CETSA interaction proteomics define specific RNA-modification pathways as key components of fluorouracil-based cancer drug cytotoxicity

Liang, Ying Yu1,2,3; Bacanu, Smaranda2; Sreekumar, Lekshmy3; Ramos, Anderson Daniel2; Dai, Lingyun1,3,9; Michaelis, Martin4; Cinatl, Jindrich5; Seki, Takahiro6,7; Cao, Yihai6; Coffill, Cynthia R.8; Lane, David P.8; Prabhu, Nayana1,3; Nordlund, Par1,2,3

2022-04-21

10.1016/j.chembiol.2021.06.007

Cell Chemical Biology   影响因子和分区

2451-9448

The optimal use of many cancer drugs is hampered by a lack of detailed understanding of their mechanism of action (MoA). Here, we apply a high-resolution implementation of the proteome-wide cellular thermal shift assay (CETSA) to follow protein interaction changes induced by the antimetabolite 5-fluorouracil (5-FU) and related nucleosides. We confirm anticipated effects on the known main target, thymidylate synthase (TYMS), and enzymes in pyrimidine metabolism and DNA damage pathways. However, most interaction changes we see are for proteins previously not associated with the MoA of 5-FU, including wide-ranging effects on RNA-modification and-processing pathways. Attenuated responses of specific proteins in a resistant cell model identify key components of the 5-FU MoA, where intriguingly the abrogation of TYMS inhibition is not required for cell proliferation.

SCI

英语

其他

Singapore's National Research Foundation[NRF-CRP22-2019-0003]

Biochemistry & Molecular Biology

Biochemistry & Molecular Biology

WOS:000798523800005

CELL PRESS

Web of Science

1.ASTAR, Inst Mol & Cell Biol, Singapore 138673, Singapore
2.Karolinska Inst, Dept Oncol & Pathol, S-17177 Stockholm, Sweden
3.Nanyang Technol Univ, Sch Biol Sci, Singapore 637551, Singapore
4.Univ Kent, Sch Biosci, Canterbury CT2 7NJ, Kent, England
5.Goethe Univ, Inst Med Virol, Frankfurt, Germany
6.Karolinska Inst, Dept Microbiol Tumour & Cell Biol, S-17177 Stockholm, Sweden
7.Kagoshima Univ, Grad Sch Med & Dent Sci, 8 Chome 35-1 Sakuragaoka, Kagoshima 8908520, Japan
8.ASTAR, p53Lab, 8A Biomed Groove,Immunos 06-06, Singapore 138648, Singapore
9.Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Affiliated Hosp 1, Clin Med Coll 2,Jinan Univ, Shenzhen 518020, Peoples R China

Liang, Ying Yu,Bacanu, Smaranda,Sreekumar, Lekshmy,et al. CETSA interaction proteomics define specific RNA-modification pathways as key components of fluorouracil-based cancer drug cytotoxicity[J]. Cell Chemical Biology,2022,29(4).

Liang, Ying Yu.,Bacanu, Smaranda.,Sreekumar, Lekshmy.,Ramos, Anderson Daniel.,Dai, Lingyun.,...&Nordlund, Par.(2022).CETSA interaction proteomics define specific RNA-modification pathways as key components of fluorouracil-based cancer drug cytotoxicity.Cell Chemical Biology,29(4).

Liang, Ying Yu,et al."CETSA interaction proteomics define specific RNA-modification pathways as key components of fluorouracil-based cancer drug cytotoxicity".Cell Chemical Biology 29.4(2022).