奥沙利铂
癌症研究
磷酸化
坏死性下垂
结直肠癌
细胞生物学
生物
化学
细胞凋亡
癌症
程序性细胞死亡
生物化学
遗传学
作者
Jin‐Fei Lin,Pei-Shan Hu,Yiyu Wang,Yue-Tao Tan,Kai Yu,Kun Liao,Qi‐Nian Wu,Ting Li,Meng Qi,Junzhong Lin,Zexian Liu,Heng‐Ying Pu,Huai‐Qiang Ju,Rui‐Hua Xu,Miao‐Zhen Qiu
标识
DOI:10.1038/s41392-022-00889-0
摘要
Metabolic enzymes have an indispensable role in metabolic reprogramming, and their aberrant expression or activity has been associated with chemosensitivity. Hence, targeting metabolic enzymes remains an attractive approach for treating tumors. However, the influence and regulation of cysteine desulfurase (NFS1), a rate-limiting enzyme in iron-sulfur (Fe-S) cluster biogenesis, in colorectal cancer (CRC) remain elusive. Here, using an in vivo metabolic enzyme gene-based clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 library screen, we revealed that loss of NFS1 significantly enhanced the sensitivity of CRC cells to oxaliplatin. In vitro and in vivo results showed that NFS1 deficiency synergizing with oxaliplatin triggered PANoptosis (apoptosis, necroptosis, pyroptosis, and ferroptosis) by increasing the intracellular levels of reactive oxygen species (ROS). Furthermore, oxaliplatin-based oxidative stress enhanced the phosphorylation level of serine residues of NFS1, which prevented PANoptosis in an S293 phosphorylation-dependent manner during oxaliplatin treatment. In addition, high expression of NFS1, transcriptionally regulated by MYC, was found in tumor tissues and was associated with poor survival and hyposensitivity to chemotherapy in patients with CRC. Overall, the findings of this study provided insights into the underlying mechanisms of NFS1 in oxaliplatin sensitivity and identified NFS1 inhibition as a promising strategy for improving the outcome of platinum-based chemotherapy in the treatment of CRC.
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