2. Academic Validation
  3. Phosphorylated NFS1 weakens oxaliplatin-based chemosensitivity of colorectal cancer by preventing PANoptosis

Phosphorylated NFS1 weakens oxaliplatin-based chemosensitivity of colorectal cancer by preventing PANoptosis

  • Signal Transduct Target Ther. 2022 Feb 28;7(1):54. doi: 10.1038/s41392-022-00889-0.
Jin-Fei Lin  # 1 2,  Pei-Shan Hu  # 3,  Yi-Yu Wang  # 1,  Yue-Tao Tan  # 1,  Kai Yu 1,  Kun Liao 1,  Qi-Nian Wu 1 4,  Ting Li 1 5,  Qi Meng 1,  Jun-Zhong Lin 1 6,  Ze-Xian Liu 1,  Heng-Ying Pu 1,  Huai-Qiang Ju 7 8,  Rui-Hua Xu 9 10,  Miao-Zhen Qiu 11 12
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, 510060, Guangzhou, P. R. China.
  • 2 Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, 510060, Guangzhou, P. R. China.
  • 3 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital (Guangdong Gastrointestinal and Anal Hospital), Sun Yat-sen University, 510655, Guangzhou, P. R. China.
  • 4 Department of Pathology, Sun Yat-sen University Cancer Center, 510060, Guangzhou, P. R. China.
  • 5 Department of Gastroenterology and Urology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410013, Changsha, P. R. China.
  • 6 Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, 510060, Guangzhou, P. R. China.
  • 7 Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, 510060, Guangzhou, P. R. China. juhq@sysucc.org.cn.
  • 8 Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, 510060, Guangzhou, P. R. China. juhq@sysucc.org.cn.
  • 9 Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, 510060, Guangzhou, P. R. China. xurh@sysucc.org.cn.
  • 10 Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, 510060, Guangzhou, P. R. China. xurh@sysucc.org.cn.
  • 11 Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, 510060, Guangzhou, P. R. China. qiumzh@sysucc.org.cn.
  • 12 Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, 510060, Guangzhou, P. R. China. qiumzh@sysucc.org.cn.
  • # Contributed equally.
PMID: 35221331 DOI: 10.1038/s41392-022-00889-0
Abstract

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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