Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer
Abstract Cetuximab is approved for the treatment of metastatic colorectal cancer (mCRC) with RAS wild-type. Nevertheless, the prognosis remains poor and the effectiveness of cetuximab is limited in KRAS mutant mCRC. Recently, emerging evidence has shown that ferroptosis, a newly discovered form of n...
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| Format: | Article |
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Nature Publishing Group
2021-11-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-04367-3 |
| _version_ | 1818837107142033408 |
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| author | Jiawen Yang Jiajie Mo Juji Dai Chenqiao Ye Wei Cen Xuzhi Zheng Lei Jiang Lechi Ye |
| author_facet | Jiawen Yang Jiajie Mo Juji Dai Chenqiao Ye Wei Cen Xuzhi Zheng Lei Jiang Lechi Ye |
| author_sort | Jiawen Yang |
| collection | DOAJ |
| description | Abstract Cetuximab is approved for the treatment of metastatic colorectal cancer (mCRC) with RAS wild-type. Nevertheless, the prognosis remains poor and the effectiveness of cetuximab is limited in KRAS mutant mCRC. Recently, emerging evidence has shown that ferroptosis, a newly discovered form of nonapoptotic cell death, is closely related to KRAS mutant cells. Here, we further investigated whether cetuximab-mediated regulation of p38/Nrf2/HO-1 promotes RSL3-induced ferroptosis and plays a pivotal role in overcoming drug resistance in KRAS mutant colorectal cancer (CRC). In our research, we used two KRAS mutant CRC cell lines, HCT116 and DLD-1, as models of intrinsic resistance to cetuximab. The viability of cells treated with the combination of RSL3 and cetuximab was assessed by the CCK-8 and colony formation assays. The effective of cetuximab to promote RSL3-induced ferroptosis was investigated by evaluating lipid reactive oxygen species accumulation and the expression of the malondialdehyde and the intracellular iron assay. Cetuximab therapy contributed to regulating the p38/Nrf2/HO-1 axis, as determined by western blotting and transfection with small interfering RNAs. Cetuximab promoted RSL3-induced ferroptosis by inhibiting the Nrf2/HO-1 in KRAS mutant CRC cells, and this was further demonstrated in a xenograft nude mouse model. Our work reveals that cetuximab enhances the cytotoxic effect of RSL3 on KRAS mutant CRC cells and that cetuximab enhances RSL3-induced ferroptosis by inhibiting the Nrf2/HO-1 axis through the activation of p38 MAPK. |
| first_indexed | 2024-12-19T03:17:14Z |
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| id | doaj.art-c2181e41f0cc462294e76d04f119e6f0 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-19T03:17:14Z |
| publishDate | 2021-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-c2181e41f0cc462294e76d04f119e6f02022-12-21T20:37:52ZengNature Publishing GroupCell Death and Disease2041-48892021-11-01121111110.1038/s41419-021-04367-3Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancerJiawen Yang0Jiajie Mo1Juji Dai2Chenqiao Ye3Wei Cen4Xuzhi Zheng5Lei Jiang6Lechi Ye7Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical UniversityCentral Laboratory, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical UniversityAbstract Cetuximab is approved for the treatment of metastatic colorectal cancer (mCRC) with RAS wild-type. Nevertheless, the prognosis remains poor and the effectiveness of cetuximab is limited in KRAS mutant mCRC. Recently, emerging evidence has shown that ferroptosis, a newly discovered form of nonapoptotic cell death, is closely related to KRAS mutant cells. Here, we further investigated whether cetuximab-mediated regulation of p38/Nrf2/HO-1 promotes RSL3-induced ferroptosis and plays a pivotal role in overcoming drug resistance in KRAS mutant colorectal cancer (CRC). In our research, we used two KRAS mutant CRC cell lines, HCT116 and DLD-1, as models of intrinsic resistance to cetuximab. The viability of cells treated with the combination of RSL3 and cetuximab was assessed by the CCK-8 and colony formation assays. The effective of cetuximab to promote RSL3-induced ferroptosis was investigated by evaluating lipid reactive oxygen species accumulation and the expression of the malondialdehyde and the intracellular iron assay. Cetuximab therapy contributed to regulating the p38/Nrf2/HO-1 axis, as determined by western blotting and transfection with small interfering RNAs. Cetuximab promoted RSL3-induced ferroptosis by inhibiting the Nrf2/HO-1 in KRAS mutant CRC cells, and this was further demonstrated in a xenograft nude mouse model. Our work reveals that cetuximab enhances the cytotoxic effect of RSL3 on KRAS mutant CRC cells and that cetuximab enhances RSL3-induced ferroptosis by inhibiting the Nrf2/HO-1 axis through the activation of p38 MAPK.https://doi.org/10.1038/s41419-021-04367-3 |
| spellingShingle | Jiawen Yang Jiajie Mo Juji Dai Chenqiao Ye Wei Cen Xuzhi Zheng Lei Jiang Lechi Ye Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer Cell Death and Disease |
| title | Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer |
| title_full | Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer |
| title_fullStr | Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer |
| title_full_unstemmed | Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer |
| title_short | Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer |
| title_sort | cetuximab promotes rsl3 induced ferroptosis by suppressing the nrf2 ho 1 signalling pathway in kras mutant colorectal cancer |
| url | https://doi.org/10.1038/s41419-021-04367-3 |
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