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.
Highlights
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are calcium (Ca2+) channels that regulate autophagy and metabolism [1].Three different tissue-specific isoforms of IP3Rs, namely IP3R type 1 (IP3R1), IP3R type 2 (IP3R2) and IP3R type 3 (IP3R3) have been reported so far [2].These receptors regulate the transfer of Ca2+ from endoplasmic reticulum (ER) to mitochondria via a mitochondrial membrane transport protein, which in turn regulates cellular bioenergetics [1]
Expression levels of IP3R2 and IP3R3 mRNA transcripts were investigated in tissues obtained from breast cancer patients using quantitative real-time PCR
Average fold change of IP3R2 and IP3R3 transcript levels were significantly higher (~4- fold) in tumor tissue compared to the adjacent non-tumorous region from the same patient (p
Summary
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are calcium (Ca2+) channels that regulate autophagy and metabolism [1].Three different tissue-specific isoforms of IP3Rs, namely IP3R type 1 (IP3R1), IP3R type 2 (IP3R2) and IP3R type 3 (IP3R3) have been reported so far [2].These receptors regulate the transfer of Ca2+ from endoplasmic reticulum (ER) to mitochondria via a mitochondrial membrane transport protein, which in turn regulates cellular bioenergetics [1]. Altered IP3R activity and/or the remodeling of IP3R expression profiles may be exploited by cancer cells to promote growth and drug resistance. This becomes important since altered expression of IP3Rs have been reported in various cancer types [3, 4]. One of the key areas that can be targeted for potential treatment of cancer is the regulation of metabolism through IP3Rs. IP3Rs regulate cell fate by interacting with a number of proteins involved in apoptotic as well as anti-apoptotic pathways [2]. Deregulation of IP3Rs play an important role in tumor growth, aggressiveness and drug resistance via modulation of different signaling pathways such as autophagy and energy metabolism [5, 6]. A number of studies reveal altered expression of Ca2+ channels and pumps in many human cancers, including breast, ovarian, glioma, liver, pancreatic, prostate, melanoma, colon, lung, bladder, thyroid, and oral cancer [7,8,9,10,11]
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