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

Jiao Wu,Lu Li,Wenli Liu,Zhongmei Zhou,Haixia Wang,Aiham Qdaisat,Rong Liu,Sicheng Liu,Dewei Jiang,Sai-Ching Jim Yeung,Zhuo Cheng,Wenjing Liu,Ceshi Chen,Chuanyu Yang,Runxiang Yang

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.

Highlights

Mean food and protein acid components, Parenteral nutrition (PN) formulations are more comprehensively and consumption per mouse were similar between cystine deprivation (CD) and cystine addition (CA) diets clearly defined than Enteral nutrition (EN) formulations
Malnutrition is a common problem in GI cancer patients and parenteral and enteral nutrition (PEN) are commonly used for the nutrition support
Our retrospective analysis of GI cancer patients receiving PN, as well as further in vitro and in vivo studies, provided clinical evidence to confirm the corollary to the previous finding that cysteinase injection or dietary restriction of cyst(e)ine suppresses cancer—i.e., we found that nutritional supplementation with cysteine promotes cancer progression

Summary

Introduction

Malnutrition is a common problem in colorectal cancer (CRC)patients, owing to clinical factors such as intestinal obstruction and cancer cachexia;[1] parenteral and enteral nutrition (PEN) play important roles in the supportive care of these patients.[2,3]Enteral nutrition (EN) generally refers to any method of feeding that uses the gastrointestinal (GI) tract to deliver part or all of the nutrients required for physiological functions in the body and EN should be preferred if the intestinal functions are preserved.[4]Parenteral nutrition (PN), supplemental or total, is a route of nutrient administration that bypasses the GI tract and nutrient solutions or emulsions are infused into a vein for patients who cannot receive feedings enterally at all or in sufficient quantities.[5]As metabolism in cancer cells is drastically different from that of non-malignant cells of the same tissue origin,[6] the nutrient needs of cells in tumors are different from those of cells in normal tissues,[7] implying that nutrition support for cancer patients should be different from patients with non-malignant diseases. Patients, owing to clinical factors such as intestinal obstruction and cancer cachexia;[1] parenteral and enteral nutrition (PEN) play important roles in the supportive care of these patients.[2,3]. Enteral nutrition (EN) generally refers to any method of feeding that uses the gastrointestinal (GI) tract to deliver part or all of the nutrients required for physiological functions in the body and EN should be preferred if the intestinal functions are preserved.[4]. Parenteral nutrition (PN), supplemental or total, is a route of nutrient administration that bypasses the GI tract and nutrient solutions or emulsions are infused into a vein for patients who cannot receive feedings enterally at all or in sufficient quantities.[5]. Clinical guidelines for nutrition support in cancer patients published by the European Society for Parenteral and Enteral. The impact of specific components of PEN such as amino acids on cancer progression has not been fully studied

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Conclusion