Inhibition of NLRP3 by Fermented Quercetin Decreases Resistin-Induced Chemoresistance to 5-Fluorouracil in Human Colorectal Cancer Cells
The drug resistance of colorectal cancer (CRC) cells against 5-fluorouracil (5-FU) therapy is a major challenge to successful cancer treatment. While previous studies have proposed several 5-FU resistance mechanisms, the effects of the adipokines on cancer cells remain unclear. Thus, this study inve...
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MDPI AG
2022-06-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/7/798 |
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| author | Ko-Chao Lee Kuen-Lin Wu Chia-Kung Yen Shun-Fu Chang Cheng-Nan Chen Ying-Chen Lu |
| author_facet | Ko-Chao Lee Kuen-Lin Wu Chia-Kung Yen Shun-Fu Chang Cheng-Nan Chen Ying-Chen Lu |
| author_sort | Ko-Chao Lee |
| collection | DOAJ |
| description | The drug resistance of colorectal cancer (CRC) cells against 5-fluorouracil (5-FU) therapy is a major challenge to successful cancer treatment. While previous studies have proposed several 5-FU resistance mechanisms, the effects of the adipokines on cancer cells remain unclear. Thus, this study investigated the effect of resistin on 5-FU-treated CRC cell lines. The upregulation of NLRP3 can regulate the inflammatory responses in cancer cells and then enhance cancer progression. This study investigated the expression level and the function of NLRP3 on 5-FU-induced cytotoxicity in CRC cells and found that resistin-induced ERK activation and increased NLRP3 expression in CRC HCT-116 and DLD-1 cells were mediated by Toll-like receptor 4 (TLR4). The inhibition of TLR4 and ERK by pharmacological inhibitors attenuated the resistin-induced NLRP3 mRNA and protein levels. In contrast, the knockdown of NLRP3 enhanced the cytotoxic effects of 5-FU. Furthermore, quercetin is an effective chemopreventive compound. This study showed that quercetin fermented by <i>Lactobacillus</i> could exhibit low cytotoxicity on normal mucosa cells and improve the function of inhibiting CRC cells. The treatment of CRC cells with fermented quercetin increased the cytotoxicity and enhanced cell death in the presence of resistin. In this study, fermented quercetin induced the cytotoxicity and cell death of 5-FU in resistin-treated CRC cells, which is associated with the downregulation of NLRP3 expression and ERK phosphorylation. These results indicate the role of NLRP3 in the development of drug resistance to 5-FU in CRC cells. Elucidating the mechanism regarding the cytotoxicity effect of quercetin may provide another vision for the development of a chemotherapy strategy for CRC in the future. |
| first_indexed | 2024-03-09T10:13:25Z |
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| language | English |
| last_indexed | 2024-03-09T10:13:25Z |
| publishDate | 2022-06-01 |
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| series | Pharmaceuticals |
| spelling | doaj.art-65115a27cc404605b39211b4e66875272023-12-01T22:33:14ZengMDPI AGPharmaceuticals1424-82472022-06-0115779810.3390/ph15070798Inhibition of NLRP3 by Fermented Quercetin Decreases Resistin-Induced Chemoresistance to 5-Fluorouracil in Human Colorectal Cancer CellsKo-Chao Lee0Kuen-Lin Wu1Chia-Kung Yen2Shun-Fu Chang3Cheng-Nan Chen4Ying-Chen Lu5Division of Colorectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung 833, TaiwanDivision of Colorectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung 833, TaiwanDivision of Colorectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung 833, TaiwanDepartment of Medical Research and Development, Chang Gung Memorial Hospital Chiayi Branch, Chiayi 600, TaiwanDepartment of Biochemical Science and Technology, National Chiayi University, Chiayi 600, TaiwanDepartment of Food Science, National Chiayi University, Chiayi 600, TaiwanThe drug resistance of colorectal cancer (CRC) cells against 5-fluorouracil (5-FU) therapy is a major challenge to successful cancer treatment. While previous studies have proposed several 5-FU resistance mechanisms, the effects of the adipokines on cancer cells remain unclear. Thus, this study investigated the effect of resistin on 5-FU-treated CRC cell lines. The upregulation of NLRP3 can regulate the inflammatory responses in cancer cells and then enhance cancer progression. This study investigated the expression level and the function of NLRP3 on 5-FU-induced cytotoxicity in CRC cells and found that resistin-induced ERK activation and increased NLRP3 expression in CRC HCT-116 and DLD-1 cells were mediated by Toll-like receptor 4 (TLR4). The inhibition of TLR4 and ERK by pharmacological inhibitors attenuated the resistin-induced NLRP3 mRNA and protein levels. In contrast, the knockdown of NLRP3 enhanced the cytotoxic effects of 5-FU. Furthermore, quercetin is an effective chemopreventive compound. This study showed that quercetin fermented by <i>Lactobacillus</i> could exhibit low cytotoxicity on normal mucosa cells and improve the function of inhibiting CRC cells. The treatment of CRC cells with fermented quercetin increased the cytotoxicity and enhanced cell death in the presence of resistin. In this study, fermented quercetin induced the cytotoxicity and cell death of 5-FU in resistin-treated CRC cells, which is associated with the downregulation of NLRP3 expression and ERK phosphorylation. These results indicate the role of NLRP3 in the development of drug resistance to 5-FU in CRC cells. Elucidating the mechanism regarding the cytotoxicity effect of quercetin may provide another vision for the development of a chemotherapy strategy for CRC in the future.https://www.mdpi.com/1424-8247/15/7/798colorectal cancerresistinNLRP3quercetin<i>Lactobacillus plantarum</i>drug resistance |
| spellingShingle | Ko-Chao Lee Kuen-Lin Wu Chia-Kung Yen Shun-Fu Chang Cheng-Nan Chen Ying-Chen Lu Inhibition of NLRP3 by Fermented Quercetin Decreases Resistin-Induced Chemoresistance to 5-Fluorouracil in Human Colorectal Cancer Cells Pharmaceuticals colorectal cancer resistin NLRP3 quercetin <i>Lactobacillus plantarum</i> drug resistance |
| title | Inhibition of NLRP3 by Fermented Quercetin Decreases Resistin-Induced Chemoresistance to 5-Fluorouracil in Human Colorectal Cancer Cells |
| title_full | Inhibition of NLRP3 by Fermented Quercetin Decreases Resistin-Induced Chemoresistance to 5-Fluorouracil in Human Colorectal Cancer Cells |
| title_fullStr | Inhibition of NLRP3 by Fermented Quercetin Decreases Resistin-Induced Chemoresistance to 5-Fluorouracil in Human Colorectal Cancer Cells |
| title_full_unstemmed | Inhibition of NLRP3 by Fermented Quercetin Decreases Resistin-Induced Chemoresistance to 5-Fluorouracil in Human Colorectal Cancer Cells |
| title_short | Inhibition of NLRP3 by Fermented Quercetin Decreases Resistin-Induced Chemoresistance to 5-Fluorouracil in Human Colorectal Cancer Cells |
| title_sort | inhibition of nlrp3 by fermented quercetin decreases resistin induced chemoresistance to 5 fluorouracil in human colorectal cancer cells |
| topic | colorectal cancer resistin NLRP3 quercetin <i>Lactobacillus plantarum</i> drug resistance |
| url | https://www.mdpi.com/1424-8247/15/7/798 |
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