Autophagic Flux Unleashes GATA4-NF-κB Axis to Promote Antioxidant Defense-Dependent Survival of Colorectal Cancer Cells under Chronic Acidosis
Solid tumors are usually associated with extracellular acidosis due to their increased dependence on glycolysis and poor vascularization. Cancer cells gradually become adapted to acidic microenvironment and even acquire increased aggressiveness. They are resistant to apoptosis but exhibit increased...
Gespeichert in:
Veröffentlicht in: | Oxidative medicine and cellular longevity 2021, Vol.2021 (1), p.8189485-8189485 |
---|---|
Hauptverfasser: | , , , , , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 8189485 |
---|---|
container_issue | 1 |
container_start_page | 8189485 |
container_title | Oxidative medicine and cellular longevity |
container_volume | 2021 |
creator | Liu, Xiaojie Zhao, Minnan Sun, Xue Meng, Zhenzhen Bai, Xiaojing Gong, Yanchao Xu, Limei Hao, Xiaohe Yang, Tingting Wei, Zhao Zhang, Xiyu Guo, Haiyang Li, Peishan Liu, Qiao Gong, Yaoqin Shi, Yufang Shao, Changshun |
description | Solid tumors are usually associated with extracellular acidosis due to their increased dependence on glycolysis and poor vascularization. Cancer cells gradually become adapted to acidic microenvironment and even acquire increased aggressiveness. They are resistant to apoptosis but exhibit increased autophagy that is essential for their survival. We here show that NF-κB, a master regulator of cellular responses to stress, is upregulated in colorectal cancer cells adapted to acidosis (CRC-AA). NF-κB is more relied upon for survival in CRC-AA than in their parental cells and drives a robust antioxidant response. Supplementation of antioxidant abolishes the increased sensitivity of CRC-AA to NF-κB inhibition or depletion, suggesting that NF-κB supports the survival of CRC-AA by maintaining redox homeostasis. Because SQSTM1/p62 is known to mediate the selective autophagy of GATA4 that augments NF-κB function, we tested whether the enhanced autophagic flux and consequently the reduction of SQSTM1/p62 in CRC-AA cells could activate the GATA4-NF-κB axis. Indeed, GATA4 is upregulated in CRC-AA cells and augments the NF-κB activity that underlies the increased expression of cytokines, inhibition of apoptosis, and reduction of reactive oxygen species. Interestingly, secretory factors derived from HCT15-AA cells, the soluble ICAM-1 in particular, also possess antioxidant cytoprotective effect against acidic stress. Together, our results demonstrate a prosurvival role of the p62-restricted GATA4-NF-κB axis in cancer cells adapted to acidic microenvironment. |
doi_str_mv | 10.1155/2021/8189485 |
format | Article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8720590</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2615861514</sourcerecordid><originalsourceid>FETCH-LOGICAL-c448t-16aefa630da76cb6eab6fb621b6082f0483cb79527e544ca2a0d7884e63f42563</originalsourceid><addsrcrecordid>eNp9kc1u1DAUhS0Eoj-wY40ssUEqobbjOM4GKaRMQaoAiXZtOc5N4ypjT-1kGJ6C9-EheCY8mmEELFhY9_r60_E9Ogg9o-Q1pUVxzgij55LKisviATqmFWcZqSr-8NATcoROYrwjROSM08foKOeVLEtSHKPv9Tz51aBvrcGLcd7gGzeCjgNEfFlf1zz7uMh-_niL642NePL4c_BLPwGu3WT9xnbaTfgCenARsgtYgesgTb7MYW3XesS-x40ffQAzpVujnYGAGxjHiOeEpn4I3qW_a2M7H218gh71eozwdF9P0c3i3XXzPrv6dPmhqa8yw7mcMio09FrkpNOlMK0A3Yq-FYy2gkjWEy5z05ZVwUooODeaadKVUnIQec9ZIfJT9Ganu5rbJXQmbR30qFbBLnX4pry26u8XZwd169dKlowUFUkCL_cCwd_PECe1tNEkZ9qBn6Nigpas5Ixs0Rf_oHd-Di7Z21KFTIfyRL3aUSb4GAP0h2UoUduk1TZptU864c__NHCAf0ebgLMdMFjX6a_2_3K_APpDsjE</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2615861514</pqid></control><display><type>article</type><title>Autophagic Flux Unleashes GATA4-NF-κB Axis to Promote Antioxidant Defense-Dependent Survival of Colorectal Cancer Cells under Chronic Acidosis</title><source>MEDLINE</source><source>Wiley Online Library Open Access</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><source>EZB Electronic Journals Library</source><source>PubMed Central Open Access</source><creator>Liu, Xiaojie ; Zhao, Minnan ; Sun, Xue ; Meng, Zhenzhen ; Bai, Xiaojing ; Gong, Yanchao ; Xu, Limei ; Hao, Xiaohe ; Yang, Tingting ; Wei, Zhao ; Zhang, Xiyu ; Guo, Haiyang ; Li, Peishan ; Liu, Qiao ; Gong, Yaoqin ; Shi, Yufang ; Shao, Changshun</creator><contributor>Ciccarone, Fabio ; Fabio Ciccarone</contributor><creatorcontrib>Liu, Xiaojie ; Zhao, Minnan ; Sun, Xue ; Meng, Zhenzhen ; Bai, Xiaojing ; Gong, Yanchao ; Xu, Limei ; Hao, Xiaohe ; Yang, Tingting ; Wei, Zhao ; Zhang, Xiyu ; Guo, Haiyang ; Li, Peishan ; Liu, Qiao ; Gong, Yaoqin ; Shi, Yufang ; Shao, Changshun ; Ciccarone, Fabio ; Fabio Ciccarone</creatorcontrib><description>Solid tumors are usually associated with extracellular acidosis due to their increased dependence on glycolysis and poor vascularization. Cancer cells gradually become adapted to acidic microenvironment and even acquire increased aggressiveness. They are resistant to apoptosis but exhibit increased autophagy that is essential for their survival. We here show that NF-κB, a master regulator of cellular responses to stress, is upregulated in colorectal cancer cells adapted to acidosis (CRC-AA). NF-κB is more relied upon for survival in CRC-AA than in their parental cells and drives a robust antioxidant response. Supplementation of antioxidant abolishes the increased sensitivity of CRC-AA to NF-κB inhibition or depletion, suggesting that NF-κB supports the survival of CRC-AA by maintaining redox homeostasis. Because SQSTM1/p62 is known to mediate the selective autophagy of GATA4 that augments NF-κB function, we tested whether the enhanced autophagic flux and consequently the reduction of SQSTM1/p62 in CRC-AA cells could activate the GATA4-NF-κB axis. Indeed, GATA4 is upregulated in CRC-AA cells and augments the NF-κB activity that underlies the increased expression of cytokines, inhibition of apoptosis, and reduction of reactive oxygen species. Interestingly, secretory factors derived from HCT15-AA cells, the soluble ICAM-1 in particular, also possess antioxidant cytoprotective effect against acidic stress. Together, our results demonstrate a prosurvival role of the p62-restricted GATA4-NF-κB axis in cancer cells adapted to acidic microenvironment.</description><identifier>ISSN: 1942-0900</identifier><identifier>EISSN: 1942-0994</identifier><identifier>DOI: 10.1155/2021/8189485</identifier><identifier>PMID: 34987705</identifier><language>eng</language><publisher>United States: Hindawi</publisher><subject>Acidosis ; Acidosis - drug therapy ; Adaptation ; Animals ; Antioxidants ; Antioxidants - pharmacology ; Antioxidants - therapeutic use ; Apoptosis ; Autophagy ; Chronic Disease ; Colorectal cancer ; Colorectal Neoplasms - drug therapy ; Colorectal Neoplasms - mortality ; Cytokines ; Defense ; GATA4 Transcription Factor - metabolism ; Homeostasis ; Humans ; Mice ; NF-kappa B - metabolism ; Reactive oxygen species ; Survival Analysis ; Tumor Microenvironment ; Tumors</subject><ispartof>Oxidative medicine and cellular longevity, 2021, Vol.2021 (1), p.8189485-8189485</ispartof><rights>Copyright © 2021 Xiaojie Liu et al.</rights><rights>Copyright © 2021 Xiaojie Liu et al. This is an open access article distributed under the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. https://creativecommons.org/licenses/by/4.0</rights><rights>Copyright © 2021 Xiaojie Liu et al. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c448t-16aefa630da76cb6eab6fb621b6082f0483cb79527e544ca2a0d7884e63f42563</citedby><cites>FETCH-LOGICAL-c448t-16aefa630da76cb6eab6fb621b6082f0483cb79527e544ca2a0d7884e63f42563</cites><orcidid>0000-0003-2618-9342</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8720590/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8720590/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,4024,27923,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34987705$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ciccarone, Fabio</contributor><contributor>Fabio Ciccarone</contributor><creatorcontrib>Liu, Xiaojie</creatorcontrib><creatorcontrib>Zhao, Minnan</creatorcontrib><creatorcontrib>Sun, Xue</creatorcontrib><creatorcontrib>Meng, Zhenzhen</creatorcontrib><creatorcontrib>Bai, Xiaojing</creatorcontrib><creatorcontrib>Gong, Yanchao</creatorcontrib><creatorcontrib>Xu, Limei</creatorcontrib><creatorcontrib>Hao, Xiaohe</creatorcontrib><creatorcontrib>Yang, Tingting</creatorcontrib><creatorcontrib>Wei, Zhao</creatorcontrib><creatorcontrib>Zhang, Xiyu</creatorcontrib><creatorcontrib>Guo, Haiyang</creatorcontrib><creatorcontrib>Li, Peishan</creatorcontrib><creatorcontrib>Liu, Qiao</creatorcontrib><creatorcontrib>Gong, Yaoqin</creatorcontrib><creatorcontrib>Shi, Yufang</creatorcontrib><creatorcontrib>Shao, Changshun</creatorcontrib><title>Autophagic Flux Unleashes GATA4-NF-κB Axis to Promote Antioxidant Defense-Dependent Survival of Colorectal Cancer Cells under Chronic Acidosis</title><title>Oxidative medicine and cellular longevity</title><addtitle>Oxid Med Cell Longev</addtitle><description>Solid tumors are usually associated with extracellular acidosis due to their increased dependence on glycolysis and poor vascularization. Cancer cells gradually become adapted to acidic microenvironment and even acquire increased aggressiveness. They are resistant to apoptosis but exhibit increased autophagy that is essential for their survival. We here show that NF-κB, a master regulator of cellular responses to stress, is upregulated in colorectal cancer cells adapted to acidosis (CRC-AA). NF-κB is more relied upon for survival in CRC-AA than in their parental cells and drives a robust antioxidant response. Supplementation of antioxidant abolishes the increased sensitivity of CRC-AA to NF-κB inhibition or depletion, suggesting that NF-κB supports the survival of CRC-AA by maintaining redox homeostasis. Because SQSTM1/p62 is known to mediate the selective autophagy of GATA4 that augments NF-κB function, we tested whether the enhanced autophagic flux and consequently the reduction of SQSTM1/p62 in CRC-AA cells could activate the GATA4-NF-κB axis. Indeed, GATA4 is upregulated in CRC-AA cells and augments the NF-κB activity that underlies the increased expression of cytokines, inhibition of apoptosis, and reduction of reactive oxygen species. Interestingly, secretory factors derived from HCT15-AA cells, the soluble ICAM-1 in particular, also possess antioxidant cytoprotective effect against acidic stress. Together, our results demonstrate a prosurvival role of the p62-restricted GATA4-NF-κB axis in cancer cells adapted to acidic microenvironment.</description><subject>Acidosis</subject><subject>Acidosis - drug therapy</subject><subject>Adaptation</subject><subject>Animals</subject><subject>Antioxidants</subject><subject>Antioxidants - pharmacology</subject><subject>Antioxidants - therapeutic use</subject><subject>Apoptosis</subject><subject>Autophagy</subject><subject>Chronic Disease</subject><subject>Colorectal cancer</subject><subject>Colorectal Neoplasms - drug therapy</subject><subject>Colorectal Neoplasms - mortality</subject><subject>Cytokines</subject><subject>Defense</subject><subject>GATA4 Transcription Factor - metabolism</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Mice</subject><subject>NF-kappa B - metabolism</subject><subject>Reactive oxygen species</subject><subject>Survival Analysis</subject><subject>Tumor Microenvironment</subject><subject>Tumors</subject><issn>1942-0900</issn><issn>1942-0994</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>RHX</sourceid><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kc1u1DAUhS0Eoj-wY40ssUEqobbjOM4GKaRMQaoAiXZtOc5N4ypjT-1kGJ6C9-EheCY8mmEELFhY9_r60_E9Ogg9o-Q1pUVxzgij55LKisviATqmFWcZqSr-8NATcoROYrwjROSM08foKOeVLEtSHKPv9Tz51aBvrcGLcd7gGzeCjgNEfFlf1zz7uMh-_niL642NePL4c_BLPwGu3WT9xnbaTfgCenARsgtYgesgTb7MYW3XesS-x40ffQAzpVujnYGAGxjHiOeEpn4I3qW_a2M7H218gh71eozwdF9P0c3i3XXzPrv6dPmhqa8yw7mcMio09FrkpNOlMK0A3Yq-FYy2gkjWEy5z05ZVwUooODeaadKVUnIQec9ZIfJT9Ganu5rbJXQmbR30qFbBLnX4pry26u8XZwd169dKlowUFUkCL_cCwd_PECe1tNEkZ9qBn6Nigpas5Ixs0Rf_oHd-Di7Z21KFTIfyRL3aUSb4GAP0h2UoUduk1TZptU864c__NHCAf0ebgLMdMFjX6a_2_3K_APpDsjE</recordid><startdate>2021</startdate><enddate>2021</enddate><creator>Liu, Xiaojie</creator><creator>Zhao, Minnan</creator><creator>Sun, Xue</creator><creator>Meng, Zhenzhen</creator><creator>Bai, Xiaojing</creator><creator>Gong, Yanchao</creator><creator>Xu, Limei</creator><creator>Hao, Xiaohe</creator><creator>Yang, Tingting</creator><creator>Wei, Zhao</creator><creator>Zhang, Xiyu</creator><creator>Guo, Haiyang</creator><creator>Li, Peishan</creator><creator>Liu, Qiao</creator><creator>Gong, Yaoqin</creator><creator>Shi, Yufang</creator><creator>Shao, Changshun</creator><general>Hindawi</general><general>Hindawi Limited</general><scope>RHU</scope><scope>RHW</scope><scope>RHX</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>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-2618-9342</orcidid></search><sort><creationdate>2021</creationdate><title>Autophagic Flux Unleashes GATA4-NF-κB Axis to Promote Antioxidant Defense-Dependent Survival of Colorectal Cancer Cells under Chronic Acidosis</title><author>Liu, Xiaojie ; Zhao, Minnan ; Sun, Xue ; Meng, Zhenzhen ; Bai, Xiaojing ; Gong, Yanchao ; Xu, Limei ; Hao, Xiaohe ; Yang, Tingting ; Wei, Zhao ; Zhang, Xiyu ; Guo, Haiyang ; Li, Peishan ; Liu, Qiao ; Gong, Yaoqin ; Shi, Yufang ; Shao, Changshun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c448t-16aefa630da76cb6eab6fb621b6082f0483cb79527e544ca2a0d7884e63f42563</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Acidosis</topic><topic>Acidosis - drug therapy</topic><topic>Adaptation</topic><topic>Animals</topic><topic>Antioxidants</topic><topic>Antioxidants - pharmacology</topic><topic>Antioxidants - therapeutic use</topic><topic>Apoptosis</topic><topic>Autophagy</topic><topic>Chronic Disease</topic><topic>Colorectal cancer</topic><topic>Colorectal Neoplasms - drug therapy</topic><topic>Colorectal Neoplasms - mortality</topic><topic>Cytokines</topic><topic>Defense</topic><topic>GATA4 Transcription Factor - metabolism</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Mice</topic><topic>NF-kappa B - metabolism</topic><topic>Reactive oxygen species</topic><topic>Survival Analysis</topic><topic>Tumor Microenvironment</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Xiaojie</creatorcontrib><creatorcontrib>Zhao, Minnan</creatorcontrib><creatorcontrib>Sun, Xue</creatorcontrib><creatorcontrib>Meng, Zhenzhen</creatorcontrib><creatorcontrib>Bai, Xiaojing</creatorcontrib><creatorcontrib>Gong, Yanchao</creatorcontrib><creatorcontrib>Xu, Limei</creatorcontrib><creatorcontrib>Hao, Xiaohe</creatorcontrib><creatorcontrib>Yang, Tingting</creatorcontrib><creatorcontrib>Wei, Zhao</creatorcontrib><creatorcontrib>Zhang, Xiyu</creatorcontrib><creatorcontrib>Guo, Haiyang</creatorcontrib><creatorcontrib>Li, Peishan</creatorcontrib><creatorcontrib>Liu, Qiao</creatorcontrib><creatorcontrib>Gong, Yaoqin</creatorcontrib><creatorcontrib>Shi, Yufang</creatorcontrib><creatorcontrib>Shao, Changshun</creatorcontrib><collection>Hindawi Publishing Complete</collection><collection>Hindawi Publishing Subscription Journals</collection><collection>Hindawi Publishing Open Access</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>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</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>Research Library Prep</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library (ProQuest Database)</collection><collection>Research Library (Corporate)</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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oxidative medicine and cellular longevity</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Xiaojie</au><au>Zhao, Minnan</au><au>Sun, Xue</au><au>Meng, Zhenzhen</au><au>Bai, Xiaojing</au><au>Gong, Yanchao</au><au>Xu, Limei</au><au>Hao, Xiaohe</au><au>Yang, Tingting</au><au>Wei, Zhao</au><au>Zhang, Xiyu</au><au>Guo, Haiyang</au><au>Li, Peishan</au><au>Liu, Qiao</au><au>Gong, Yaoqin</au><au>Shi, Yufang</au><au>Shao, Changshun</au><au>Ciccarone, Fabio</au><au>Fabio Ciccarone</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Autophagic Flux Unleashes GATA4-NF-κB Axis to Promote Antioxidant Defense-Dependent Survival of Colorectal Cancer Cells under Chronic Acidosis</atitle><jtitle>Oxidative medicine and cellular longevity</jtitle><addtitle>Oxid Med Cell Longev</addtitle><date>2021</date><risdate>2021</risdate><volume>2021</volume><issue>1</issue><spage>8189485</spage><epage>8189485</epage><pages>8189485-8189485</pages><issn>1942-0900</issn><eissn>1942-0994</eissn><abstract>Solid tumors are usually associated with extracellular acidosis due to their increased dependence on glycolysis and poor vascularization. Cancer cells gradually become adapted to acidic microenvironment and even acquire increased aggressiveness. They are resistant to apoptosis but exhibit increased autophagy that is essential for their survival. We here show that NF-κB, a master regulator of cellular responses to stress, is upregulated in colorectal cancer cells adapted to acidosis (CRC-AA). NF-κB is more relied upon for survival in CRC-AA than in their parental cells and drives a robust antioxidant response. Supplementation of antioxidant abolishes the increased sensitivity of CRC-AA to NF-κB inhibition or depletion, suggesting that NF-κB supports the survival of CRC-AA by maintaining redox homeostasis. Because SQSTM1/p62 is known to mediate the selective autophagy of GATA4 that augments NF-κB function, we tested whether the enhanced autophagic flux and consequently the reduction of SQSTM1/p62 in CRC-AA cells could activate the GATA4-NF-κB axis. Indeed, GATA4 is upregulated in CRC-AA cells and augments the NF-κB activity that underlies the increased expression of cytokines, inhibition of apoptosis, and reduction of reactive oxygen species. Interestingly, secretory factors derived from HCT15-AA cells, the soluble ICAM-1 in particular, also possess antioxidant cytoprotective effect against acidic stress. Together, our results demonstrate a prosurvival role of the p62-restricted GATA4-NF-κB axis in cancer cells adapted to acidic microenvironment.</abstract><cop>United States</cop><pub>Hindawi</pub><pmid>34987705</pmid><doi>10.1155/2021/8189485</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0003-2618-9342</orcidid><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1942-0900 |
ispartof | Oxidative medicine and cellular longevity, 2021, Vol.2021 (1), p.8189485-8189485 |
issn | 1942-0900 1942-0994 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8720590 |
source | MEDLINE; Wiley Online Library Open Access; PubMed Central; Alma/SFX Local Collection; EZB Electronic Journals Library; PubMed Central Open Access |
subjects | Acidosis Acidosis - drug therapy Adaptation Animals Antioxidants Antioxidants - pharmacology Antioxidants - therapeutic use Apoptosis Autophagy Chronic Disease Colorectal cancer Colorectal Neoplasms - drug therapy Colorectal Neoplasms - mortality Cytokines Defense GATA4 Transcription Factor - metabolism Homeostasis Humans Mice NF-kappa B - metabolism Reactive oxygen species Survival Analysis Tumor Microenvironment Tumors |
title | Autophagic Flux Unleashes GATA4-NF-κB Axis to Promote Antioxidant Defense-Dependent Survival of Colorectal Cancer Cells under Chronic Acidosis |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-03T16%3A52%3A32IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Autophagic%20Flux%20Unleashes%20GATA4-NF-%CE%BAB%20Axis%20to%20Promote%20Antioxidant%20Defense-Dependent%20Survival%20of%20Colorectal%20Cancer%20Cells%20under%20Chronic%20Acidosis&rft.jtitle=Oxidative%20medicine%20and%20cellular%20longevity&rft.au=Liu,%20Xiaojie&rft.date=2021&rft.volume=2021&rft.issue=1&rft.spage=8189485&rft.epage=8189485&rft.pages=8189485-8189485&rft.issn=1942-0900&rft.eissn=1942-0994&rft_id=info:doi/10.1155/2021/8189485&rft_dat=%3Cproquest_pubme%3E2615861514%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2615861514&rft_id=info:pmid/34987705&rfr_iscdi=true |