Apart from their antimicrobial properties, tetracyclines demonstrate clinically validated effects in the amelioration of pathological inflammation and human cancer. Delineation of the target(s) and mechanism(s) responsible for these effects, however, has remained elusive. Here, employing quantitative mass spectrometry-based proteomics, we identified human 80S ribosomes as targets of the tetracyclines Col-3 and doxycycline. We then developed in-cell click selective crosslinking with RNA sequence profiling (icCL-seq) to map binding sites for these tetracyclines on key human rRNA substructures at nucleotide resolution. Importantly, we found that structurally and phenotypically variant tetracycline analogs could chemically discriminate these rRNA binding sites. We also found that tetracyclines both subtly modify human ribosomal translation and selectively activate the cellular integrated stress response (ISR). Together, the data reveal that targeting of specific rRNA substructures, activation of the ISR, and inhibition of translation are correlated with the anti-proliferative properties of tetracyclines in human cancer cell lines.
Pubmed ID: 30318461 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This recombinant monoclonal targets IRE1-alpha
View all literature mentionsThis monoclonal targets alpha-Tubulin
View all literature mentionsThis monoclonal targets beta-Actin
View all literature mentionsThis monoclonal targets IRE1 (phospho S724) antibody [EPR5253]
View all literature mentionsThis monoclonal targets eIF2alpha
View all literature mentionsThis monoclonal targets ATF-4
View all literature mentionsThis monoclonal targets A synthetic phospho-peptide corresponding to residues surrounding Ser51 of human EIF2S1.
View all literature mentionsThis monoclonal targets GAPDH
View all literature mentionsCell line DLD-1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HL-60 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line RPMI-8226 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line SK-MEL-2 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line K-562 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line A-375 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HeLa is a Cancer cell line with a species of origin Homo sapiens
View all literature mentions