Roles of theTrkB/BDNF and autophagy in colorectal cancer cells survival
Identifieur interne : 000112 ( France/Analysis ); précédent : 000111; suivant : 000113Roles of theTrkB/BDNF and autophagy in colorectal cancer cells survival
Auteurs : Clément Mazouffre [France]Source :
Descripteurs français
- mix :
English descriptors
- mix :
Abstract
Colorectal cancer (CRC) is the first digestive cancer in occidental countries. Despite effective therapies, cases of resistance and/or recurrence exist. Our laboratory works on two signaling pathways regulating balance between survival and cell death: neurotrophins (NTs, growth factors involved in cancer cells survival) and autophagy (cellular recycling involved in stress resistance). The aim of this study was to investigate relationship between these two pathways and the impact of their inhibition on cell fate and tumor evolution.Studies were performed on two CRC cell lines derived from the same patient: SW480 (primary tumor) and SW620 (node invasion), also used for subcutaneous xenografts on Nude mouse model. In addition, presence of major proteins of NTs (TrkB) and autophagy (LC3) were assessed in patient’s tissues.Previous work showed that TrkB overexpression is associated with pro-survival signaling in CRC cell. So, we choose to inhibit NTs pathway with K252a (100 nM). As expected, inactivation of the PI3K / AKT pathway was observed and CRC cells were able to activate autophagy. At the opposite, blocking autophagic flux by pharmacologic approach (chloroquine; CQ; 25µM) or by transcriptomic approach (siRNA against ATG5) induced over-activation of the NTs pathway, via TrkB/BDNF. Thus, both survival pathways compensate each other. Moreover, dual inhibition allowed improving the effect of single treatment through a significant reduction of metabolic activity. The using of both inhibitors in vivo induces a spectacular reduction of tumor volume (or even disappearance in some cases). Presence of active form of TrkB (phospho TrkB) and active form of LC3 (LC3-II) demonstrating activation of these two pathways, in patient’s tissues have been observed. Taken together, our results showed that activation of NTs and autophagy contribute to CRC cell survival. The approach consisting of dual inhibition of NTs and autophagy could be a major point for new CRC therapies development.
Url:
Affiliations:
Links toward previous steps (curation, corpus...)
- to stream Hal, to step Corpus: 000211
- to stream Hal, to step Curation: 000211
- to stream Hal, to step Checkpoint: 000068
- to stream Main, to step Merge: 000D33
- to stream Main, to step Curation: 000D33
- to stream Main, to step Exploration: 000D33
- to stream France, to step Extraction: 000112
Links to Exploration step
Hal:tel-01501403Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Roles of theTrkB/BDNF and autophagy in colorectal cancer cells survival</title>
<title xml:lang="fr">Rôles du couple TrkB/BDNF et de l’autophagie dans la survie de cellules de cancer colorectal</title>
<author><name sortKey="Mazouffre, Clement" sort="Mazouffre, Clement" uniqKey="Mazouffre C" first="Clément" last="Mazouffre">Clément Mazouffre</name>
<affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-70831" status="OLD"> <idno type="IdRef">188534881</idno>
<idno type="RNSR">200415102C</idno>
<orgName>Homéostasie Cellulaire et Pathologies</orgName>
<orgName type="acronym">HCP</orgName>
<date type="start">2004-01-01</date>
<date type="end">2017-12-31</date>
<desc> <address> <addrLine>Université de Limoges Faculté de médecine 2 avenue Martin Luther King 87025 LIMOGES cedex</addrLine>
<country key="FR"></country>
</address>
<ref type="url">http://www.avrul.fr/-Homeostasie-Cellulaire-et-.html</ref>
</desc>
<listRelation> <relation name="EA3842" active="#struct-5928" type="direct"></relation>
<relation name="EA3842" active="#struct-302082" type="direct"></relation>
<relation name="EA3842" active="#struct-300906" type="direct"></relation>
</listRelation>
<tutelles><tutelle name="EA3842" active="#struct-5928" type="direct"><org type="institution" xml:id="struct-5928" status="VALID"> <idno type="IdRef">026403315</idno>
<idno type="ISNI">0000000121654861</idno>
<orgName>Université de Limoges</orgName>
<orgName type="acronym">UNILIM</orgName>
<date type="start">1968-10-01</date>
<desc> <address> <addrLine>33 rue François Mitterrand BP23204 87032 Limoges</addrLine>
<country key="FR"></country>
</address>
<ref type="url">http://www.unilim.fr</ref>
</desc>
</org>
</tutelle>
<tutelle name="EA3842" active="#struct-302082" type="direct"><org type="institution" xml:id="struct-302082" status="OLD"> <idno type="RNSR">201220465X</idno>
<idno type="IdRef">188832599</idno>
<orgName>Génomique, Environnement, Immunité, Santé, Thérapeutique</orgName>
<orgName type="acronym">GEIST FR CNRS 3503</orgName>
<date type="start">2007-01-01</date>
<date type="end">2018-01-01</date>
<desc> <address> <addrLine>Université de Limoges - Faculté de Médecine - 2 rue du Dr Marcland 87025 Limoges cedex</addrLine>
<country key="FR"></country>
</address>
<ref type="url">http://www.unilim.fr/recherche/laboratoires/geist/</ref>
</desc>
</org>
</tutelle>
<tutelle name="EA3842" active="#struct-300906" type="direct"><org type="institution" xml:id="struct-300906" status="VALID"> <orgName>CHU Limoges</orgName>
<desc> <address> <addrLine>Centre Hospitalier Universitaire Dupuytren - 2 avenue Martin Luther King 87042 LIMOGES </addrLine>
<country key="FR"></country>
</address>
<ref type="url">http://www.chu-limoges.fr/</ref>
</desc>
</org>
</tutelle>
</tutelles>
</hal:affiliation>
<country>France</country>
<placeName><settlement type="city">Limoges</settlement>
<region type="region" nuts="2">Limousin</region>
</placeName>
<orgName type="university">Université de Limoges</orgName>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">HAL</idno>
<idno type="RBID">Hal:tel-01501403</idno>
<idno type="halId">tel-01501403</idno>
<idno type="halUri">https://tel.archives-ouvertes.fr/tel-01501403</idno>
<idno type="url">https://tel.archives-ouvertes.fr/tel-01501403</idno>
<date when="2016-12-12">2016-12-12</date>
<idno type="wicri:Area/Hal/Corpus">000211</idno>
<idno type="wicri:Area/Hal/Curation">000211</idno>
<idno type="wicri:Area/Hal/Checkpoint">000068</idno>
<idno type="wicri:explorRef" wicri:stream="Hal" wicri:step="Checkpoint">000068</idno>
<idno type="wicri:Area/Main/Merge">000D33</idno>
<idno type="wicri:Area/Main/Curation">000D33</idno>
<idno type="wicri:Area/Main/Exploration">000D33</idno>
<idno type="wicri:Area/France/Extraction">000112</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en">Roles of theTrkB/BDNF and autophagy in colorectal cancer cells survival</title>
<title xml:lang="fr">Rôles du couple TrkB/BDNF et de l’autophagie dans la survie de cellules de cancer colorectal</title>
<author><name sortKey="Mazouffre, Clement" sort="Mazouffre, Clement" uniqKey="Mazouffre C" first="Clément" last="Mazouffre">Clément Mazouffre</name>
<affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-70831" status="OLD"> <idno type="IdRef">188534881</idno>
<idno type="RNSR">200415102C</idno>
<orgName>Homéostasie Cellulaire et Pathologies</orgName>
<orgName type="acronym">HCP</orgName>
<date type="start">2004-01-01</date>
<date type="end">2017-12-31</date>
<desc> <address> <addrLine>Université de Limoges Faculté de médecine 2 avenue Martin Luther King 87025 LIMOGES cedex</addrLine>
<country key="FR"></country>
</address>
<ref type="url">http://www.avrul.fr/-Homeostasie-Cellulaire-et-.html</ref>
</desc>
<listRelation> <relation name="EA3842" active="#struct-5928" type="direct"></relation>
<relation name="EA3842" active="#struct-302082" type="direct"></relation>
<relation name="EA3842" active="#struct-300906" type="direct"></relation>
</listRelation>
<tutelles><tutelle name="EA3842" active="#struct-5928" type="direct"><org type="institution" xml:id="struct-5928" status="VALID"> <idno type="IdRef">026403315</idno>
<idno type="ISNI">0000000121654861</idno>
<orgName>Université de Limoges</orgName>
<orgName type="acronym">UNILIM</orgName>
<date type="start">1968-10-01</date>
<desc> <address> <addrLine>33 rue François Mitterrand BP23204 87032 Limoges</addrLine>
<country key="FR"></country>
</address>
<ref type="url">http://www.unilim.fr</ref>
</desc>
</org>
</tutelle>
<tutelle name="EA3842" active="#struct-302082" type="direct"><org type="institution" xml:id="struct-302082" status="OLD"> <idno type="RNSR">201220465X</idno>
<idno type="IdRef">188832599</idno>
<orgName>Génomique, Environnement, Immunité, Santé, Thérapeutique</orgName>
<orgName type="acronym">GEIST FR CNRS 3503</orgName>
<date type="start">2007-01-01</date>
<date type="end">2018-01-01</date>
<desc> <address> <addrLine>Université de Limoges - Faculté de Médecine - 2 rue du Dr Marcland 87025 Limoges cedex</addrLine>
<country key="FR"></country>
</address>
<ref type="url">http://www.unilim.fr/recherche/laboratoires/geist/</ref>
</desc>
</org>
</tutelle>
<tutelle name="EA3842" active="#struct-300906" type="direct"><org type="institution" xml:id="struct-300906" status="VALID"> <orgName>CHU Limoges</orgName>
<desc> <address> <addrLine>Centre Hospitalier Universitaire Dupuytren - 2 avenue Martin Luther King 87042 LIMOGES </addrLine>
<country key="FR"></country>
</address>
<ref type="url">http://www.chu-limoges.fr/</ref>
</desc>
</org>
</tutelle>
</tutelles>
</hal:affiliation>
<country>France</country>
<placeName><settlement type="city">Limoges</settlement>
<region type="region" nuts="2">Limousin</region>
</placeName>
<orgName type="university">Université de Limoges</orgName>
</affiliation>
</author>
</analytic>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="mix" xml:lang="en"><term>Autophagy</term>
<term>Colorectal cancer</term>
<term>Neurotrophins</term>
<term>Survival</term>
</keywords>
<keywords scheme="mix" xml:lang="fr"><term>Autophagie</term>
<term>Cancer colorectal</term>
<term>Neurotrophines</term>
<term>Survie</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"> <p>Colorectal cancer (CRC) is the first digestive cancer in occidental countries. Despite effective therapies, cases of resistance and/or recurrence exist. Our laboratory works on two signaling pathways regulating balance between survival and cell death: neurotrophins (NTs, growth factors involved in cancer cells survival) and autophagy (cellular recycling involved in stress resistance). The aim of this study was to investigate relationship between these two pathways and the impact of their inhibition on cell fate and tumor evolution.Studies were performed on two CRC cell lines derived from the same patient: SW480 (primary tumor) and SW620 (node invasion), also used for subcutaneous xenografts on Nude mouse model. In addition, presence of major proteins of NTs (TrkB) and autophagy (LC3) were assessed in patient’s tissues.Previous work showed that TrkB overexpression is associated with pro-survival signaling in CRC cell. So, we choose to inhibit NTs pathway with K252a (100 nM). As expected, inactivation of the PI3K / AKT pathway was observed and CRC cells were able to activate autophagy. At the opposite, blocking autophagic flux by pharmacologic approach (chloroquine; CQ; 25µM) or by transcriptomic approach (siRNA against ATG5) induced over-activation of the NTs pathway, via TrkB/BDNF. Thus, both survival pathways compensate each other. Moreover, dual inhibition allowed improving the effect of single treatment through a significant reduction of metabolic activity. The using of both inhibitors in vivo induces a spectacular reduction of tumor volume (or even disappearance in some cases). Presence of active form of TrkB (phospho TrkB) and active form of LC3 (LC3-II) demonstrating activation of these two pathways, in patient’s tissues have been observed. Taken together, our results showed that activation of NTs and autophagy contribute to CRC cell survival. The approach consisting of dual inhibition of NTs and autophagy could be a major point for new CRC therapies development.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>France</li>
</country>
<region><li>Limousin</li>
</region>
<settlement><li>Limoges</li>
</settlement>
<orgName><li>Université de Limoges</li>
</orgName>
</list>
<tree><country name="France"><region name="Limousin"><name sortKey="Mazouffre, Clement" sort="Mazouffre, Clement" uniqKey="Mazouffre C" first="Clément" last="Mazouffre">Clément Mazouffre</name>
</region>
</country>
</tree>
</affiliations>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/ChloroquineV1/Data/France/Analysis
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000112 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/France/Analysis/biblio.hfd -nk 000112 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Sante |area= ChloroquineV1 |flux= France |étape= Analysis |type= RBID |clé= Hal:tel-01501403 |texte= Roles of theTrkB/BDNF and autophagy in colorectal cancer cells survival }}
This area was generated with Dilib version V0.6.33. |