Autophagy Regulated by Gain of Function Mutant p53 Enhances Proteasomal Inhibitor-Mediated Cell Death through Induction of ROS and ERK in Lung Cancer Cells.
Identifieur interne : 000A44 ( Main/Merge ); précédent : 000A43; suivant : 000A45Autophagy Regulated by Gain of Function Mutant p53 Enhances Proteasomal Inhibitor-Mediated Cell Death through Induction of ROS and ERK in Lung Cancer Cells.
Auteurs : Heena Saini [Inde] ; Ifrah Hakeem [Inde] ; Sudeshna Mukherjee [Inde] ; Shibasish Chowdhury [Inde] ; Rajdeep Chowdhury [Inde]Source :
- Journal of oncology [ 1687-8450 ] ; 2019.
Abstract
Mutations in p53, especially gain of function (GOF) mutations, are highly frequent in lung cancers and are known to facilitate tumor aggressiveness. Yet, the links between mutant GOF-p53 and lung cancers are not well established. In the present study, we set to examine how we can better sensitize resistant GOF-p53 lung cancer cells through modulation of cellular protein degradation machineries, proteasome and autophagy. H1299 p53 null lung cancer cells were stably transfected with R273H mutant GOF-p53 or wild-type (wt) p53 or empty vectors. The presence of R273H-P53 conferred the cancer cells with drug resistance not only against the widely used chemotherapeutic agents like cisplatin (CDDP) or 5-flurouracil (5-FU) but also against potent alternative modes of therapy like proteasomal inhibition. Therefore, there is an urgent need for new strategies that can overcome GOF-p53 induced drug resistance and prolong patient survival following failure of standard therapies. We observed that the proteasomal inhibitor, peptide aldehyde N-acetyl-leu-leu-norleucinal (commonly termed as ALLN), caused an activation of cellular homeostatic machinery, autophagy in R273H-P53 cells. Interestingly, inhibition of autophagy by chloroquine (CQ) alone or in combination with ALLN failed to induce enhanced cell death in the R273H-P53 cells; however, in contrast, an activation of autophagy by serum starvation or rapamycin increased sensitivity of cells to ALLN-induced cytotoxicity. An activated autophagy was associated with increased ROS and ERK signaling and an inhibition of either ROS or ERK signaling resulted in reduced cytotoxicity. Furthermore, inhibition of GOF-p53 was found to enhance autophagy resulting in increased cell death. Our findings provide novel insights pertaining to mechanisms by which a GOF-p53 harboring lung cancer cell is better sensitized, which can lead to the development of advanced therapy against resistant lung cancer cells.
DOI: 10.1155/2019/6164807
PubMed: 30723502
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: 000067
- to stream PubMed, to step Curation: 000067
- to stream PubMed, to step Checkpoint: 000065
- to stream Ncbi, to step Merge: 000495
- to stream Ncbi, to step Curation: 000495
- to stream Ncbi, to step Checkpoint: 000495
Links to Exploration step
pubmed:30723502Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Autophagy Regulated by Gain of Function Mutant p53 Enhances Proteasomal Inhibitor-Mediated Cell Death through Induction of ROS and ERK in Lung Cancer Cells.</title>
<author><name sortKey="Saini, Heena" sort="Saini, Heena" uniqKey="Saini H" first="Heena" last="Saini">Heena Saini</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Biological Sciences, Pilani Campus, BITS, Pilani, Rajasthan 333031, India.</nlm:affiliation>
<country xml:lang="fr">Inde</country>
<wicri:regionArea>Department of Biological Sciences, Pilani Campus, BITS, Pilani, Rajasthan 333031</wicri:regionArea>
<wicri:noRegion>Rajasthan 333031</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Hakeem, Ifrah" sort="Hakeem, Ifrah" uniqKey="Hakeem I" first="Ifrah" last="Hakeem">Ifrah Hakeem</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Biological Sciences, Pilani Campus, BITS, Pilani, Rajasthan 333031, India.</nlm:affiliation>
<country xml:lang="fr">Inde</country>
<wicri:regionArea>Department of Biological Sciences, Pilani Campus, BITS, Pilani, Rajasthan 333031</wicri:regionArea>
<wicri:noRegion>Rajasthan 333031</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Mukherjee, Sudeshna" sort="Mukherjee, Sudeshna" uniqKey="Mukherjee S" first="Sudeshna" last="Mukherjee">Sudeshna Mukherjee</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Biological Sciences, Pilani Campus, BITS, Pilani, Rajasthan 333031, India.</nlm:affiliation>
<country xml:lang="fr">Inde</country>
<wicri:regionArea>Department of Biological Sciences, Pilani Campus, BITS, Pilani, Rajasthan 333031</wicri:regionArea>
<wicri:noRegion>Rajasthan 333031</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Chowdhury, Shibasish" sort="Chowdhury, Shibasish" uniqKey="Chowdhury S" first="Shibasish" last="Chowdhury">Shibasish Chowdhury</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Biological Sciences, Pilani Campus, BITS, Pilani, Rajasthan 333031, India.</nlm:affiliation>
<country xml:lang="fr">Inde</country>
<wicri:regionArea>Department of Biological Sciences, Pilani Campus, BITS, Pilani, Rajasthan 333031</wicri:regionArea>
<wicri:noRegion>Rajasthan 333031</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Chowdhury, Rajdeep" sort="Chowdhury, Rajdeep" uniqKey="Chowdhury R" first="Rajdeep" last="Chowdhury">Rajdeep Chowdhury</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Biological Sciences, Pilani Campus, BITS, Pilani, Rajasthan 333031, India.</nlm:affiliation>
<country xml:lang="fr">Inde</country>
<wicri:regionArea>Department of Biological Sciences, Pilani Campus, BITS, Pilani, Rajasthan 333031</wicri:regionArea>
<wicri:noRegion>Rajasthan 333031</wicri:noRegion>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PubMed</idno>
<date when="2019">2019</date>
<idno type="RBID">pubmed:30723502</idno>
<idno type="pmid">30723502</idno>
<idno type="doi">10.1155/2019/6164807</idno>
<idno type="wicri:Area/PubMed/Corpus">000067</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000067</idno>
<idno type="wicri:Area/PubMed/Curation">000067</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000067</idno>
<idno type="wicri:Area/PubMed/Checkpoint">000065</idno>
<idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000065</idno>
<idno type="wicri:Area/Ncbi/Merge">000495</idno>
<idno type="wicri:Area/Ncbi/Curation">000495</idno>
<idno type="wicri:Area/Ncbi/Checkpoint">000495</idno>
<idno type="wicri:doubleKey">1687-8450:2019:Saini H:autophagy:regulated:by</idno>
<idno type="wicri:Area/Main/Merge">000A44</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en">Autophagy Regulated by Gain of Function Mutant p53 Enhances Proteasomal Inhibitor-Mediated Cell Death through Induction of ROS and ERK in Lung Cancer Cells.</title>
<author><name sortKey="Saini, Heena" sort="Saini, Heena" uniqKey="Saini H" first="Heena" last="Saini">Heena Saini</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Biological Sciences, Pilani Campus, BITS, Pilani, Rajasthan 333031, India.</nlm:affiliation>
<country xml:lang="fr">Inde</country>
<wicri:regionArea>Department of Biological Sciences, Pilani Campus, BITS, Pilani, Rajasthan 333031</wicri:regionArea>
<wicri:noRegion>Rajasthan 333031</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Hakeem, Ifrah" sort="Hakeem, Ifrah" uniqKey="Hakeem I" first="Ifrah" last="Hakeem">Ifrah Hakeem</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Biological Sciences, Pilani Campus, BITS, Pilani, Rajasthan 333031, India.</nlm:affiliation>
<country xml:lang="fr">Inde</country>
<wicri:regionArea>Department of Biological Sciences, Pilani Campus, BITS, Pilani, Rajasthan 333031</wicri:regionArea>
<wicri:noRegion>Rajasthan 333031</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Mukherjee, Sudeshna" sort="Mukherjee, Sudeshna" uniqKey="Mukherjee S" first="Sudeshna" last="Mukherjee">Sudeshna Mukherjee</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Biological Sciences, Pilani Campus, BITS, Pilani, Rajasthan 333031, India.</nlm:affiliation>
<country xml:lang="fr">Inde</country>
<wicri:regionArea>Department of Biological Sciences, Pilani Campus, BITS, Pilani, Rajasthan 333031</wicri:regionArea>
<wicri:noRegion>Rajasthan 333031</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Chowdhury, Shibasish" sort="Chowdhury, Shibasish" uniqKey="Chowdhury S" first="Shibasish" last="Chowdhury">Shibasish Chowdhury</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Biological Sciences, Pilani Campus, BITS, Pilani, Rajasthan 333031, India.</nlm:affiliation>
<country xml:lang="fr">Inde</country>
<wicri:regionArea>Department of Biological Sciences, Pilani Campus, BITS, Pilani, Rajasthan 333031</wicri:regionArea>
<wicri:noRegion>Rajasthan 333031</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Chowdhury, Rajdeep" sort="Chowdhury, Rajdeep" uniqKey="Chowdhury R" first="Rajdeep" last="Chowdhury">Rajdeep Chowdhury</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Biological Sciences, Pilani Campus, BITS, Pilani, Rajasthan 333031, India.</nlm:affiliation>
<country xml:lang="fr">Inde</country>
<wicri:regionArea>Department of Biological Sciences, Pilani Campus, BITS, Pilani, Rajasthan 333031</wicri:regionArea>
<wicri:noRegion>Rajasthan 333031</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j">Journal of oncology</title>
<idno type="ISSN">1687-8450</idno>
<imprint><date when="2019" type="published">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">Mutations in p53, especially gain of function (GOF) mutations, are highly frequent in lung cancers and are known to facilitate tumor aggressiveness. Yet, the links between mutant GOF-p53 and lung cancers are not well established. In the present study, we set to examine how we can better sensitize resistant GOF-p53 lung cancer cells through modulation of cellular protein degradation machineries, proteasome and autophagy. H1299 p53 null lung cancer cells were stably transfected with R273H mutant GOF-p53 or wild-type (wt) p53 or empty vectors. The presence of R273H-P53 conferred the cancer cells with drug resistance not only against the widely used chemotherapeutic agents like cisplatin (CDDP) or 5-flurouracil (5-FU) but also against potent alternative modes of therapy like proteasomal inhibition. Therefore, there is an urgent need for new strategies that can overcome GOF-p53 induced drug resistance and prolong patient survival following failure of standard therapies. We observed that the proteasomal inhibitor, peptide aldehyde N-acetyl-leu-leu-norleucinal (commonly termed as ALLN), caused an activation of cellular homeostatic machinery, autophagy in R273H-P53 cells. Interestingly, inhibition of autophagy by chloroquine (CQ) alone or in combination with ALLN failed to induce enhanced cell death in the R273H-P53 cells; however, in contrast, an activation of autophagy by serum starvation or rapamycin increased sensitivity of cells to ALLN-induced cytotoxicity. An activated autophagy was associated with increased ROS and ERK signaling and an inhibition of either ROS or ERK signaling resulted in reduced cytotoxicity. Furthermore, inhibition of GOF-p53 was found to enhance autophagy resulting in increased cell death. Our findings provide novel insights pertaining to mechanisms by which a GOF-p53 harboring lung cancer cell is better sensitized, which can lead to the development of advanced therapy against resistant lung cancer cells.</div>
</front>
</TEI>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/ChloroquineV1/Data/Main/Merge
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000A44 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Merge/biblio.hfd -nk 000A44 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Sante |area= ChloroquineV1 |flux= Main |étape= Merge |type= RBID |clé= pubmed:30723502 |texte= Autophagy Regulated by Gain of Function Mutant p53 Enhances Proteasomal Inhibitor-Mediated Cell Death through Induction of ROS and ERK in Lung Cancer Cells. }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Merge/RBID.i -Sk "pubmed:30723502" \ | HfdSelect -Kh $EXPLOR_AREA/Data/Main/Merge/biblio.hfd \ | NlmPubMed2Wicri -a ChloroquineV1
![]() | This area was generated with Dilib version V0.6.33. | ![]() |