Functional metabolome profiling may improve individual outcomes in colorectal cancer management implementing concepts of predictive, preventive, and personalized medical approach

Yu Yuan; Chenxin Yang; Yingzhi Wang; Mingming Sun; Chenghao Bi; Sitong Sun; Guijiang Sun; Jingpeng Hao; Lingling Li; Changliang Shan; Shuai Zhang; Yubo Li

doi:10.1007/s13167-021-00269-8

Functional metabolome profiling may improve individual outcomes in colorectal cancer management implementing concepts of predictive, preventive, and personalized medical approach

EPMA J. 2022 Jan 27;13(1):39-55. doi: 10.1007/s13167-021-00269-8. eCollection 2022 Mar.

Authors

Yu Yuan^#¹, Chenxin Yang^#², Yingzhi Wang³, Mingming Sun³, Chenghao Bi¹, Sitong Sun¹, Guijiang Sun⁴, Jingpeng Hao⁵, Lingling Li², Changliang Shan³, Shuai Zhang², Yubo Li¹

Affiliations

¹ Tianjin State Key Laboratory of Modern Chinese Medicine, School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617 China.
² School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617 China.
³ State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350 China.
⁴ Department of Kidney Disease and Blood Purification, Second Hospital of Tianjin Medical University, Tianjin, 300211 China.
⁵ Department of Anorectal Surgery, Second Hospital of Tianjin Medical University, Tianjin, 300211 China.

^# Contributed equally.

Abstract

Objectives: Colorectal cancer (CRC) is one of the most common solid tumors worldwide, but its diagnosis and treatment are limited. The objectives of our study were to compare the metabolic differences between CRC patients and healthy controls (HC), and to identify potential biomarkers in the serum that can be used for early diagnosis and as effective therapeutic targets. The aim was to provide a new direction for CRC predictive, preventive, and personalized medicine (PPPM).

Methods: In this study, CRC patients (n = 30) and HC (n = 30) were recruited. Serum metabolites were assayed using an ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) technology. Subsequently, CRC cell lines (HCT116 and HCT8) were treated with metabolites to verify their function. Key targets were identified by molecular docking, thermal shift assay, and protein overexpression/inhibition experiments. The inhibitory effect of celastrol on tumor growth was also assessed, which included IC50 analysis, nude mice xenografting, molecular docking, protein overexpression/inhibition experiments, and network pharmacology technology.

Results: In the CRC group, 15 serum metabolites were significantly different in comparison with the HC group. The level of glycodeoxycholic acid (GDCA) was positively correlated with CRC and showed high sensitivity and specificity for the clinical diagnostic reference (AUC = 0.825). In vitro findings showed that GDCA promoted the proliferation and migration of CRC cell lines (HCT116 and HCT8), and Poly(ADP-ribose) polymerase-1 (PARP-1) was identified as one of the key targets of GDCA. The IC50 of celastrol in HCT116 cells was 121.1 nM, and the anticancer effect of celastrol was supported by in vivo experiments. Based on the potential of GDCA in PPPM, PARP-1 was found to be significantly correlated with the anticancer functions of celastrol.

Conclusion: These findings suggest that GDCA is an abnormally produced metabolite of CRC, which may provide an innovative molecular biomarker for the predictive identification and targeted prevention of CRC. In addition, PARP-1 was found to be an important target of GDCA that promotes CRC; therefore, celastrol may be a potential targeted therapy for CRC via its effects on PARP-1. Taken together, the pathophysiology and progress of tumor molecules mediated by changes in metabolite content provide a new perspective for predictive, preventive, and personalized medical of clinical cancer patients based on the target of metabolites in vivo.Clinical trials registration number: ChiCTR2000039410.

Supplementary information: The online version contains supplementary material available at 10.1007/s13167-021-00269-8.

Keywords: Celastrol; Colorectal cancer; Glycodeoxycholic acid; Metabolomics; Poly(ADP-ribose) polymerase-1; Predictive preventive personalized medicine; Serum; Therapeutic targets; UPLC-Q-TOF/MS.