Regorafenib Inhibits Colorectal Tumor Growth through PUMA-Mediated Apoptosis
Identifieur interne : 005006 ( Main/Exploration ); précédent : 005005; suivant : 005007Regorafenib Inhibits Colorectal Tumor Growth through PUMA-Mediated Apoptosis
Auteurs : DONGSHI CHEN [États-Unis] ; LIANG WEI [États-Unis] ; JIAN YU [États-Unis] ; LIN ZHANG [États-Unis]Source :
- Clinical cancer research : (Print) [ 1078-0432 ] ; 2014.
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- Pascal (Inist)
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Abstract
Purpose: Regorafenib, a multikinase inhibitor targeting the Ras/Raf/MEK/ERK pathway, has recently been approved for the treatment of metastatic colorectal cancer. However, the mechanisms of action of regorafenib in colorectal cancer cells have been unclear. We investigated how regorafenib suppresses colorectal cancer cell growth and potentiates effects of other chemotherapeutic drugs. Experimental Design: We determined whether and how regorafenib induces the expression of PUMA, a p53 target and a critical mediator of apoptosis in colorectal cancer cells. We also investigated whether PUMA is necessary for the killing and chemosensitization effects of regorafenib in colorectal cancer cells. Furthermore, xenograft tumors were used to test if PUMA mediates the in vivo antitumor, antiangiogenic, and chemosensitization effects of regorafenib. Results: We found that regorafenib treatment induces PUMA in colorectal cancer cells irrespective of p53 status through the NF-κB pathway following ERK inhibition and glycogen synthase kinase 3β activation. Upregulation of PUMA is correlated with apoptosis induction in different colorectal cancer cell lines. PUMA is necessary for regorafenib-induced apoptosis in colorectal cancer cells. Chemosensitization by regorafenib is mediated by enhanced PUMA induction through different pathways. Furthermore, deficiency in PUMA abrogates the in vivo antitumor, antiangiogenic, and chemosensitization effects of regorafenib. Conclusions: Our results demonstrate a key role of PUMA in mediating the anticancer effects of regorafenib in colorectal cancer cells. They suggest that PUMA induction can be used as an indicator of regorafenib sensitivity, and also provide a rationale for manipulating the apoptotic machinery to improve the therapeutic efficacy of regorafenib and other targeted drugs.
Affiliations:
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type="wicri:Area/Main/Exploration">005006</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Regorafenib Inhibits Colorectal Tumor Growth through PUMA-Mediated Apoptosis</title><author><name sortKey="Dongshi Chen" sort="Dongshi Chen" uniqKey="Dongshi Chen" last="Dongshi Chen">DONGSHI CHEN</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>University of Pittsburgh Cancer Institute</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="02"><s1>Department of Pharmacology and Chemical Biology</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Liang Wei" sort="Liang Wei" uniqKey="Liang Wei" last="Liang Wei">LIANG WEI</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>University of Pittsburgh Cancer Institute</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Department of Pathology, University of Pittsburgh School of Medicine</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>2 aut.</sZ><sZ>3 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Jian Yu" sort="Jian Yu" uniqKey="Jian Yu" last="Jian Yu">JIAN YU</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>University of Pittsburgh Cancer Institute</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Department of Pathology, University of Pittsburgh School of Medicine</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>2 aut.</sZ><sZ>3 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Lin Zhang" sort="Lin Zhang" uniqKey="Lin Zhang" last="Lin Zhang">LIN ZHANG</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>University of Pittsburgh Cancer Institute</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="02"><s1>Department of Pharmacology and Chemical Biology</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author></analytic><series><title level="j" type="main">Clinical cancer research : (Print)</title><title level="j" type="abbreviated">Clin. cancer res. : (Print)</title><idno type="ISSN">1078-0432</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Clinical cancer research : (Print)</title><title level="j" type="abbreviated">Clin. cancer res. : (Print)</title><idno type="ISSN">1078-0432</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antineoplastic agent</term><term>Apoptosis</term><term>Cell death</term><term>Colon</term><term>Malignant tumor</term><term>Rectum</term><term>Regorafenib</term><term>Tumor growth</term><term>p53 up-regulated modulator of apoptosis</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Côlon</term><term>Rectum</term><term>Croissance tumorale</term><term>Tumeur maligne</term><term>Apoptose</term><term>Mort cellulaire</term><term>Anticancéreux</term><term>Régorafénib</term><term>Protéine Puma</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Purpose: Regorafenib, a multikinase inhibitor targeting the Ras/Raf/MEK/ERK pathway, has recently been approved for the treatment of metastatic colorectal cancer. However, the mechanisms of action of regorafenib in colorectal cancer cells have been unclear. We investigated how regorafenib suppresses colorectal cancer cell growth and potentiates effects of other chemotherapeutic drugs. Experimental Design: We determined whether and how regorafenib induces the expression of PUMA, a p53 target and a critical mediator of apoptosis in colorectal cancer cells. We also investigated whether PUMA is necessary for the killing and chemosensitization effects of regorafenib in colorectal cancer cells. Furthermore, xenograft tumors were used to test if PUMA mediates the in vivo antitumor, antiangiogenic, and chemosensitization effects of regorafenib. Results: We found that regorafenib treatment induces PUMA in colorectal cancer cells irrespective of p53 status through the NF-κB pathway following ERK inhibition and glycogen synthase kinase 3β activation. Upregulation of PUMA is correlated with apoptosis induction in different colorectal cancer cell lines. PUMA is necessary for regorafenib-induced apoptosis in colorectal cancer cells. Chemosensitization by regorafenib is mediated by enhanced PUMA induction through different pathways. Furthermore, deficiency in PUMA abrogates the in vivo antitumor, antiangiogenic, and chemosensitization effects of regorafenib. Conclusions: Our results demonstrate a key role of PUMA in mediating the anticancer effects of regorafenib in colorectal cancer cells. They suggest that PUMA induction can be used as an indicator of regorafenib sensitivity, and also provide a rationale for manipulating the apoptotic machinery to improve the therapeutic efficacy of regorafenib and other targeted drugs.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Pennsylvanie</li></region></list><tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Dongshi Chen" sort="Dongshi Chen" uniqKey="Dongshi Chen" last="Dongshi Chen">DONGSHI CHEN</name></region><name sortKey="Dongshi Chen" sort="Dongshi Chen" uniqKey="Dongshi Chen" last="Dongshi Chen">DONGSHI CHEN</name><name sortKey="Jian Yu" sort="Jian Yu" uniqKey="Jian Yu" last="Jian Yu">JIAN YU</name><name sortKey="Jian Yu" sort="Jian Yu" uniqKey="Jian Yu" last="Jian Yu">JIAN YU</name><name sortKey="Liang Wei" sort="Liang Wei" uniqKey="Liang Wei" last="Liang Wei">LIANG WEI</name><name sortKey="Liang Wei" sort="Liang Wei" uniqKey="Liang Wei" last="Liang Wei">LIANG WEI</name><name sortKey="Lin Zhang" sort="Lin Zhang" uniqKey="Lin Zhang" last="Lin Zhang">LIN ZHANG</name><name sortKey="Lin Zhang" sort="Lin Zhang" uniqKey="Lin Zhang" last="Lin Zhang">LIN ZHANG</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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