PlantImRecepV1, Main, Exploration, bibRecord, 000091

Par-4 mediated Smad4 induction in PDAC cells restores canonical TGF-β/ Smad4 axis driving the cells towards lethal EMT.

Identifieur interne : 000091 ( Main/Exploration ); précédent : 000090; suivant : 000092

Par-4 mediated Smad4 induction in PDAC cells restores canonical TGF-β/ Smad4 axis driving the cells towards lethal EMT.

Auteurs : Mir Mohd Faheem [Inde] ; Reyaz Ur Rasool [États-Unis] ; Syed Mudabir Ahmad [Inde] ; Vijay Lakshmi Jamwal [Inde] ; Souneek Chakraborty [Inde] ; Archana Katoch [Inde] ; Sumit G. Gandhi [Inde] ; Madhulika Bhagat [Inde] ; Anindya Goswami [Inde]

Source :

European journal of cell biology [ 1618-1298 ] ; 2020.

RBID : pubmed:32439219

Descripteurs français

English descriptors

KwdEn :
- Carcinoma, Pancreatic Ductal (metabolism), Carcinoma, Pancreatic Ductal (pathology), Cell Line, Tumor (MeSH), Epithelial-Mesenchymal Transition (MeSH), G1 Phase Cell Cycle Checkpoints (MeSH), Humans (MeSH), NM23 Nucleoside Diphosphate Kinases (genetics), NM23 Nucleoside Diphosphate Kinases (metabolism), Pancreatic Neoplasms (metabolism), Pancreatic Neoplasms (pathology), Plasmids (genetics), Proto-Oncogene Proteins c-akt (antagonists & inhibitors), Proto-Oncogene Proteins c-akt (metabolism), RNA, Small Interfering (administration & dosage), RNA, Small Interfering (genetics), RNA-Binding Proteins (metabolism), Receptors, Thrombin (genetics), Receptors, Thrombin (metabolism), Signal Transduction (MeSH), Smad4 Protein (biosynthesis), Smad4 Protein (genetics), Smad4 Protein (metabolism), Transforming Growth Factor beta (metabolism), Up-Regulation (MeSH).
MESH :
- chemical , administration & dosage : RNA, Small Interfering.
- chemical , antagonists & inhibitors : Proto-Oncogene Proteins c-akt.
- chemical , biosynthesis : Smad4 Protein.
- chemical , genetics : NM23 Nucleoside Diphosphate Kinases, RNA, Small Interfering, Receptors, Thrombin, Smad4 Protein.
- genetics : Plasmids.
- metabolism : Carcinoma, Pancreatic Ductal, NM23 Nucleoside Diphosphate Kinases, Pancreatic Neoplasms, Proto-Oncogene Proteins c-akt, RNA-Binding Proteins, Receptors, Thrombin, Smad4 Protein, Transforming Growth Factor beta.
- pathology : Carcinoma, Pancreatic Ductal, Pancreatic Neoplasms.
- Cell Line, Tumor, Epithelial-Mesenchymal Transition, G1 Phase Cell Cycle Checkpoints, Humans, Signal Transduction, Up-Regulation.

Abstract

Deregulation of TGF-β signaling is intricately engrossed in the pathophysiology of pancreatic adenocarcinomas (PDACs). The role of TGF-β all through pancreatic cancer initiation and progression is multifarious and somewhat paradoxical. TGF-β plays a tumor suppressive role in early-stage pancreatic cancer by promoting apoptosis and inhibiting epithelial cell cycle progression, but incites tumor promotion in late-stage by modulating genomic instability, neo-angiogenesis, immune evasion, cell motility, and metastasis. Here, we provide evidences that Par-4 acts as one of the vital mediators to regulate TGF-β/Smad4 pathway, wherein, Par-4 induction/over-expression induced EMT which was later culminated in to apoptosis in presence of TGF-β via positive regulation of Smad4. Intriguingly, Par-4^-/- cells were devoid of significant Smad4 induction compared to Par-4^+/+ cells in presence of TGF-β and ectopic Par-4 steadily augmented Smad4 expression by restoring TGF-β/Smad4 axis in Panc-1 cells. Further, our FACS and western blotting results unveiled that Par-4 dragged the PDAC cells to G₁ arrest in presence of TGF-β byelevating p21 and p27 levels while attenuating Cyclin E and A levels and augmenting caspase 3 cleavage triggering lethal EMT. Through restoration of Smad4, we further establish that in BxPC3 cell line (Smad4^-/-), Smad4 is essential for Par-4 to indulge TGF-β dependent lethal EMT program. The mechanistic relevance of Par-4 mediated Smad4 activation was additionally validated by co-immunoprecipitation wherein disruption of NM23H1-STRAP interaction by Par-4 rescues TGF-β/Smad4 pathway in PDAC and mediates the tumor suppressive role of TGF-β, therefore serving as a vital cog to restore the apoptotic functions of TGF-β pathway.

DOI: 10.1016/j.ejcb.2020.151076
PubMed: 32439219

Affiliations:

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<sourceDesc><biblStruct><analytic><title xml:lang="en">Par-4 mediated Smad4 induction in PDAC cells restores canonical TGF-β/ Smad4 axis driving the cells towards lethal EMT.</title>
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<term>Carcinoma, Pancreatic Ductal (pathology)</term>
<term>Cell Line, Tumor (MeSH)</term>
<term>Epithelial-Mesenchymal Transition (MeSH)</term>
<term>G1 Phase Cell Cycle Checkpoints (MeSH)</term>
<term>Humans (MeSH)</term>
<term>NM23 Nucleoside Diphosphate Kinases (genetics)</term>
<term>NM23 Nucleoside Diphosphate Kinases (metabolism)</term>
<term>Pancreatic Neoplasms (metabolism)</term>
<term>Pancreatic Neoplasms (pathology)</term>
<term>Plasmids (genetics)</term>
<term>Proto-Oncogene Proteins c-akt (antagonists & inhibitors)</term>
<term>Proto-Oncogene Proteins c-akt (metabolism)</term>
<term>RNA, Small Interfering (administration & dosage)</term>
<term>RNA, Small Interfering (genetics)</term>
<term>RNA-Binding Proteins (metabolism)</term>
<term>Receptors, Thrombin (genetics)</term>
<term>Receptors, Thrombin (metabolism)</term>
<term>Signal Transduction (MeSH)</term>
<term>Smad4 Protein (biosynthesis)</term>
<term>Smad4 Protein (genetics)</term>
<term>Smad4 Protein (metabolism)</term>
<term>Transforming Growth Factor beta (metabolism)</term>
<term>Up-Regulation (MeSH)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Carcinome du canal pancréatique (anatomopathologie)</term>
<term>Carcinome du canal pancréatique (métabolisme)</term>
<term>Facteur de croissance transformant bêta (métabolisme)</term>
<term>Humains (MeSH)</term>
<term>Lignée cellulaire tumorale (MeSH)</term>
<term>NM23 Nucleoside Diphosphate kinases (génétique)</term>
<term>NM23 Nucleoside Diphosphate kinases (métabolisme)</term>
<term>Petit ARN interférent (administration et posologie)</term>
<term>Petit ARN interférent (génétique)</term>
<term>Plasmides (génétique)</term>
<term>Points de contrôle de la phase G1 du cycle cellulaire (MeSH)</term>
<term>Protéine Smad-4 (biosynthèse)</term>
<term>Protéine Smad-4 (génétique)</term>
<term>Protéine Smad-4 (métabolisme)</term>
<term>Protéines de liaison à l'ARN (métabolisme)</term>
<term>Protéines proto-oncogènes c-akt (antagonistes et inhibiteurs)</term>
<term>Protéines proto-oncogènes c-akt (métabolisme)</term>
<term>Récepteurs à la thrombine (génétique)</term>
<term>Récepteurs à la thrombine (métabolisme)</term>
<term>Régulation positive (MeSH)</term>
<term>Transduction du signal (MeSH)</term>
<term>Transition épithélio-mésenchymateuse (MeSH)</term>
<term>Tumeurs du pancréas (anatomopathologie)</term>
<term>Tumeurs du pancréas (métabolisme)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en"><term>RNA, Small Interfering</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Proto-Oncogene Proteins c-akt</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="biosynthesis" xml:lang="en"><term>Smad4 Protein</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>NM23 Nucleoside Diphosphate Kinases</term>
<term>RNA, Small Interfering</term>
<term>Receptors, Thrombin</term>
<term>Smad4 Protein</term>
</keywords>
<keywords scheme="MESH" qualifier="administration et posologie" xml:lang="fr"><term>Petit ARN interférent</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Carcinome du canal pancréatique</term>
<term>Tumeurs du pancréas</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines proto-oncogènes c-akt</term>
</keywords>
<keywords scheme="MESH" qualifier="biosynthèse" xml:lang="fr"><term>Protéine Smad-4</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Plasmids</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>NM23 Nucleoside Diphosphate kinases</term>
<term>Petit ARN interférent</term>
<term>Plasmides</term>
<term>Protéine Smad-4</term>
<term>Récepteurs à la thrombine</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Carcinoma, Pancreatic Ductal</term>
<term>NM23 Nucleoside Diphosphate Kinases</term>
<term>Pancreatic Neoplasms</term>
<term>Proto-Oncogene Proteins c-akt</term>
<term>RNA-Binding Proteins</term>
<term>Receptors, Thrombin</term>
<term>Smad4 Protein</term>
<term>Transforming Growth Factor beta</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Carcinome du canal pancréatique</term>
<term>Facteur de croissance transformant bêta</term>
<term>NM23 Nucleoside Diphosphate kinases</term>
<term>Protéine Smad-4</term>
<term>Protéines de liaison à l'ARN</term>
<term>Protéines proto-oncogènes c-akt</term>
<term>Récepteurs à la thrombine</term>
<term>Tumeurs du pancréas</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Carcinoma, Pancreatic Ductal</term>
<term>Pancreatic Neoplasms</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Cell Line, Tumor</term>
<term>Epithelial-Mesenchymal Transition</term>
<term>G1 Phase Cell Cycle Checkpoints</term>
<term>Humans</term>
<term>Signal Transduction</term>
<term>Up-Regulation</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Humains</term>
<term>Lignée cellulaire tumorale</term>
<term>Points de contrôle de la phase G1 du cycle cellulaire</term>
<term>Régulation positive</term>
<term>Transduction du signal</term>
<term>Transition épithélio-mésenchymateuse</term>
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<front><div type="abstract" xml:lang="en">Deregulation of TGF-β signaling is intricately engrossed in the pathophysiology of pancreatic adenocarcinomas (PDACs). The role of TGF-β all through pancreatic cancer initiation and progression is multifarious and somewhat paradoxical. TGF-β plays a tumor suppressive role in early-stage pancreatic cancer by promoting apoptosis and inhibiting epithelial cell cycle progression, but incites tumor promotion in late-stage by modulating genomic instability, neo-angiogenesis, immune evasion, cell motility, and metastasis. Here, we provide evidences that Par-4 acts as one of the vital mediators to regulate TGF-β/Smad4 pathway, wherein, Par-4 induction/over-expression induced EMT which was later culminated in to apoptosis in presence of TGF-β via positive regulation of Smad4. Intriguingly, Par-4<sup>-/-</sup>
 cells were devoid of significant Smad4 induction compared to Par-4<sup>+/+</sup>
 cells in presence of TGF-β and ectopic Par-4 steadily augmented Smad4 expression by restoring TGF-β/Smad4 axis in Panc-1 cells. Further, our FACS and western blotting results unveiled that Par-4 dragged the PDAC cells to G<sub>1</sub>
 arrest in presence of TGF-β byelevating p21 and p27 levels while attenuating Cyclin E and A levels and augmenting caspase 3 cleavage triggering lethal EMT. Through restoration of Smad4, we further establish that in BxPC3 cell line (Smad4<sup>-/-</sup>
), Smad4 is essential for Par-4 to indulge TGF-β dependent lethal EMT program. The mechanistic relevance of Par-4 mediated Smad4 activation was additionally validated by co-immunoprecipitation wherein disruption of NM23H1-STRAP interaction by Par-4 rescues TGF-β/Smad4 pathway in PDAC and mediates the tumor suppressive role of TGF-β, therefore serving as a vital cog to restore the apoptotic functions of TGF-β pathway.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">32439219</PMID>
<DateCompleted><Year>2020</Year>
<Month>10</Month>
<Day>27</Day>
</DateCompleted>
<DateRevised><Year>2020</Year>
<Month>10</Month>
<Day>27</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1618-1298</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>99</Volume>
<Issue>4</Issue>
<PubDate><Year>2020</Year>
<Month>May</Month>
</PubDate>
</JournalIssue>
<Title>European journal of cell biology</Title>
<ISOAbbreviation>Eur J Cell Biol</ISOAbbreviation>
</Journal>
<ArticleTitle>Par-4 mediated Smad4 induction in PDAC cells restores canonical TGF-β/ Smad4 axis driving the cells towards lethal EMT.</ArticleTitle>
<Pagination><MedlinePgn>151076</MedlinePgn>
</Pagination>
<ELocationID EIdType="pii" ValidYN="Y">S0171-9335(20)30015-7</ELocationID>
<ELocationID EIdType="doi" ValidYN="Y">10.1016/j.ejcb.2020.151076</ELocationID>
<Abstract><AbstractText>Deregulation of TGF-β signaling is intricately engrossed in the pathophysiology of pancreatic adenocarcinomas (PDACs). The role of TGF-β all through pancreatic cancer initiation and progression is multifarious and somewhat paradoxical. TGF-β plays a tumor suppressive role in early-stage pancreatic cancer by promoting apoptosis and inhibiting epithelial cell cycle progression, but incites tumor promotion in late-stage by modulating genomic instability, neo-angiogenesis, immune evasion, cell motility, and metastasis. Here, we provide evidences that Par-4 acts as one of the vital mediators to regulate TGF-β/Smad4 pathway, wherein, Par-4 induction/over-expression induced EMT which was later culminated in to apoptosis in presence of TGF-β via positive regulation of Smad4. Intriguingly, Par-4<sup>-/-</sup>
 cells were devoid of significant Smad4 induction compared to Par-4<sup>+/+</sup>
 cells in presence of TGF-β and ectopic Par-4 steadily augmented Smad4 expression by restoring TGF-β/Smad4 axis in Panc-1 cells. Further, our FACS and western blotting results unveiled that Par-4 dragged the PDAC cells to G<sub>1</sub>
 arrest in presence of TGF-β byelevating p21 and p27 levels while attenuating Cyclin E and A levels and augmenting caspase 3 cleavage triggering lethal EMT. Through restoration of Smad4, we further establish that in BxPC3 cell line (Smad4<sup>-/-</sup>
), Smad4 is essential for Par-4 to indulge TGF-β dependent lethal EMT program. The mechanistic relevance of Par-4 mediated Smad4 activation was additionally validated by co-immunoprecipitation wherein disruption of NM23H1-STRAP interaction by Par-4 rescues TGF-β/Smad4 pathway in PDAC and mediates the tumor suppressive role of TGF-β, therefore serving as a vital cog to restore the apoptotic functions of TGF-β pathway.</AbstractText>
<CopyrightInformation>Copyright © 2020 Elsevier GmbH. All rights reserved.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Mohd Faheem</LastName>
<ForeName>Mir</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India; School of Biotechnology, University of Jammu, Jammu, 180006, India.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Rasool</LastName>
<ForeName>Reyaz Ur</ForeName>
<Initials>RU</Initials>
<AffiliationInfo><Affiliation>Perelman School of Medicine, Cancer Biology Division, University of Pennsylvania, PA-19104, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ahmad</LastName>
<ForeName>Syed Mudabir</ForeName>
<Initials>SM</Initials>
<AffiliationInfo><Affiliation>Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Jamwal</LastName>
<ForeName>Vijay Lakshmi</ForeName>
<Initials>VL</Initials>
<AffiliationInfo><Affiliation>Plant Biotechnology and System Biology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Chakraborty</LastName>
<ForeName>Souneek</ForeName>
<Initials>S</Initials>
<AffiliationInfo><Affiliation>Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Katoch</LastName>
<ForeName>Archana</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Gandhi</LastName>
<ForeName>Sumit G</ForeName>
<Initials>SG</Initials>
<AffiliationInfo><Affiliation>Plant Biotechnology and System Biology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Bhagat</LastName>
<ForeName>Madhulika</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>School of Biotechnology, University of Jammu, Jammu, 180006, India.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Goswami</LastName>
<ForeName>Anindya</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India. Electronic address: agoswami@iiim.ac.in.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2020</Year>
<Month>05</Month>
<Day>11</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>Germany</Country>
<MedlineTA>Eur J Cell Biol</MedlineTA>
<NlmUniqueID>7906240</NlmUniqueID>
<ISSNLinking>0171-9335</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D054778">NM23 Nucleoside Diphosphate Kinases</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D034741">RNA, Small Interfering</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D016601">RNA-Binding Proteins</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D018179">Receptors, Thrombin</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C497796">SMAD4 protein, human</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C403447">STRAP protein, human</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D051901">Smad4 Protein</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D016212">Transforming Growth Factor beta</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber>
<NameOfSubstance UI="D051057">Proto-Oncogene Proteins c-akt</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.7.4.6</RegistryNumber>
<NameOfSubstance UI="C517938">NME1 protein, human</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>JWE1M73YZN</RegistryNumber>
<NameOfSubstance UI="C112908">protease-activated receptor 4</NameOfSubstance>
</Chemical>
</ChemicalList>
<CitationSubset>IM</CitationSubset>
<MeshHeadingList><MeshHeading><DescriptorName UI="D021441" MajorTopicYN="N">Carcinoma, Pancreatic Ductal</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
<QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D058750" MajorTopicYN="N">Epithelial-Mesenchymal Transition</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D059585" MajorTopicYN="N">G1 Phase Cell Cycle Checkpoints</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D054778" MajorTopicYN="N">NM23 Nucleoside Diphosphate Kinases</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D010190" MajorTopicYN="N">Pancreatic Neoplasms</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
<QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D010957" MajorTopicYN="N">Plasmids</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D051057" MajorTopicYN="N">Proto-Oncogene Proteins c-akt</DescriptorName>
<QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D034741" MajorTopicYN="N">RNA, Small Interfering</DescriptorName>
<QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D016601" MajorTopicYN="N">RNA-Binding Proteins</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D018179" MajorTopicYN="N">Receptors, Thrombin</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D015398" MajorTopicYN="N">Signal Transduction</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D051901" MajorTopicYN="N">Smad4 Protein</DescriptorName>
<QualifierName UI="Q000096" MajorTopicYN="N">biosynthesis</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D016212" MajorTopicYN="N">Transforming Growth Factor beta</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D015854" MajorTopicYN="N">Up-Regulation</DescriptorName>
</MeshHeading>
</MeshHeadingList>
<KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Lethal EMT</Keyword>
<Keyword MajorTopicYN="N">NM23H1</Keyword>
<Keyword MajorTopicYN="N">Par-4</Keyword>
<Keyword MajorTopicYN="N">TGF-β/Smad4</Keyword>
</KeywordList>
<CoiStatement>Declaration of Competing Interest The authors declare no conflict of interest.</CoiStatement>
</MedlineCitation>
<PubmedData><History><PubMedPubDate PubStatus="received"><Year>2019</Year>
<Month>09</Month>
<Day>06</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="revised"><Year>2020</Year>
<Month>03</Month>
<Day>20</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="accepted"><Year>2020</Year>
<Month>03</Month>
<Day>20</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="pubmed"><Year>2020</Year>
<Month>5</Month>
<Day>23</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="medline"><Year>2020</Year>
<Month>10</Month>
<Day>28</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="entrez"><Year>2020</Year>
<Month>5</Month>
<Day>23</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
</History>
<PublicationStatus>ppublish</PublicationStatus>
<ArticleIdList><ArticleId IdType="pubmed">32439219</ArticleId>
<ArticleId IdType="pii">S0171-9335(20)30015-7</ArticleId>
<ArticleId IdType="doi">10.1016/j.ejcb.2020.151076</ArticleId>
</ArticleIdList>
</PubmedData>
</pubmed>
<affiliations><list><country><li>Inde</li>
<li>États-Unis</li>
</country>
<region><li>Pennsylvanie</li>
</region>
</list>
<tree><country name="Inde"><noRegion><name sortKey="Mohd Faheem, Mir" sort="Mohd Faheem, Mir" uniqKey="Mohd Faheem M" first="Mir" last="Mohd Faheem">Mir Mohd Faheem</name>
</noRegion>
<name sortKey="Ahmad, Syed Mudabir" sort="Ahmad, Syed Mudabir" uniqKey="Ahmad S" first="Syed Mudabir" last="Ahmad">Syed Mudabir Ahmad</name>
<name sortKey="Bhagat, Madhulika" sort="Bhagat, Madhulika" uniqKey="Bhagat M" first="Madhulika" last="Bhagat">Madhulika Bhagat</name>
<name sortKey="Chakraborty, Souneek" sort="Chakraborty, Souneek" uniqKey="Chakraborty S" first="Souneek" last="Chakraborty">Souneek Chakraborty</name>
<name sortKey="Gandhi, Sumit G" sort="Gandhi, Sumit G" uniqKey="Gandhi S" first="Sumit G" last="Gandhi">Sumit G. Gandhi</name>
<name sortKey="Goswami, Anindya" sort="Goswami, Anindya" uniqKey="Goswami A" first="Anindya" last="Goswami">Anindya Goswami</name>
<name sortKey="Jamwal, Vijay Lakshmi" sort="Jamwal, Vijay Lakshmi" uniqKey="Jamwal V" first="Vijay Lakshmi" last="Jamwal">Vijay Lakshmi Jamwal</name>
<name sortKey="Katoch, Archana" sort="Katoch, Archana" uniqKey="Katoch A" first="Archana" last="Katoch">Archana Katoch</name>
</country>
<country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Rasool, Reyaz Ur" sort="Rasool, Reyaz Ur" uniqKey="Rasool R" first="Reyaz Ur" last="Rasool">Reyaz Ur Rasool</name>
</region>
</country>
</tree>
</affiliations>
</record>

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Par-4 mediated Smad4 induction in PDAC cells restores canonical TGF-β/ Smad4 axis driving the cells towards lethal EMT.

Par-4 mediated Smad4 induction in PDAC cells restores canonical TGF-β/ Smad4 axis driving the cells towards lethal EMT.

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