Ribitol alters multiple metabolic pathways of central carbon metabolism with enhanced glycolysis: A metabolomics and transcriptomics profiling of breast cancer

Abstract

Breast cancer is heterogenous in development and cell population with prognoses being highly dependent on numerous factors from driving mutations, biomarker expression and variation in extracellular environment, all affecting response to therapies. Recently, much attention has been given to the role of metabolic alteration in cancers, expanding from the Warburg effect to highlight unique patterns in different cancer cell populations for improving diagnostic and therapeutic approaches. We recently reported on modulation of mannosylation of α-dystroglycan with the metabolite ribitol in breast cancer lines. Here we investigate the effects of pentose sugars ribitol, ribose, and xylitol media supplementation in breast cancer cells by metabolomics and differential gene expression profiling. This combined approach revealed distinctive patterns of alterations in metabolic pathways by ribitol, contrasted with the closely related pentose ribose and pentitol xylitol. Significantly, ribitol supplementation enhances utilization of glucose by glycolysis, whereas ribose improves oxidative phosphorylation and fatty acid synthesis. Ribitol supplementation also increased levels of reduced glutathione (associated with a decrease in oxidative phosphorylation, gluconeogenesis), where ribose supplementation elevated levels of oxidized glutathione (GSSG) indicating an increase in oxidative stress. Treatment with ribitol also enhanced nucleotide biosynthesis. The apparent TCA cycle dysregulation, with distinctive pattern in response to the individual pentitol and pentose, such as ribitol increasing succinate and fumarate while decreasing citrate, demonstrate the adaptive capability of cancer cells to nutritional environment. This metabolic reprogramming presents new avenues for developing targeted therapies to cancers with metabolites, especially in combination with other drug treatments.

Metabolic Reprogramming by Ribitol Expands the Therapeutic Window of BETi JQ1 against Breast Cancer

“…This result contrasts with early reports that enhanced matriglycan expression is associated with inhibition of cancer growth and invasion [5][6][7]. Our follow-up study to understand the metabolic effect of ribitol by metabolomics revealed that ribitol-induced enhancement in matriglycan is associated with an alteration in glycolysis in MCF-7 cells [8]. Considering that breast cancers are heterogeneous in cell types with variation in metabolic pathways, the effect of ribitol treatment on cell growth may vary cell-type dependently.…”

The Influence of the Amino Acid Transporter LAT1 on Patient Prognosis and the Relationships between Tumor Immunometabolic and Proliferative Features Depend on Menopausal Status in Breast Cancer

“…Increasing interest in the relationship between systemic metabolism, tumor metabolism, immunometabolism, and cancer outcomes, alongside evolving technologies expanding both the available data and the community's ability to mine it to develop new insights. To that end, in this study, we utilized multiple publicly available breast cancer datasets, including "ACRIN-FLT-Breast (ACRIN 6688)", TCGA BRCA "Phenotypes", TCGA BRCA "IlluminaHiSeq", "TCGA TARGET GTEx", "Node-negative breast cancer (Desmedt 2007)", "ICGC (donor centric)", As opposed to genes or metabolic fluxes involved in glucose [24][25][26][27][28][29][30][31]or lipid metabolism [31][32][33][34][35][36][37][38][39], there exists a relative paucity of studies exploring the impact of expression of genes regulating amino acid uptake in breast cancer. Therefore, we elected to focus the current study on the expression of LAT1, which transports large amino acids including leucine, isoleucine, valine, phenylalanine, methionine, tyrosine, histidine, and tryptophan into the cell, and its relationships with body weight, tumor cell proliferation, and immune infiltration.…”

The association between the amino acid transporter LAT1, tumor immunometabolic and proliferative features and menopausal status in breast cancer

“…As opposed to genes or metabolic fluxes involved in glucose [24][25][26][27][28][29][30][31] or lipid metabolism [31][32][33][34][35][36][37][38][39], there exists a relative paucity of studies exploring the impact of expression of genes regulating amino acid uptake in breast cancer. Therefore, we elected to focus the current study on the expression of LAT1, which transports large amino acids including leucine, isoleucine, valine, phenylalanine, methionine, tyrosine, histidine, and tryptophan into the cell, and its relationships with body weight, tumor cell proliferation, and immune infiltration.…”