1. Academic Validation
  2. Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer

Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer

  • Cell Death Dis. 2021 Nov 13;12(11):1079. doi: 10.1038/s41419-021-04367-3.
Jiawen Yang 1 Jiajie Mo 1 Juji Dai 1 Chenqiao Ye 1 Wei Cen 1 Xuzhi Zheng 1 Lei Jiang 2 Lechi Ye 3
Affiliations

Affiliations

  • 1 Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, People's Republic of China.
  • 2 Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, People's Republic of China. jiangleistone79@163.com.
  • 3 Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, People's Republic of China. yelechi@wzhospital.cn.
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.

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