Targeting ribosomal G-quadruplexes with naphthalene-diimides as RNA polymerase I inhibitors for colorectal cancer treatment.
Victoria Sanchez-Martin, David A Schneider, Matilde Ortiz-Gonzalez, Ana Soriano-Lerma, Angel Linde-Rodriguez, Virginia Perez-Carrasco, Jose Gutierrez-Fernandez, Marta Cuadros, Carlos Gonz��lez, Miguel Soriano, Jose A Garcia-Salcedo
Author Information
Victoria Sanchez-Martin: GENYO. Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Granada 18016, Spain; Microbiology Unit, Biosanitary Research Institute IBS.Granada, University Hospital Virgen de las Nieves, Granada 18014, Spain; Department of Biochemistry, Molecular Biology III and Immunology, University of Granada, Granada 18016, Spain.
David A Schneider: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Matilde Ortiz-Gonzalez: GENYO. Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Granada 18016, Spain; Centre for Intensive Mediterranean Agrosystems and Agri-food Biotechnology (CIAIMBITAL), University of Almeria, Almeria 04001, Spain.
Ana Soriano-Lerma: GENYO. Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Granada 18016, Spain; Department of Physiology, University of Granada, Granada 18011, Spain.
Angel Linde-Rodriguez: GENYO. Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Granada 18016, Spain; Microbiology Unit, Biosanitary Research Institute IBS.Granada, University Hospital Virgen de las Nieves, Granada 18014, Spain.
Virginia Perez-Carrasco: GENYO. Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Granada 18016, Spain; Microbiology Unit, Biosanitary Research Institute IBS.Granada, University Hospital Virgen de las Nieves, Granada 18014, Spain.
Jose Gutierrez-Fernandez: Microbiology Unit, Biosanitary Research Institute IBS.Granada, University Hospital Virgen de las Nieves, Granada 18014, Spain; Department of Microbiology, University of Granada, Granada 18011, Spain.
Marta Cuadros: GENYO. Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Granada 18016, Spain; Department of Biochemistry, Molecular Biology III and Immunology, University of Granada, Granada 18016, Spain.
Carlos Gonz��lez: Instituto de Qu��mica F��sica "Rocasolano", CSIC, Madrid 28006, Spain.
Miguel Soriano: GENYO. Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Granada 18016, Spain; Centre for Intensive Mediterranean Agrosystems and Agri-food Biotechnology (CIAIMBITAL), University of Almeria, Almeria 04001, Spain.
Jose A Garcia-Salcedo: GENYO. Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Granada 18016, Spain; Microbiology Unit, Biosanitary Research Institute IBS.Granada, University Hospital Virgen de las Nieves, Granada 18014, Spain. Electronic address: jags@genyo.es.
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.
