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Lysosomal membrane permeabilization enhances the anticancer effects of POLR1 (RNA polymerase I) transcription inhibitors.

dc.rights.licenseopenen_US
dc.contributor.authorFERRET, Lucille
dc.contributor.authorPOL, Jonathan G
dc.contributor.authorSAUVAT, Allan
dc.contributor.authorSTOLL, Gautier
dc.contributor.authorALVAREZ-VALADEZ, Karla
dc.contributor.authorMULLER, Alexandra
dc.contributor.authorLE NAOUR, Julie
dc.contributor.authorPEYRE, Felix
dc.contributor.authorANAGNOSTOPOULOS, Gerasimos
dc.contributor.authorMARTINS, Isabelle
dc.contributor.authorMAIURI, Maria Chiara
hal.structure.identifierMicrobiologie Fondamentale et Pathogénicité [MFP]
dc.contributor.authorWODRICH, Harald
dc.contributor.authorGUITTAT, Lionel
dc.contributor.authorMERGNY, Jean-Louis
dc.contributor.authorKROEMER, Guido
dc.contributor.authorDJAVAHERI-MERGNY, Mojgan
dc.date.accessioned2025-07-17T10:28:49Z
dc.date.available2025-07-17T10:28:49Z
dc.date.issued2025-06-18
dc.identifier.issn1554-8635en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/207346
dc.description.abstractEnLysosomes contribute to the development of drug resistance through various mechanisms that include drug sequestration and the activation of adaptive stress pathways. While inhibitors of DNA-to-RNA transcription exhibit potent anticancer effects, the role of lysosomes in modulating responses to such transcription inhibitors remains largely unexplored. This study investigates this aspect in the context of two potent POLR1 (RNA polymerase I) transcription inhibitors, CX-3543 (quarfloxin) and CX-5461 (pidnarulex). Unexpectedly, CX-3543 was found to accumulate within lysosomes, leading to lysosomal membrane permeabilization (LMP) and the subsequent activation of cellular stress adaptation pathways, including those regulated by the transcription factor TFEB and autophagy. Disrupting TFEB or autophagy increased cell sensitivity to CX-3543, highlighting the cytoprotective role of these processes in counteracting CX-3543-induced cell death. Moreover, targeting lysosomal membranes with chloroquine derivatives or blue light exposure induced substantial LMP, releasing compound CX-3543 from lysosomes. This effect enhanced both the inhibition of DNA-to-RNA transcription and CX-3543-induced cell death. Similar effects were observed when chloroquine derivatives were combined with CX-5461. Additionally, combining CX-3543 with the chloroquine derivative DC661 more effectively reduced the fibrosarcoma growth in immunocompetent mice than either agent alone. Altogether, our results reveal an unanticipated lysosome-related mechanism that contributes to cancer cell resistance to POLR1 inhibitors and propose a strategy to overcome this resistance.: ATG7: autophagy related 7; ATG13: autophagy related 13; Baf A: bafilomycin A; CTSB: cathepsin B; DKO: double knockout; G4: Guanine quadruplex; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; LGALS3: galectin 3; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTORC1: mechanistic target of rapamycin kinase complex 1; NCL: nucleolin; POLR1: RNA polymerase I; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TFE3: transcription factor E3; ULK1: unc-51 like autophagy activating kinase 1.
dc.language.isoENen_US
dc.subject.enAutophagy; TFEB; cancer; cell death; guanine quadruplex ligands; resistance to therapy
dc.title.enLysosomal membrane permeabilization enhances the anticancer effects of POLR1 (RNA polymerase I) transcription inhibitors.
dc.title.alternativeAutophagyen_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1080/15548627.2025.2497614en_US
dc.subject.halSciences du Vivant [q-bio]/Microbiologie et Parasitologieen_US
dc.identifier.pubmed40528705en_US
bordeaux.journalAutophagyen_US
bordeaux.page1-20en_US
bordeaux.hal.laboratoriesMFP (Laboratoire Microbiologie Fondamentale et Pathogénicité) - UMR 5234en_US
bordeaux.institutionCNRSen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.import.sourcepubmed
hal.identifierhal-05167358
hal.version1
hal.date.transferred2025-07-17T10:28:52Z
hal.popularnonen_US
hal.audienceInternationaleen_US
hal.exporttrue
workflow.import.sourcepubmed
dc.rights.ccPas de Licence CCen_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Autophagy&rft.date=2025-06-18&rft.spage=1-20&rft.epage=1-20&rft.eissn=1554-8635&rft.issn=1554-8635&rft.au=FERRET,%20Lucille&POL,%20Jonathan%20G&SAUVAT,%20Allan&STOLL,%20Gautier&ALVAREZ-VALADEZ,%20Karla&rft.genre=article


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