Targeting Thymidylate Synthase and TRNA-Derived Non-Coding RNAs Improves Therapeutic Sensitivity in Colorectal Cancer

Overview

Journal Antioxidants (Basel)

Date 2022 Nov 11

PMID 36358529

Authors

Changwon Yang

Jisoo Song

Sunwoo Park

Jiyeon Ham

Wonhyoung Park

Hahyun Park

Garam An

Taeyeon Hong

Hee Seung Kim

Gwonhwa Song

Whasun Lim

Affiliations

Soon will be listed here.

Abstract

Some colorectal cancer (CRC) patients are resistant to 5-fluorouracil (5-FU), and high expression levels of thymidylate synthase (TS) contribute to this resistance. This study investigated whether quercetin, a representative polyphenol compound, could enhance the effect of 5-FU in CRC cells. Quercetin suppressed TS levels that were increased by 5-FU in CRC cells and promoted the expression of p53. Quercetin also induced intracellular and mitochondrial reactive oxygen species (ROS) production and Ca dysregulation in a 5-FU-independent pathway in CRC cells. Furthermore, quercetin decreased mitochondrial membrane potential in CRC cells and inhibited mitochondrial respiration. Moreover, quercetin regulated the expression of specific tiRNAs, including tiRNA, and transfection of a tiRNA mimic further enhanced the apoptotic effect of quercetin in CRC cells. An enhanced sensitivity to 5-FU was also confirmed in colitis-associated CRC mice treated with quercetin. The treatment of quercetin decreased survival rates of the CRC mouse model, with reductions in the number of tumors and in the disease activity index. Also, quercetin suppressed TS and PCNA protein expression in the distal colon tissue of CRC mice. These results suggest that quercetin has the potential to be used as an adjuvant with 5-FU for the treatment of CRC.

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