Targeting Thymidylate Synthase and tRNA-Derived Non-Coding RNAs Improves Therapeutic Sensitivity in Colorectal Cancer
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. Quercet...
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| Format: | Article |
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MDPI AG
2022-10-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/11/2158 |
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| author | Changwon Yang Jisoo Song Sunwoo Park Jiyeon Ham Wonhyoung Park Hahyun Park Garam An Taeyeon Hong Hee Seung Kim Gwonhwa Song Whasun Lim |
| author_facet | Changwon Yang Jisoo Song Sunwoo Park Jiyeon Ham Wonhyoung Park Hahyun Park Garam An Taeyeon Hong Hee Seung Kim Gwonhwa Song Whasun Lim |
| author_sort | Changwon Yang |
| collection | DOAJ |
| description | 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<sup>2+</sup> 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<sup>HisGTG</sup>, and transfection of a tiRNA<sup>HisGTG</sup> 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. |
| first_indexed | 2024-03-09T19:19:08Z |
| format | Article |
| id | doaj.art-79b73eccca87486c9ee4a28862c7f224 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T19:19:08Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-79b73eccca87486c9ee4a28862c7f2242023-11-24T03:30:08ZengMDPI AGAntioxidants2076-39212022-10-011111215810.3390/antiox11112158Targeting Thymidylate Synthase and tRNA-Derived Non-Coding RNAs Improves Therapeutic Sensitivity in Colorectal CancerChangwon Yang0Jisoo Song1Sunwoo Park2Jiyeon Ham3Wonhyoung Park4Hahyun Park5Garam An6Taeyeon Hong7Hee Seung Kim8Gwonhwa Song9Whasun Lim10Department of Biotechnology, Institute of Animal Molecular Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, KoreaDepartment of Biological Sciences, College of Science, Sungkyunkwan University, Suwon 16419, KoreaDepartment of Plant & Biomaterials Science, Gyeongsang National University, Jinju 52725, KoreaDepartment of Biotechnology, Institute of Animal Molecular Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, KoreaDepartment of Biotechnology, Institute of Animal Molecular Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, KoreaDepartment of Biotechnology, Institute of Animal Molecular Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, KoreaDepartment of Biotechnology, Institute of Animal Molecular Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, KoreaDepartment of Biological Sciences, College of Science, Sungkyunkwan University, Suwon 16419, KoreaDepartment of Obstetrics and Gynecology, College of Medicine, Seoul National University, Seoul 03080, KoreaDepartment of Biotechnology, Institute of Animal Molecular Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, KoreaDepartment of Biological Sciences, College of Science, Sungkyunkwan University, Suwon 16419, KoreaSome 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<sup>2+</sup> 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<sup>HisGTG</sup>, and transfection of a tiRNA<sup>HisGTG</sup> 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.https://www.mdpi.com/2076-3921/11/11/2158colorectal cancerquercetinthymidylate synthasep535-fluorouracil |
| spellingShingle | Changwon Yang Jisoo Song Sunwoo Park Jiyeon Ham Wonhyoung Park Hahyun Park Garam An Taeyeon Hong Hee Seung Kim Gwonhwa Song Whasun Lim Targeting Thymidylate Synthase and tRNA-Derived Non-Coding RNAs Improves Therapeutic Sensitivity in Colorectal Cancer Antioxidants colorectal cancer quercetin thymidylate synthase p53 5-fluorouracil |
| title | Targeting Thymidylate Synthase and tRNA-Derived Non-Coding RNAs Improves Therapeutic Sensitivity in Colorectal Cancer |
| title_full | Targeting Thymidylate Synthase and tRNA-Derived Non-Coding RNAs Improves Therapeutic Sensitivity in Colorectal Cancer |
| title_fullStr | Targeting Thymidylate Synthase and tRNA-Derived Non-Coding RNAs Improves Therapeutic Sensitivity in Colorectal Cancer |
| title_full_unstemmed | Targeting Thymidylate Synthase and tRNA-Derived Non-Coding RNAs Improves Therapeutic Sensitivity in Colorectal Cancer |
| title_short | Targeting Thymidylate Synthase and tRNA-Derived Non-Coding RNAs Improves Therapeutic Sensitivity in Colorectal Cancer |
| title_sort | targeting thymidylate synthase and trna derived non coding rnas improves therapeutic sensitivity in colorectal cancer |
| topic | colorectal cancer quercetin thymidylate synthase p53 5-fluorouracil |
| url | https://www.mdpi.com/2076-3921/11/11/2158 |
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