RNA polymerase I inhibition induces terminal differentiation, growth arrest, and vulnerability to senolytics in colorectal cancer cells.

Autor: Otto C; Experimental Visceral Surgery, Department of General, Visceral, Transplantation, Vascular and Pediatric Surgery (Department of Surgery I), University Hospital Würzburg, Germany., Kastner C; Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Germany.; Department of General, Visceral, Transplantation, Vascular and Pediatric Surgery (Department of Surgery I), University Hospital Würzburg, Germany., Schmidt S; Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Germany.; Department of General, Visceral, Transplantation, Vascular and Pediatric Surgery (Department of Surgery I), University Hospital Würzburg, Germany., Uttinger K; Experimental Visceral Surgery, Department of General, Visceral, Transplantation, Vascular and Pediatric Surgery (Department of Surgery I), University Hospital Würzburg, Germany., Baluapuri A; Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Germany., Denk S; Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Germany.; Department of General, Visceral, Transplantation, Vascular and Pediatric Surgery (Department of Surgery I), University Hospital Würzburg, Germany., Rosenfeldt MT; Institute of Pathology, Universität of Würzburg, Germany., Rosenwald A; Institute of Pathology, Universität of Würzburg, Germany., Roehrig F; Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Germany., Ade CP; Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Germany., Schuelein-Voelk C; Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Germany., Diefenbacher ME; Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Germany., Germer CT; Department of General, Visceral, Transplantation, Vascular and Pediatric Surgery (Department of Surgery I), University Hospital Würzburg, Germany.; Comprehensive Cancer Center Mainfranken, University of Würzburg, Germany., Wolf E; Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Germany., Eilers M; Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Germany.; Comprehensive Cancer Center Mainfranken, University of Würzburg, Germany., Wiegering A; Experimental Visceral Surgery, Department of General, Visceral, Transplantation, Vascular and Pediatric Surgery (Department of Surgery I), University Hospital Würzburg, Germany.; Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Germany.; Department of General, Visceral, Transplantation, Vascular and Pediatric Surgery (Department of Surgery I), University Hospital Würzburg, Germany.; Comprehensive Cancer Center Mainfranken, University of Würzburg, Germany.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2022 Aug; Vol. 16 (15), pp. 2788-2809. Date of Electronic Publication: 2022 Jul 01.
DOI: 10.1002/1878-0261.13265
Abstrakt: Ribosomal biogenesis and protein synthesis are deregulated in most cancers, suggesting that interfering with translation machinery may hold significant therapeutic potential. Here, we show that loss of the tumor suppressor adenomatous polyposis coli (APC), which constitutes the initiating event in the adenoma carcinoma sequence for colorectal cancer (CRC), induces the expression of RNA polymerase I (RNAPOL1) transcription machinery, and subsequently upregulates ribosomal DNA (rDNA) transcription. Targeting RNAPOL1 with a specific inhibitor, CX5461, disrupts nucleolar integrity, and induces a disbalance of ribosomal proteins. Surprisingly, CX5461-induced growth arrest is irreversible and exhibits features of senescence and terminal differentiation. Mechanistically, CX5461 promotes differentiation in an MYC-interacting zinc-finger protein 1 (MIZ1)- and retinoblastoma protein (Rb)-dependent manner. In addition, the inhibition of RNAPOL1 renders CRC cells vulnerable towards senolytic agents. We validated this therapeutic effect of CX5461 in murine- and patient-derived organoids, and in a xenograft mouse model. These results show that targeting ribosomal biogenesis together with targeting the consecutive, senescent phenotype using approved drugs is a new therapeutic approach, which can rapidly be transferred from bench to bedside.
(© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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