RT Journal Article
T1 Targeting ribosomal G-quadruplexes with naphthalene-diimides as RNA polymerase I inhibitors for colorectal cancer treatment
A1 Sanchez-Martin, Victoria
A1 Schneider, David A.
A1 Ortiz-Gonzalez, Matilde
A1 Soriano-Lerma, Ana
A1 Linde-Rodriguez, Angel
A1 Perez-Carrasco, Virginia
A1 Gutierrez-Fernandez, Jose
A1 Cuadros, Marta
A1 Gonzalez, Carlos
A1 Soriano, Miguel
A1 Garcia-Salcedo, Jose A.
K1 Transcription
K1 Binding
K1 Visualization
K1 Transporters
K1 Vitro
AB Guanine quadruplexes (G4s) are non-canonical nucleic acid structures commonly found in regulatory genomic regions. G4 targeting has emerged as a therapeutic approach in cancer. We have screened naphthalene-diimides (NDIs), a class of G4 ligands, in a cellular model of colorectal cancer (CRC). Here, we identify the leading compound T5 with a potent and selective inhibition of cell growth by high-affinity binding to G4s in ribosomal DNA, impairing RNA polymerase I (Pol I) elongation. Consequently, T5 induces a rapid inhibition of Pol I transcription, nucleolus disruption, proteasome-dependent Pol I catalytic subunit A degradation and autophagy. Moreover, we attribute the higher selectivity of carbohydrate-conjugated T5 for tumoral cells to its preferential uptake through the overexpressed glucose transporter 1. Finally, we succinctly demonstrate that T5 could be explored as a therapeutic agent in a patient cohort with CRC. Therefore, we report a mode of action for these NDIs involving ribosomal G4 targeting.
PB Cell press
SN 2451-9448
YR 2021
FD 2021-11-18
LK https://hdl.handle.net/10668/26375
UL https://hdl.handle.net/10668/26375
LA en
DS RISalud
RD Apr 8, 2025