2. Academic Validation
  3. Cyst(e)ine in nutrition formulation promotes colon cancer growth and chemoresistance by activating mTORC1 and scavenging ROS

Cyst(e)ine in nutrition formulation promotes colon cancer growth and chemoresistance by activating mTORC1 and scavenging ROS

  • Signal Transduct Target Ther. 2021 May 28;6(1):188. doi: 10.1038/s41392-021-00581-9.
Jiao Wu  # 1,  Sai-Ching Jim Yeung  # 2,  Sicheng Liu  # 1,  Aiham Qdaisat 2,  Dewei Jiang 3,  Wenli Liu 4,  Zhuo Cheng 3,  Wenjing Liu 3,  Haixia Wang 3,  Lu Li 5,  Zhongmei Zhou 3,  Rong Liu 3,  Chuanyu Yang 3,  Ceshi Chen 6 7 8,  Runxiang Yang 9
Affiliations

Affiliations

  • 1 Department of the Second Medical Oncology, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China.
  • 2 Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 3 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
  • 4 Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 5 Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
  • 6 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China. chenc@mail.kiz.ac.cn.
  • 7 KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China. chenc@mail.kiz.ac.cn.
  • 8 Institute of Translation Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China. chenc@mail.kiz.ac.cn.
  • 9 Department of the Second Medical Oncology, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China. yrx_research@163.com.
  • # Contributed equally.
PMID: 34045438 DOI: 10.1038/s41392-021-00581-9
Abstract

Weight loss and cachexia are common problems in colorectal Cancer patients; thus, parenteral and enteral nutrition support play important roles in Cancer care. However, the impact of nonessential amino acid components of nutritional intake on Cancer progression has not been fully studied. In this study, we discovered that gastrointestinal Cancer patients who received cysteine as part of the parenteral nutrition had shorter overall survival (P < 0.001) than those who did not. Cystine indeed robustly promotes colon Cancer cell growth in vitro and in immunodeficient mice, predominately by inhibiting SESN2 transcription via the GCN2-ATF4 axis, resulting in mTORC1 activation. mTORC1 inhibitors Rapamycin and Everolimus block cystine-induced Cancer cell proliferation. In addition, cystine confers resistance to oxaliplatin and irinotecan chemotherapy by quenching chemotherapy-induced Reactive Oxygen Species via synthesizing glutathione. We demonstrated that dietary deprivation of cystine suppressed colon Cancer xenograft growth without weight loss in mice and boosted the antitumor effect of oxaliplatin. These findings indicate that cyst(e)ine, as part of supplemental nutrition, plays an important role in colorectal Cancer and manipulation of cyst(e)ine content in nutritional formulations may optimize colorectal Cancer patient survival.

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