%0 Journal Article
%A Sanchez-Martin, Victoria
%A Schneider, David A.
%A Ortiz-Gonzalez, Matilde
%A Soriano-Lerma, Ana
%A Linde-Rodriguez, Angel
%A Perez-Carrasco, Virginia
%A Gutierrez-Fernandez, Jose
%A Cuadros, Marta
%A Gonzalez, Carlos
%A Soriano, Miguel
%A Garcia-Salcedo, Jose A.
%T Targeting ribosomal G-quadruplexes with naphthalene-diimides as RNA polymerase I inhibitors for colorectal cancer treatment
%D 2021
%@ 2451-9448
%U https://hdl.handle.net/10668/26375
%X 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.
%K Transcription
%K Binding
%K Visualization
%K Transporters
%K Vitro
%~