An RNA damage response network mediates the lethality of 5-FU in colorectal cancer
Journal
Cell Reports Medicine
Journal Volume
5
Journal Issue
10
Start Page
101778
ISSN
2666-3791
Date Issued
2024-10
Author(s)
Karl A. Merrick
Yi Wen Kong
Anita Izrael-Tomasevic
George Eng
Erika D. Handly
Jesse C. Patterson
Ian G. Cannell
Lucia Suarez-Lopez
Aaron M. Hosios
Anh Dinh
Donald S. Kirkpatrick
Kebing Yu
Christopher M. Rose
Jonathan M. Hernandez
Haeun Hwangbo
Adam C. Palmer
Matthew G. Vander Heiden
Ömer H. Yilmaz
Michael B. Yaffe
Abstract
5-fluorouracil (5-FU), a major anti-cancer therapeutic, is believed to function primarily by inhibiting thymidylate synthase, depleting deoxythymidine triphosphate (dTTP), and causing DNA damage. Here, we show that clinical combinations of 5-FU with oxaliplatin or irinotecan show no synergy in human colorectal cancer (CRC) trials and sub-additive killing in CRC cell lines. Using selective 5-FU metabolites, phospho- and ubiquitin proteomics, and primary human CRC organoids, we demonstrate that 5-FU-mediated CRC cell killing primarily involves an RNA damage response during ribosome biogenesis, causing lysosomal degradation of damaged rRNAs and proteasomal degradation of ubiquitinated ribosomal proteins. Tumor types clinically responsive to 5-FU treatment show upregulated rRNA biogenesis while 5-FU clinically non-responsive tumor types do not, instead showing greater sensitivity to 5-FU's DNA damage effects. Finally, we show that treatments upregulating ribosome biogenesis, including KDM2A inhibition, promote RNA-dependent cell killing by 5-FU, demonstrating the potential for combinatorial targeting of this ribosomal RNA damage response for improved cancer therapy.
Subjects
5-FU
5-FU-based chemotherapy
RNA damage
ribosomal RNA
ribosomal protein
Publisher
Elsevier BV
Type
journal article