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 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.

A novel circular RNA confers trastuzumab resistance in human epidermal growth factor receptor 2‐positive breast cancer through regulating ferroptosis

“…25 For example, cetuximab promoted RSL3-induced ferroptosis by regulating the Nrf2/ HO-1 signaling pathway in KRAS mutant colorectal cancer. 26 Metallothionein-1G has been reported as a negative regulator of ferroptosis, leading to sorafenib resistance in hepatocellular carcinoma. 27 And miR-522 secreted by cancer-associated fibroblasts promoted acquired chemo-resistance in gastric cancer via blocking lipid-ROS accumulation and ferroptosis.…”

“…Ferroptosis, first coined by Dr. Brent R Stockwell in 2012, 24 is a new form of programmed cell death characterized by the accumulation of iron‐dependent lethal lipid peroxides, linking to cancer initiation, development, metastasis, and especially drug effectiveness 25 . For example, cetuximab promoted RSL3‐induced ferroptosis by regulating the Nrf2/HO‐1 signaling pathway in KRAS mutant colorectal cancer 26 . Metallothionein‐1G has been reported as a negative regulator of ferroptosis, leading to sorafenib resistance in hepatocellular carcinoma 27 .…”

Nobiletin Induces Ferroptosis in Human Skin Melanoma Cells Through the GSK3β-Mediated Keap1/Nrf2/HO-1 Signalling Pathway

“…The Keap1/Nrf2/HO-1 signalling pathway is recognised as an important antioxidant system that protects cancer cells from ferroptosis ( Lippmann et al, 2020 ). In KRAS -mutant colorectal cancer cells, inhibition of the Nrf2/HO-1 axis contributed to the promotion of ferroptosis induced by RSL3, a GPX4 inhibitor ( Yang et al, 2021 ). Here, we revealed that nobiletin could inhibit the Keap1/Nrf2/HO-1 axis in SK-MEL-28 cells, which might be the potential mechanism of nobiletin-induced ferroptosis.…”

Persistent ferroptosis promotes cervical squamous intraepithelial lesion development and oncogenesis by regulating KRAS expression in patients with high risk-HPV infection

“…Increased HRAS expression levels promote gastric carcinoma cell aggressiveness [ 34 ]. Resent research has reported that the blockade of Nrf2/HO-1 signaling promotes RSL3-induced ferroptosis in KRAS mutant colorectal cancer [ 35 ]. However, it was reported that KRAS mutations were rarely found in CSCC but were frequently observed in cervical adenocarcinomas, indicating that KRAS mutations in CSCC were uncommon [ 36 ].…”