ChloroquineV1, Main, Exploration, bibRecord, 000573

Oncogenic Kras induces Nix-mediated mitophagy to promote pancreatic cancer

Identifieur interne : 000573 ( Main/Exploration ); précédent : 000572; suivant : 000574

Oncogenic Kras induces Nix-mediated mitophagy to promote pancreatic cancer

Auteurs : Timothy J. Humpton ; Brinda Alagesan ; Gina M. Denicola ; Dan Lu ; Georgi N. Yordanov ; Carl S. Leonhardt ; Melissa A. Yao ; Priya Alagesan ; Maya N. Zaatari ; Youngkyu Park ; Jeremy N. Skepper ; Kay F. Macleod ; Pedro A. Perez-Mancera ; Michael P. Murphy ; Gerard I. Evan ; Karen H. Vousden ; David A. Tuveson

Source :

Cancer discovery [ 2159-8274 ] ; 2019.

RBID : PMC:6726540

Abstract

Activating KRAS mutations are found in nearly all cases of pancreatic ductal adenocarcinoma (PDAC), yet effective clinical targeting of oncogenic KRAS remains elusive. Understanding of KRAS-dependent PDAC-promoting pathways could lead to the identification of vulnerabilities and the development of new treatments. We show that oncogenic KRAS induces BNIP3L/NIX expression and a selective mitophagy program that restricts glucose flux to the mitochondria and enhances redox capacity. Loss of Nix restores functional mitochondria to cells, increasing demands for NADPH reducing power and decreasing proliferation in glucose-limited conditions. Nix deletion markedly delays progression of pancreatic cancer and improves survival in a murine (KPC) model of PDAC. While conditional Nix ablation in vivo initially results in the accumulation of mitochondria, mitochondrial content eventually normalizes via increased mitochondrial clearance programs, and PanIN lesions progress to PDAC. We identify the Kras-Nix mitophagy program as a novel driver of glycolysis, redox robustness, and disease progression in PDAC.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726540

DOI: 10.1158/2159-8290.CD-18-1409
PubMed: 31263025
PubMed Central: 6726540

Affiliations:

Le document en format XML

<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Oncogenic Kras induces Nix-mediated mitophagy to promote pancreatic cancer</title>
<author><name sortKey="Humpton, Timothy J" sort="Humpton, Timothy J" uniqKey="Humpton T" first="Timothy J." last="Humpton">Timothy J. Humpton</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Alagesan, Brinda" sort="Alagesan, Brinda" uniqKey="Alagesan B" first="Brinda" last="Alagesan">Brinda Alagesan</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Denicola, Gina M" sort="Denicola, Gina M" uniqKey="Denicola G" first="Gina M." last="Denicola">Gina M. Denicola</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lu, Dan" sort="Lu, Dan" uniqKey="Lu D" first="Dan" last="Lu">Dan Lu</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Yordanov, Georgi N" sort="Yordanov, Georgi N" uniqKey="Yordanov G" first="Georgi N." last="Yordanov">Georgi N. Yordanov</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Leonhardt, Carl S" sort="Leonhardt, Carl S" uniqKey="Leonhardt C" first="Carl S." last="Leonhardt">Carl S. Leonhardt</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Yao, Melissa A" sort="Yao, Melissa A" uniqKey="Yao M" first="Melissa A." last="Yao">Melissa A. Yao</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Alagesan, Priya" sort="Alagesan, Priya" uniqKey="Alagesan P" first="Priya" last="Alagesan">Priya Alagesan</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Zaatari, Maya N" sort="Zaatari, Maya N" uniqKey="Zaatari M" first="Maya N." last="Zaatari">Maya N. Zaatari</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Park, Youngkyu" sort="Park, Youngkyu" uniqKey="Park Y" first="Youngkyu" last="Park">Youngkyu Park</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Skepper, Jeremy N" sort="Skepper, Jeremy N" uniqKey="Skepper J" first="Jeremy N." last="Skepper">Jeremy N. Skepper</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Macleod, Kay F" sort="Macleod, Kay F" uniqKey="Macleod K" first="Kay F." last="Macleod">Kay F. Macleod</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Perez Mancera, Pedro A" sort="Perez Mancera, Pedro A" uniqKey="Perez Mancera P" first="Pedro A." last="Perez-Mancera">Pedro A. Perez-Mancera</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Murphy, Michael P" sort="Murphy, Michael P" uniqKey="Murphy M" first="Michael P." last="Murphy">Michael P. Murphy</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Evan, Gerard I" sort="Evan, Gerard I" uniqKey="Evan G" first="Gerard I." last="Evan">Gerard I. Evan</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Vousden, Karen H" sort="Vousden, Karen H" uniqKey="Vousden K" first="Karen H." last="Vousden">Karen H. Vousden</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tuveson, David A" sort="Tuveson, David A" uniqKey="Tuveson D" first="David A." last="Tuveson">David A. Tuveson</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">31263025</idno>
<idno type="pmc">6726540</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726540</idno>
<idno type="RBID">PMC:6726540</idno>
<idno type="doi">10.1158/2159-8290.CD-18-1409</idno>
<date when="2019">2019</date>
<idno type="wicri:Area/Pmc/Corpus">000383</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000383</idno>
<idno type="wicri:Area/Pmc/Curation">000383</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000383</idno>
<idno type="wicri:Area/Pmc/Checkpoint">000524</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000524</idno>
<idno type="wicri:Area/Ncbi/Merge">000750</idno>
<idno type="wicri:Area/Ncbi/Curation">000750</idno>
<idno type="wicri:Area/Ncbi/Checkpoint">000750</idno>
<idno type="wicri:doubleKey">2159-8274:2019:Humpton T:oncogenic:kras:induces</idno>
<idno type="wicri:Area/Main/Merge">000573</idno>
<idno type="wicri:Area/Main/Curation">000573</idno>
<idno type="wicri:Area/Main/Exploration">000573</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Oncogenic Kras induces Nix-mediated mitophagy to promote pancreatic cancer</title>
<author><name sortKey="Humpton, Timothy J" sort="Humpton, Timothy J" uniqKey="Humpton T" first="Timothy J." last="Humpton">Timothy J. Humpton</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Alagesan, Brinda" sort="Alagesan, Brinda" uniqKey="Alagesan B" first="Brinda" last="Alagesan">Brinda Alagesan</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Denicola, Gina M" sort="Denicola, Gina M" uniqKey="Denicola G" first="Gina M." last="Denicola">Gina M. Denicola</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lu, Dan" sort="Lu, Dan" uniqKey="Lu D" first="Dan" last="Lu">Dan Lu</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Yordanov, Georgi N" sort="Yordanov, Georgi N" uniqKey="Yordanov G" first="Georgi N." last="Yordanov">Georgi N. Yordanov</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Leonhardt, Carl S" sort="Leonhardt, Carl S" uniqKey="Leonhardt C" first="Carl S." last="Leonhardt">Carl S. Leonhardt</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Yao, Melissa A" sort="Yao, Melissa A" uniqKey="Yao M" first="Melissa A." last="Yao">Melissa A. Yao</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Alagesan, Priya" sort="Alagesan, Priya" uniqKey="Alagesan P" first="Priya" last="Alagesan">Priya Alagesan</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Zaatari, Maya N" sort="Zaatari, Maya N" uniqKey="Zaatari M" first="Maya N." last="Zaatari">Maya N. Zaatari</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Park, Youngkyu" sort="Park, Youngkyu" uniqKey="Park Y" first="Youngkyu" last="Park">Youngkyu Park</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Skepper, Jeremy N" sort="Skepper, Jeremy N" uniqKey="Skepper J" first="Jeremy N." last="Skepper">Jeremy N. Skepper</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Macleod, Kay F" sort="Macleod, Kay F" uniqKey="Macleod K" first="Kay F." last="Macleod">Kay F. Macleod</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Perez Mancera, Pedro A" sort="Perez Mancera, Pedro A" uniqKey="Perez Mancera P" first="Pedro A." last="Perez-Mancera">Pedro A. Perez-Mancera</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Murphy, Michael P" sort="Murphy, Michael P" uniqKey="Murphy M" first="Michael P." last="Murphy">Michael P. Murphy</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Evan, Gerard I" sort="Evan, Gerard I" uniqKey="Evan G" first="Gerard I." last="Evan">Gerard I. Evan</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Vousden, Karen H" sort="Vousden, Karen H" uniqKey="Vousden K" first="Karen H." last="Vousden">Karen H. Vousden</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tuveson, David A" sort="Tuveson, David A" uniqKey="Tuveson D" first="David A." last="Tuveson">David A. Tuveson</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Cancer discovery</title>
<idno type="ISSN">2159-8274</idno>
<idno type="eISSN">2159-8290</idno>
<imprint><date when="2019">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p id="P4">Activating <italic>KRAS</italic>
 mutations are found in nearly all cases of pancreatic ductal adenocarcinoma (PDAC), yet effective clinical targeting of oncogenic KRAS remains elusive. Understanding of KRAS-dependent PDAC-promoting pathways could lead to the identification of vulnerabilities and the development of new treatments. We show that oncogenic <italic>KRAS</italic>
 induces <italic>BNIP3L</italic>
/NIX expression and a selective mitophagy program that restricts glucose flux to the mitochondria and enhances redox capacity. Loss of <italic>Nix</italic>
 restores functional mitochondria to cells, increasing demands for NADPH reducing power and decreasing proliferation in glucose-limited conditions. Nix deletion markedly delays progression of pancreatic cancer and improves survival in a murine (KPC) model of PDAC. While conditional <italic>Nix</italic>
 ablation <italic>in vivo</italic>
 initially results in the accumulation of mitochondria, mitochondrial content eventually normalizes via increased mitochondrial clearance programs, and PanIN lesions progress to PDAC. We identify the Kras-Nix mitophagy program as a novel driver of glycolysis, redox robustness, and disease progression in PDAC.</p>
</div>
</front>
</TEI>
<affiliations><list></list>
<tree><noCountry><name sortKey="Alagesan, Brinda" sort="Alagesan, Brinda" uniqKey="Alagesan B" first="Brinda" last="Alagesan">Brinda Alagesan</name>
<name sortKey="Alagesan, Priya" sort="Alagesan, Priya" uniqKey="Alagesan P" first="Priya" last="Alagesan">Priya Alagesan</name>
<name sortKey="Denicola, Gina M" sort="Denicola, Gina M" uniqKey="Denicola G" first="Gina M." last="Denicola">Gina M. Denicola</name>
<name sortKey="Evan, Gerard I" sort="Evan, Gerard I" uniqKey="Evan G" first="Gerard I." last="Evan">Gerard I. Evan</name>
<name sortKey="Humpton, Timothy J" sort="Humpton, Timothy J" uniqKey="Humpton T" first="Timothy J." last="Humpton">Timothy J. Humpton</name>
<name sortKey="Leonhardt, Carl S" sort="Leonhardt, Carl S" uniqKey="Leonhardt C" first="Carl S." last="Leonhardt">Carl S. Leonhardt</name>
<name sortKey="Lu, Dan" sort="Lu, Dan" uniqKey="Lu D" first="Dan" last="Lu">Dan Lu</name>
<name sortKey="Macleod, Kay F" sort="Macleod, Kay F" uniqKey="Macleod K" first="Kay F." last="Macleod">Kay F. Macleod</name>
<name sortKey="Murphy, Michael P" sort="Murphy, Michael P" uniqKey="Murphy M" first="Michael P." last="Murphy">Michael P. Murphy</name>
<name sortKey="Park, Youngkyu" sort="Park, Youngkyu" uniqKey="Park Y" first="Youngkyu" last="Park">Youngkyu Park</name>
<name sortKey="Perez Mancera, Pedro A" sort="Perez Mancera, Pedro A" uniqKey="Perez Mancera P" first="Pedro A." last="Perez-Mancera">Pedro A. Perez-Mancera</name>
<name sortKey="Skepper, Jeremy N" sort="Skepper, Jeremy N" uniqKey="Skepper J" first="Jeremy N." last="Skepper">Jeremy N. Skepper</name>
<name sortKey="Tuveson, David A" sort="Tuveson, David A" uniqKey="Tuveson D" first="David A." last="Tuveson">David A. Tuveson</name>
<name sortKey="Vousden, Karen H" sort="Vousden, Karen H" uniqKey="Vousden K" first="Karen H." last="Vousden">Karen H. Vousden</name>
<name sortKey="Yao, Melissa A" sort="Yao, Melissa A" uniqKey="Yao M" first="Melissa A." last="Yao">Melissa A. Yao</name>
<name sortKey="Yordanov, Georgi N" sort="Yordanov, Georgi N" uniqKey="Yordanov G" first="Georgi N." last="Yordanov">Georgi N. Yordanov</name>
<name sortKey="Zaatari, Maya N" sort="Zaatari, Maya N" uniqKey="Zaatari M" first="Maya N." last="Zaatari">Maya N. Zaatari</name>
</noCountry>
</tree>
</affiliations>
</record>

Pour manipuler ce document sous Unix (Dilib)

EXPLOR_STEP=$WICRI_ROOT/Sante/explor/ChloroquineV1/Data/Main/Exploration

HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000573 | SxmlIndent | more

HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 000573 | SxmlIndent | more

Pour mettre un lien sur cette page dans le réseau Wicri

{{Explor lien
   |wiki=    Sante
   |area=    ChloroquineV1
   |flux=    Main
   |étape=   Exploration
   |type=    RBID
   |clé=     PMC:6726540
   |texte=   Oncogenic Kras induces Nix-mediated mitophagy to promote pancreatic cancer
}}

Pour générer des pages wiki

HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i   -Sk "pubmed:31263025" \
       | HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd   \
       | NlmPubMed2Wicri -a ChloroquineV1

This area was generated with Dilib version V0.6.33.
Data generation: Wed Mar 25 22:43:59 2020. Site generation: Sun Jan 31 12:44:45 2021

Serveur d'exploration Chloroquine

Oncogenic Kras induces Nix-mediated mitophagy to promote pancreatic cancer

Oncogenic Kras induces Nix-mediated mitophagy to promote pancreatic cancer

Source :

Abstract

Links toward previous steps (curation, corpus...)

Le document en format XML

Pour manipuler ce document sous Unix (Dilib)

Pour mettre un lien sur cette page dans le réseau Wicri

Pour générer des pages wiki

	Serveur d'exploration Chloroquine
	Attention, ce site est en cours de développement ! Attention, site généré par des moyens informatiques à partir de corpus bruts. Les informations ne sont donc pas validées.