TY  - JOUR
A1  - Otto, Christoph
A1  - Kastner, Carolin
A1  - Schmidt, Stefanie
A1  - Uttinger, Konstantin
A1  - Baluapuri, Apoorva
A1  - Denk, Sarah
A1  - Rosenfeldt, Mathias T.
A1  - Rosenwald, Andreas
A1  - Roehrig, Florian
A1  - Ade, Carsten P.
A1  - Schuelein-Voelk, Christina
A1  - Diefenbacher, Markus E.
A1  - Germer, Christoph-Thomas
A1  - Wolf, Elmar
A1  - Eilers, Martin
A1  - Wiegering, Armin
T1  - RNA polymerase I inhibition induces terminal differentiation, growth arrest, and vulnerability to senolytics in colorectal cancer cells
JF  - Molecular Oncology
N2  - 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.
KW  - CRC
KW  - CX5461
KW  - MIZ1
KW  - MYC
KW  - ribosome
KW  - RNAPOL1
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312806
VL  - 16
IS  - 15
ER  - 
TY  - JOUR
A1  - Schmidt, Stefanie
A1  - Denk, Sarah
A1  - Wiegering, Armin
T1  - Targeting protein synthesis in colorectal cancer
JF  - Cancers
N2  - Under physiological conditions, protein synthesis controls cell growth and survival and is strictly regulated. Deregulation of protein synthesis is a frequent event in cancer. The majority of mutations found in colorectal cancer (CRC), including alterations in the WNT pathway as well as activation of RAS/MAPK and PI3K/AKT and, subsequently, mTOR signaling, lead to deregulation of the translational machinery. Besides mutations in upstream signaling pathways, deregulation of global protein synthesis occurs through additional mechanisms including altered expression or activity of initiation and elongation factors (e.g., eIF4F, eIF2α/eIF2B, eEF2) as well as upregulation of components involved in ribosome biogenesis and factors that control the adaptation of translation in response to stress (e.g., GCN2). Therefore, influencing mechanisms that control mRNA translation may open a therapeutic window for CRC. Over the last decade, several potential therapeutic strategies targeting these alterations have been investigated and have shown promising results in cell lines, intestinal organoids, and mouse models. Despite these encouraging in vitro results, patients have not clinically benefited from those advances so far. In this review, we outline the mechanisms that lead to deregulated mRNA translation in CRC and highlight recent progress that has been made in developing therapeutic strategies that target these mechanisms for tumor therapy.
KW  - colorectal cancer
KW  - protein synthesis
KW  - translation initiation
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206014
SN  - 2072-6694
VL  - 12
IS  - 5
ER  -