Promotion of the Warburg effect is associated with poor benefit from adjuvant chemotherapy in colorectal cancer

Abstract

Metabolic reprogramming, including the Warburg effect, is a hallmark of cancer.Indeed, the diversity of cancer metabolism leads to cancer heterogeneity, but accurate assessment of metabolic properties in tumors has not yet been undertaken. Here, we performed absolute quantification of the expression levels of 113 proteins related to carbohydrate metabolism and antioxidant pathways, in stage III colorectal cancer surgical specimens from 70 patients. The Warburg effect appeared in absolute protein levels between tumor and normal mucosa specimens demonstrated. Notably, the levels of proteins associated with the tricarboxylic citric acid cycle were remarkably reduced in the malignant tumors which had relapsed after surgery and treatment with 5-fluorouracil-based adjuvant therapy. In addition, the efficacy of 5-fluorouracil also decreased in the cultured cancer cell lines with promotion of the Warburg effect. We further identified nine and eight important proteins, which are closely related to the Warburg effect, for relapse risk and 5-fluorouracil benefit, respectively, using a biomarker exploration procedure. These results provide us a clue for bridging between metabolic protein expression profiles and benefit from 5-fluorouracil adjuvant chemotherapy. K E Y W O R D Sabsolute protein levels, colorectal cancer, relapse risk and chemotherapy benefit, tegafururacil, Warburg effect | 659 KITAZAWA eT Al.

Adenylosuccinate lyase is oncogenic in colorectal cancer by causing mitochondrial dysfunction and independent activation of NRF2 and mTOR-MYC-axis

“…Reduced aerobic respiration is usually accompanied by a higher glycolytic rate in cancer cells 47 . However, ADSL- overexpressing cells additionally showed a significantly lower basal and maximal glycolytic capacity ( Figure 5 G-H ).…”

Identification and Verification of a 17 Immune-Related Gene Pair Prognostic Signature for Colon Cancer

“…Therein, the "RNA degradation" pathway can regulate the function of lncRNA GAS5 in mammalian cells [29], while GAS5 contributes to not only the susceptibility but also the lymphatic metastasis of colorectal cancer [30]. The other three pathways have been proved to be related to the tumorigenesis and progression of CC [31][32][33].…”

An Integrated Network, RNA Sequencing, and Experiment Pharmacology Approach Reveals the Active Component, Potential Target, and Mechanism of Gelsemium elegans in the Treatment of Colorectal Cancer

“…The DEGs were mainly enriched in the GO analysis corresponded to biological process such as the steroid metabolic and biosynthetic process and KEGG pathways related to metabolism including glycolysis/gluconeogenesis and fructose, mannose metabolism and steroid biosynthesis. The growth of malignancies including CRC prefers to metabolize glucose by glycolysis even in normoxic condition to meet high biogenetic demands in support of rapid and uncontrolled growth ( 25 , 26 ). Such a reprogrammed cellular metabolism, known as ‘‘Warburg effect’’, is now recognized as a key hallmark of cancer which not only promotes tumor cell growth and spread but also relapse and chemotherapy resistance ( 27 ).…”