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Free keywords:
Antimetabolites, Antineoplastic/metabolism/*pharmacology
Azacitidine/metabolism
Cell Line
DNA/metabolism
Eukaryotic Initiation Factor-2/metabolism
Fluorouracil/metabolism/*pharmacology
GTP-Binding Proteins/analysis
HeLa Cells
Humans
Neoplasm Proteins/analysis
Oxidative Stress
RNA/*metabolism
Receptors, Cell Surface/analysis
Ribonucleoproteins/analysis/*metabolism
*Stress, Physiological
Thioguanine/metabolism
Abstract:
The antimetabolite 5-fluorouracil is a widely used chemotherapeutic for the treatment of several solid cancers. However, resistance to 5-fluorouracil remains a major drawback in its clinical use. In this study we report that treatment of HeLa cells with 5-fluorouracil resulted in de novo assembly of stress granules. Moreover, we revealed that stress granule assembly under stress conditions as well as disassembly is altered in cells treated with 5-fluorouracil. Notably, we discovered that RACK1, a protein mediating cell survival and apoptosis, is a component of 5-fluorouracil-induced stress granules. To explore the mode of action of 5-fluorouracil accountable for de novo stress granule assembly, we analyzed 5-fluorouracil metabolites and noticed that stress granule assembly is caused by RNA, not DNA incorporating 5-fluorouracil metabolites. Interestingly, we observed that other RNA incorporating drugs also cause assembly of stress granules. Thus, our results suggest that incorporation of chemotherapeutics into RNA may result in stress granule assembly with potential significance in chemoresistance.
