subject><subject>Colon cancer</subject><subject>Colonic Neoplasms - metabolism</subject><subject>Colonic Neoplasms - pathology</subject><subject>Colorectal cancer</subject><subject>Cyclin B1</subject><subject>Cyclin D1 - metabolism</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</subject><subject>Cyclin-Dependent Kinases - metabolism</subject><subject>Depolarization</subject><subject>Dose-Response Relationship, Drug</subject><subject>Enzyme Activation - drug effects</subject><subject>Enzyme inhibitors</subject><subject>G2 Phase Cell Cycle Checkpoints - drug effects</subject><subject>Genetic aspects</subject><subject>GTP-binding protein</subject><subject>Health sciences</subject><subject>Humans</subject><subject>Immunoglobulins</subject><subject>Internal medicine</subject><subject>Kinases</subject><subject>Leukemia</subject><subject>Lymphocytes B</subject><subject>Lymphoma</subject><subject>Lysosomes</subject><subject>MAP kinase</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Membrane potential</subject><subject>Membrane Potential, Mitochondrial - drug effects</subject><subject>Microtubule-associated protein 1</subject><subject>Mortality</subject><subject>Oxides - pharmacology</subject><subject>Oxygen</subject><subject>p38 Mitogen-Activated Protein Kinases - metabolism</subject><subject>Phagocytosis</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Physiological aspects</subject><subject>Poly(ADP-ribose) polymerase</subject><subject>Protein kinases</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Reactive oxygen species</subject><subject>Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism</subject><subject>Research and Analysis Methods</subject><subject>Ribose</subject><subject>Studies</subject><subject>Surgery</subject><subject>Time Factors</subject><subject>Tumor necrosis factor-TNF</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9tuEzEQhlcIREvhDRBYQkIgkWR92NMNUlRBidqqFS1waU3s2cTtxl7s3Sp9EZ4Xp0mrBPUC-WK9429-2_94kuQ1TYeUF3R05XpvoRm2zuIwpYXIKvok2acVZ4Ocpfzp1nwveRHCVZpmvMzz58keK3mWsSrfT_5cYucBfEBrFJnj0i2NRmKs7hUGcsRGpwS8x9B9ItC6tnPBhDi1mkDfuXYOs1tyY4CcT_jxaHzdkdC3beSDcfYOa3lJTsfnxwRUZ26gW8WNJRe_4sHIvF-AJco1MajAKvREYdOEl8mzGpqArzbfg-TH1y-Xh98GJ2dHk8PxyUDlFesGRVqXQgPUqKYUVcY0FBSmAKLWnOqqzDMUOauqgos6j_-Z5nxaCSw0oxQEP0jernXbxgW5sTRIWpaM5ZWgRSQma0I7uJKtNwvwt9KBkXcB52cSfGdUg7KuqwqjeF7kQvCyLplioqxpmReaIqqo9XmzWz9doFZoo_fNjujuijVzOXM3MosF55xFgQ8bAe9-97EocmHCyjCw6Pr1ubNY5iyN6Lt_0Mdvt6FmEC9gbO3ivmolKseiLArGWJVFavgIFYfGhVHx_dUmxncSPu4kRKbDZTeDPgQ5ufj-_-zZz132_RY7R2i6eXBNv3pUYRcUa1B5F4LH-sFkmspV-9y7IVftIzftE9PebBfoIem-X_hfhdoVHg</recordid><startdate>20170329</startdate><enddate>20170329</enddate><creator>Nagappan, Arulkumar</creator><creator>Lee, Won Sup</creator><creator>Yun, Jeong Won</creator><creator>Lu, Jing Nan</creator><creator>Chang, Seong-Hwan</creator><creator>Jeong, Jae-Hoon</creator><creator>Kim, Gon Sup</creator><creator>Jung, Jin-Myung</creator><creator>Hong, Soon Chan</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20170329</creationdate><title>Tetraarsenic hexoxide induces G2/M arrest, apoptosis, and autophagy via PI3K/Akt suppression and p38 MAPK activation in SW620 human colon cancer cells</title><author>Nagappan, Arulkumar ; Lee, Won Sup ; Yun, Jeong Won ; Lu, Jing Nan ; Chang, Seong-Hwan ; Jeong, Jae-Hoon ; Kim, Gon Sup ; Jung, Jin-Myung ; Hong, Soon Chan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-70f84daafecb1ec52da71abaa4fd31d9865e46299734f6d985d33b94e7d211a43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>Adenosine</topic><topic>Adenosine diphosphate</topic><topic>AKT protein</topic><topic>Annexin V</topic><topic>Anticancer properties</topic><topic>Antineoplastic Agents - 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metabolism</topic><topic>Reactive oxygen species</topic><topic>Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism</topic><topic>Research and Analysis Methods</topic><topic>Ribose</topic><topic>Studies</topic><topic>Surgery</topic><topic>Time Factors</topic><topic>Tumor necrosis factor-TNF</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nagappan, Arulkumar</creatorcontrib><creatorcontrib>Lee, Won Sup</creatorcontrib><creatorcontrib>Yun, Jeong Won</creatorcontrib><creatorcontrib>Lu, Jing Nan</creatorcontrib><creatorcontrib>Chang, Seong-Hwan</creatorcontrib><creatorcontrib>Jeong, Jae-Hoon</creatorcontrib><creatorcontrib>Kim, Gon Sup</creatorcontrib><creatorcontrib>Jung, Jin-Myung</creatorcontrib><creatorcontrib>Hong, Soon Chan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology 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>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nagappan, Arulkumar</au><au>Lee, Won Sup</au><au>Yun, Jeong Won</au><au>Lu, Jing Nan</au><au>Chang, Seong-Hwan</au><au>Jeong, Jae-Hoon</au><au>Kim, Gon Sup</au><au>Jung, Jin-Myung</au><au>Hong, Soon Chan</au><au>Pizzo, Salvatore V.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tetraarsenic hexoxide induces G2/M arrest, apoptosis, and autophagy via PI3K/Akt suppression and p38 MAPK activation in SW620 human colon cancer cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-03-29</date><risdate>2017</risdate><volume>12</volume><issue>3</issue><spage>e0174591</spage><epage>e0174591</epage><pages>e0174591-e0174591</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Tetraarsenic hexoxide (As4O6) has been used in Korean folk medicines for the treatment of cancer, however its anti-cancer mechanisms remain obscured. Here, this study investigated the anti-cancer effect of As4O6 on SW620 human colon cancer cells. As4O6 has showed a dose-dependent inhibition of SW620 cells proliferation. As4O6 significantly increased the sub-G1 and G2/M phase population, and Annexin V-positive cells in a dose-dependent manner. G2/M arrest was concomitant with augment of p21 and reduction in cyclin B1, cell division cycle 2 (cdc 2) expressions. Nuclear condensation, cleaved nuclei and poly (adenosine diphosphate‑ribose) polymerase (PARP) activation were also observed in As4O6-treated SW620 cells. As4O6 induced depolarization of mitochondrial membrane potential (MMP, ΔΨm) but not reactive oxygen species (ROS) generation. Further, As4O6 increased death receptor 5 (DR5), not DR4 and suppressed the B‑cell lymphoma‑2 (Bcl-2) and X-linked inhibitor of apoptosis protein (XIAP) family proteins. As4O6 increased the formation of AVOs (lysosomes and autophagolysosomes) and promoted the conversion of microtubule-associated protein 1A/1B-light chain 3 (LC3)-I to LC3-II in a dose- and time- dependent manner. Interestingly, a specific phosphoinositide 3-kinase (PI3K)/Akt inhibitor (LY294002) augmented the As4O6 induced cell death; whereas p38 mitogen-activated protein kinases (p38 MAPK) inhibitor (SB203580) abrogated the cell death. Thus, the present study provides the first evidence that As4O6 induced G2/M arrest, apoptosis and autophagic cell death through PI3K/Akt and p38 MAPK pathways alteration in SW620 cells.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28355296</pmid><doi>10.1371/journal.pone.0174591</doi><tpages>e0174591</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2017-03, Vol.12 (3), p.e0174591-e0174591 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1882269417 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 1-Phosphatidylinositol 3-kinase Adenosine Adenosine diphosphate AKT protein Annexin V Anticancer properties Antineoplastic Agents - pharmacology Apoptosis Apoptosis - drug effects Arsenicals - pharmacology Autophagy Autophagy - drug effects Bcl protein Bcl-2 protein Biology and Life Sciences Blotting, Western Cancer therapies CDC2 Protein Kinase Cell cycle Cell death Cell division Cell Line, Tumor Cell proliferation Cell Survival - drug effects Chemotherapy Colon cancer Colonic Neoplasms - metabolism Colonic Neoplasms - pathology Colorectal cancer Cyclin B1 Cyclin D1 - metabolism Cyclin-Dependent Kinase Inhibitor p21 - metabolism Cyclin-Dependent Kinases - metabolism Depolarization Dose-Response Relationship, Drug Enzyme Activation - drug effects Enzyme inhibitors G2 Phase Cell Cycle Checkpoints - drug effects Genetic aspects GTP-binding protein Health sciences Humans Immunoglobulins Internal medicine Kinases Leukemia Lymphocytes B Lymphoma Lysosomes MAP kinase Medical research Medicine Medicine and Health Sciences Membrane potential Membrane Potential, Mitochondrial - drug effects Microtubule-associated protein 1 Mortality Oxides - pharmacology Oxygen p38 Mitogen-Activated Protein Kinases - metabolism Phagocytosis Phosphatidylinositol 3-Kinases - metabolism Physiological aspects Poly(ADP-ribose) polymerase Protein kinases Proteins Proto-Oncogene Proteins c-akt - metabolism Reactive oxygen species Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism Research and Analysis Methods Ribose Studies Surgery Time Factors Tumor necrosis factor-TNF |
| title | Tetraarsenic hexoxide induces G2/M arrest, apoptosis, and autophagy via PI3K/Akt suppression and p38 MAPK activation in SW620 human colon cancer cells |
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