000306796 001__ 306796
000306796 005__ 20251218100330.0
000306796 0247_ $$2doi$$a10.1016/j.phrs.2025.108057
000306796 0247_ $$2pmid$$apmid:41349849
000306796 0247_ $$2ISSN$$a1043-6618
000306796 0247_ $$2ISSN$$a0031-6989
000306796 0247_ $$2ISSN$$a1096-1186
000306796 0247_ $$2ISSN$$a1879-2936
000306796 037__ $$aDKFZ-2025-02773
000306796 041__ $$aEnglish
000306796 082__ $$a610
000306796 1001_ $$aMenig-Benzig, Lena-Sophie$$b0
000306796 245__ $$aDrug targeting of the monocarboxylate transporter MCT4 is a novel treatment strategy for metastatic ccRCC.
000306796 260__ $$aLondon$$bAcademic Press$$c2025
000306796 3367_ $$2DRIVER$$aarticle
000306796 3367_ $$2DataCite$$aOutput Types/Journal article
000306796 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1766048557_2624439
000306796 3367_ $$2BibTeX$$aARTICLE
000306796 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000306796 3367_ $$00$$2EndNote$$aJournal Article
000306796 500__ $$a222, 108057
000306796 520__ $$aClear cell renal cell carcinoma (ccRCC) is characterized by a metabolic shift towards enhanced aerobic glycolysis and increased lactate production. The survival rate for metastatic RCC is still poor. We evaluated the lactate monocarboxylate transporter 4 (MCT4), encoded by SLC16A3, as drug target for metastatic disease. MCT4 protein expression in 209 distant ccRCC metastases, including 40 recurrent metastases, was generally as high as compared to primary tumor tissue and significantly increased compared to non-tumor tissue (P<1E-15). MCT4 expression was irrespective of affected organs and mutations in RCC driver genes. DNA methylation in the SLC16A3 promoter, assessed by MALDI TOF mass spectrometry and correlated with clinicopathological data, were not significantly different in metastases of all investigated organ sites, and between paired tumor and metastases samples. Visualization of expression in single-cell and spatial RNA sequencing datasets reveals main expression of SLC16A3 in cells derived from tumor, tumor-normal interface, metastatic and lymph node tissue. Alone or combined with inhibition of mitochondrial respiration by metformin and phenformin, the MCT4 inhibitor syrosingopine significantly inhibits lactate efflux, induces cell viability reduction in four different RCC cell lines and patient-derived 2D/3D models, and alterations in cellular metabolism and mitochondrial respiration. Six patient-derived RCC air-liquid interface models, mimicking the complex RCC architecture, corroborate these data. Beyond potential prediction of patient outcome using MCT4 expression and DNA methylation at specific CpG sites, drug targeting of MCT4 and inhibiting mitochondrial respiration synergistically is a novel treatment strategy for metastatic ccRCC.
000306796 536__ $$0G:(DE-HGF)POF4-899$$a899 - ohne Topic (POF4-899)$$cPOF4-899$$fPOF IV$$x0
000306796 588__ $$aDataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de
000306796 650_7 $$2Other$$aDNA methylation
000306796 650_7 $$2Other$$aMCT4
000306796 650_7 $$2Other$$aMetformin (PubChem CID: 4091)
000306796 650_7 $$2Other$$aPhenformin (PubChem CID: 8249)
000306796 650_7 $$2Other$$aSLC16A3
000306796 650_7 $$2Other$$aSyrosingopine (PubChem CID: 6769)
000306796 650_7 $$2Other$$ametastasis
000306796 650_7 $$2Other$$amonocarboxylate transporter
000306796 650_7 $$2Other$$arenal cell carcinoma
000306796 7001_ $$aStühler, Viktoria$$b1
000306796 7001_ $$aMazzola, Pascale$$b2
000306796 7001_ $$aHeinrich, Hannah$$b3
000306796 7001_ $$aHofmann, Ute$$b4
000306796 7001_ $$aWidmann, Natalie$$b5
000306796 7001_ $$aBohnert, Regina$$b6
000306796 7001_ $$aNeef, Sylvia K$$b7
000306796 7001_ $$aSauter-Meyerhoff, Carolin$$b8
000306796 7001_ $$aSchmees, Christian$$b9
000306796 7001_ $$aFuhr, Anika$$b10
000306796 7001_ $$aKlumpp, Verena$$b11
000306796 7001_ $$aRausch, Steffen$$b12
000306796 7001_ $$aGürgen, Dennis$$b13
000306796 7001_ $$aMürdter, Thomas E$$b14
000306796 7001_ $$aWinter, Stefan$$b15
000306796 7001_ $$aBüttner, Florian A$$b16
000306796 7001_ $$aKruck, Stephan$$b17
000306796 7001_ $$0P:(DE-HGF)0$$aChoffart, Anaïs$$b18
000306796 7001_ $$0P:(DE-He78)aa2cd10f8b1dcaa55db6a9a34fa2ef3e$$aMartins, André F$$b19$$udkfz
000306796 7001_ $$aHennenlotter, Jörg$$b20
000306796 7001_ $$aBarcena, Maria Luisa$$b21
000306796 7001_ $$aVakhrusheva, Olesya$$b22
000306796 7001_ $$aBahlinger, Veronika$$b23
000306796 7001_ $$aFend, Falko$$b24
000306796 7001_ $$aTsaur, Igor$$b25
000306796 7001_ $$aBedke, Jens$$b26
000306796 7001_ $$0P:(DE-He78)0321c153233e619c095d93d9d5546c9d$$aSchwab, Matthias$$b27
000306796 7001_ $$aSchaeffeler, Elke$$b28
000306796 773__ $$0PERI:(DE-600)1471456-5$$a10.1016/j.phrs.2025.108057$$gp. 108057 -$$p108057$$tPharmacological research$$v222$$x1043-6618$$y2025
000306796 909CO $$ooai:inrepo02.dkfz.de:306796$$pVDB
000306796 9101_ $$0I:(DE-588b)2036810-0$$6P:(DE-HGF)0$$aDeutsches Krebsforschungszentrum$$b18$$kDKFZ
000306796 9101_ $$0I:(DE-588b)2036810-0$$6P:(DE-He78)aa2cd10f8b1dcaa55db6a9a34fa2ef3e$$aDeutsches Krebsforschungszentrum$$b19$$kDKFZ
000306796 9101_ $$0I:(DE-588b)2036810-0$$6P:(DE-He78)0321c153233e619c095d93d9d5546c9d$$aDeutsches Krebsforschungszentrum$$b27$$kDKFZ
000306796 9131_ $$0G:(DE-HGF)POF4-899$$1G:(DE-HGF)POF4-890$$2G:(DE-HGF)POF4-800$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bProgrammungebundene Forschung$$lohne Programm$$vohne Topic$$x0
000306796 9141_ $$y2025
000306796 915__ $$0StatID:(DE-HGF)0420$$2StatID$$aNationallizenz$$d2023-08-23$$wger
000306796 915__ $$0StatID:(DE-HGF)0100$$2StatID$$aJCR$$bPHARMACOL RES : 2022$$d2023-08-23
000306796 915__ $$0StatID:(DE-HGF)0200$$2StatID$$aDBCoverage$$bSCOPUS$$d2023-08-23
000306796 915__ $$0StatID:(DE-HGF)0300$$2StatID$$aDBCoverage$$bMedline$$d2023-08-23
000306796 915__ $$0StatID:(DE-HGF)0600$$2StatID$$aDBCoverage$$bEbsco Academic Search$$d2023-08-23
000306796 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bASC$$d2023-08-23
000306796 915__ $$0StatID:(DE-HGF)0199$$2StatID$$aDBCoverage$$bClarivate Analytics Master Journal List$$d2023-08-23
000306796 915__ $$0StatID:(DE-HGF)1050$$2StatID$$aDBCoverage$$bBIOSIS Previews$$d2023-08-23
000306796 915__ $$0StatID:(DE-HGF)0113$$2StatID$$aWoS$$bScience Citation Index Expanded$$d2023-08-23
000306796 915__ $$0StatID:(DE-HGF)0150$$2StatID$$aDBCoverage$$bWeb of Science Core Collection$$d2023-08-23
000306796 915__ $$0StatID:(DE-HGF)1030$$2StatID$$aDBCoverage$$bCurrent Contents - Life Sciences$$d2023-08-23
000306796 915__ $$0StatID:(DE-HGF)1190$$2StatID$$aDBCoverage$$bBiological Abstracts$$d2023-08-23
000306796 915__ $$0StatID:(DE-HGF)0160$$2StatID$$aDBCoverage$$bEssential Science Indicators$$d2023-08-23
000306796 915__ $$0StatID:(DE-HGF)0501$$2StatID$$aDBCoverage$$bDOAJ Seal$$d2023-06-19T11:14:09Z
000306796 915__ $$0StatID:(DE-HGF)0500$$2StatID$$aDBCoverage$$bDOAJ$$d2023-06-19T11:14:09Z
000306796 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bDOAJ : Anonymous peer review$$d2023-06-19T11:14:09Z
000306796 915__ $$0StatID:(DE-HGF)9905$$2StatID$$aIF >= 5$$bPHARMACOL RES : 2022$$d2023-08-23
000306796 915__ $$0StatID:(DE-HGF)0561$$2StatID$$aArticle Processing Charges$$d2023-08-23
000306796 915__ $$0StatID:(DE-HGF)0700$$2StatID$$aFees$$d2023-08-23
000306796 9201_ $$0I:(DE-He78)TU01-20160331$$kTU01$$lDKTK Koordinierungsstelle Tübingen$$x0
000306796 980__ $$ajournal
000306796 980__ $$aVDB
000306796 980__ $$aI:(DE-He78)TU01-20160331
000306796 980__ $$aUNRESTRICTED