title: 1H NMR Metabolomics Reveals Association of High Expression of Inositol 1, 4, 5 Trisphosphate Receptor and Metabolites in Breast Cancer Patients.
abstract: 1H NMR is used to detect alterations in metabolites and their linkage to metabolic processes in a number of pathological conditions including breast cancer. Inositol 1, 4, 5 trisphosphate (IP3R) receptor is an intracellular calcium channel known to regulate metabolism and cellular bioenergetics. Its expression is up regulated in a number of cancers. However, its linkage to metabolism in disease conditions has not been evaluated. This study was designed to determine the association if any, of these metabolites with altered expression of IP3R in breast cancer. We used 1H NMR to identify metabolites in the serum of breast cancer patients (n = 27) and performed Real-time Polymerase Chain Reaction analysis for quantifying the expression of IP3R type 3 and type 2 in tissues from breast cancer patients (n = 40). Principal Component Analysis (PCA) and Partial Least Square-Discriminant Analysis (PLS-DA) clearly distinguished patients with high/low IP3R expression from healthy subjects. The present study revealed high expression of IP3R type 2 and type 3 in human breast tumor tissue compared to adjacent non-tumorous tissue. Moreover, patients with ≥ 2-fold increase in IP3R (high IP3R group) had significantly higher concentration of metabolic intermediates compared to those with < 2-fold increase in IP3R (low IP3R group). We observed an increase in lipoprotein content and the levels of metabolites like lactate, lysine and alanine and a decrease in the levels of pyruvate and glucose in serum of high IP3R group patients when compared to those in healthy subjects. Receiver operating characteristic (ROC) curve analysis was performed to show the clinical utility of metabolites. In addition to the human studies, functional relevance of IP3Rs in causing metabolic disruption was observed in MCF-7 and MDA MB-231 cells. Results from our studies bring forth the importance of metabolic (or metabolomics) profiling of serum by 1H NMR in conjunction with tissue expression studies for characterizing breast cancer patients. The results from this study provide new insights into relationship of breast cancer metabolites with IP3R.
authors.affiliation: Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, India.
authors.forename: Aru
authors.initials: A
authors.lastname: Singh
authors.affiliation: Centre of Biomedical Research, Raebareli Road, Lucknow, India.
authors.forename: Raj Kumar
authors.initials: RK
authors.lastname: Sharma
authors.affiliation: Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, India.
authors.forename: Megha
authors.initials: M
authors.lastname: Chagtoo
authors.affiliation: Department of Endocrine Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, India.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Agarwal
authors.affiliation: Department of Endocrine Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, India.
authors.forename: Nelson
authors.initials: N
authors.lastname: George
authors.affiliation: Centre of Biomedical Research, Raebareli Road, Lucknow, India.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Sinha
authors.affiliation: Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, India.
authors.forename: Madan M
authors.initials: MM
authors.lastname: Godbole
mesh_terms: D015415:Biomarkers; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D066244:Proton Magnetic Resonance Spectroscopy
chemical_list: D015415:Biomarkers; D053496:Inositol 1,4,5-Trisphosphate Receptors