bims-glucam 2020-09-20 papers

Funct Integr Genomics. 2020 Sep 19.

Occurrence of differing metabolic dysregulations, a glucose driven and another fatty acid centric in gastric cancer subtypes.

Karthik Balakrishnan, Kumaresan Ganesan.

Gastric cancer is one of the most common cancers and ranks third in cancer-related deaths across globe. Cancer cells are known to take advantage of the altered metabolic processes to sustain their survival, proliferation, and cancer progression. In this investigation, we explored the available genome-wide expression profiles of few hundreds of gastric tumors and non-cancerous gastric tissues and analyzed in the context of metabolic pathways. Gastric tumors were investigated for the metabolic processes related to glucose metabolism, glucose transport, glutamine metabolism, and fatty acid metabolism, by metabolic pathway-focused gene set enrichment analysis. Notably, all glucose metabolism and glutamine metabolism-related gene sets were found enriched in intestinal subtype gastric tumors. On the other hand, the gene sets related to glucose transport and glucan (glycan) metabolisms are enriched in diffuse subtype gastric tumors. Strikingly, fatty acid metabolisms, fatty acid transport, and fat differentiation-related signatures are also highly activated in diffuse subtype gastric tumors. Exploration of the recently established metabolome profile of the massive panel of cell lines also revealed the metabolites of glucose and fatty acid metabolic pathways to show the differing abundance across gastric cancer subtypes. The subtype-specific metabolic rewiring and the existence of two distinct metabolic dysregulations involving glucose and fatty acid metabolism in gastric cancer subtypes have been identified. The identified differing metabolic dysregulations would pave way for the development of targeted therapeutic strategies for the gastric cancer subtypes.

Keywords: Fatty acid metabolism; Gastric cancer; Glucose metabolism; Metabolism

DOI: https://doi.org/10.1007/s10142-020-00753-w

Methods Mol Biol. 2021 ;2179 327-340

Studying the Metabolism of Epithelial-Mesenchymal Plasticity Using the Seahorse XFe96 Extracellular Flux Analyzer.

Sugandha Bhatia, Erik W Thompson, Jennifer H Gunter.

The critical role of metabolism in facilitating cancer cell growth and survival has been demonstrated by a combination of methods including, but not limited to, genomic sequencing, transcriptomic and proteomic analyses, measurements of radio-labelled substrate flux and the high throughput measurement of oxidative metabolism in unlabelled live cells using the Seahorse Extracellular Flux (XF) technology. These studies have revealed that tumour cells exhibit a dynamic metabolic plasticity, using numerous pathways including both glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) to support cell proliferation, energy production and the synthesis of biomass. These advanced technologies have also demonstrated metabolic differences between cancer cell types, between molecular subtypes within cancers and between cell states. This has been exemplified by examining the transitions of cancer cells between epithelial and mesenchymal phenotypes, referred to as epithelial-mesenchymal plasticity (EMP). A growing number of studies are demonstrating significant metabolic alterations associated with these transitions, such as increased use of glycolysis by triple negative breast cancers (TNBC) or glutamine addiction in lung cancer. Models of EMP, including invasive cell lines and xenografts, isolated circulating tumour cells and metastatic tissue have been used to examine EMP metabolism. Understanding the metabolism supporting molecular and cellular plasticity and increased metastatic capacity may reveal metabolic vulnerabilities that can be therapeutically exploited. This chapter describes protocols for using the Seahorse Extracellular Flux Analyzer (XFe96), which simultaneously performs real-time monitoring of oxidative phosphorylation and glycolysis in living cells. As an example, we compare the metabolic profiles generated from two breast cancer sublines that reflect epithelial and mesenchymal phenotypes, respectively. We use this example to show how the methodology described can generate bioenergetic results that in turn can be correlated to EMP phenotypes. Normalisation of bioenergetic studies should be considered with respect to cell number, and to potential differences in mitochondrial mass, itself being an important bioenergetics endpoint.

Keywords: Cellular bioenergetics; Epithelial-to-mesenchymal plasticity; Extracellular acidification; Glycolysis; Metabolic phenotype; Metabolism; Mitochondrial CMxRos; Mitochondrial RedFM; Oxidative phosphorylation; Oxygen consumption; Respiration; Seahorse Extracellular Flux Analyzer

DOI: https://doi.org/10.1007/978-1-0716-0779-4_25

Int J Mol Sci. 2020 Sep 16. pii: E6799. [Epub ahead of print]21(18):

NASH, Fibrosis and Hepatocellular Carcinoma: Lipid Synthesis and Glutamine/Acetate Signaling.

Yoshiaki Sunami.

Primary liver cancer is predicted to be the sixth most common cancer and the fourth leading cause of cancer mortality worldwide. Recent studies identified nonalcoholic fatty liver disease (NAFLD) as the underlying cause in 13-38.2% of patients with hepatocellular carcinoma unrelated to viral hepatitis and alcohol abuse. NAFLD progresses to nonalcoholic steatohepatitis (NASH), which increases the risk for the development of liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD is characterized by dysregulation of lipid metabolism. In addition, lipid metabolism is effected not only in NAFLD, but also in a broad range of chronic liver diseases and tumor development. Cancer cells manipulate a variety of metabolic pathways, including lipid metabolism, in order to build up their own cellular components. Identifying tumor dependencies on lipid metabolism would provide options for novel targeting strategies. This review article summarizes the research evidence on metabolic reprogramming and focuses on lipid metabolism in NAFLD, NASH, fibrosis, and cancer. As alternative routes of acetyl-CoA production for fatty acid synthesis, topics on glutamine and acetate metabolism are included. Further, studies on small compound inhibitors targeting lipid metabolism are discussed. Understanding reprogramming strategies in liver diseases, as well as the visualization of the metabolism reprogramming networks, could uncover novel therapeutic options.

Keywords: NAFLD; NASH; acetate metabolism; glutamine metabolism; hepatocellular carcinoma; lipid metabolism; liver fibrosis

DOI: https://doi.org/10.3390/ijms21186799

Cancers (Basel). 2020 Sep 14. pii: E2624. [Epub ahead of print]12(9):

Metabolic Signaling Cascades Prompted by Glutaminolysis in Cancer.

Raj Shah, Suzie Chen.

Aberrant glutamatergic signaling has been implicated in altered metabolic activity and the demand to synthesize biomass in several types of cancer including melanoma. In the last decade, there has been a significant contribution to our understanding of metabolic pathways. An increasing number of studies are now emphasizing the importance of glutamate functioning as a signaling molecule and a building block for cancer progression. To that end, our group has previously illustrated the role of glutamatergic signaling mediated by metabotropic glutamate receptor 1 (GRM1) in neoplastic transformation of melanocytes in vitro and spontaneous development of metastatic melanoma in vivo. Glutamate, the natural ligand of GRM1, is one of the most abundant amino acids in humans and the predominant excitatory neurotransmitter in the central nervous system. Elevated levels of glutaminolytic mitochondrial tricarboxylic acid (TCA) cycle intermediates, especially glutamate, have been reported in numerous cancer cells. Herein, we highlight and critically review metabolic bottlenecks that are prevalent during tumor evolution along with therapeutic implications of limiting glutamate bioavailability in tumors.

Keywords: CB-839; cancer; glutamate; glutaminase (GLS); glutamine; glutaminolysis; metabolism

DOI: https://doi.org/10.3390/cancers12092624

Exp Mol Med. 2020 Sep 17.

Glutamine reliance in cell metabolism.

Hee Chan Yoo, Ya Chun Yu, Yulseung Sung, Jung Min Han.

As knowledge of cell metabolism has advanced, glutamine has been considered an important amino acid that supplies carbon and nitrogen to fuel biosynthesis. A recent study provided a new perspective on mitochondrial glutamine metabolism, offering mechanistic insights into metabolic adaptation during tumor hypoxia, the emergence of drug resistance, and glutaminolysis-induced metabolic reprogramming and presenting metabolic strategies to target glutamine metabolism in cancer cells. In this review, we introduce the various biosynthetic and bioenergetic roles of glutamine based on the compartmentalization of glutamine metabolism to explain why cells exhibit metabolic reliance on glutamine. Additionally, we examined whether glutamine derivatives contribute to epigenetic regulation associated with tumorigenesis. In addition, in discussing glutamine transporters, we propose a metabolic target for therapeutic intervention in cancer.

DOI: https://doi.org/10.1038/s12276-020-00504-8

Transpl Immunol. 2020 Sep 13. pii: S0966-3274(20)30076-9. [Epub ahead of print] 101336

Targeting glutamine metabolism as an effective means to promote allograft acceptance while inhibit tumor growth.

Chen-Fang Lee, Chih-Hsien Cheng, Hao-Chien Hung, Kun-Ming Chan, Wei-Chen Lee.

Recently the role of metabolic signaling pathways has emerged as playing a critical role in dictating the outcome of T cell responses. The uptake and metabolism of the amino acid glutamine is essential for effector T cell activation. Since the growth and expansion of tumor cells relies on similar anabolic and metabolic requirements, we hypothesized that glutamine blockage might represent a promising strategy to promote allograft survival while inhibit tumor growth. 6-Diazo-5-oxo-L-norleucine (DON) was used as a glutamine antagonist. First, an in vitro study of T cell proliferation was performed to examine the ability of glutamine antagonism to inhibit T cell proliferation. Then we investigated whether DON could prolong allograft survival and inhibit tumor growth by using a fully MHC-mismatched mice full thickness skin transplantation model and a mice TC-1 tumor-bearing model. The proliferation study demonstrated that DON inhibited effector T cells proliferation in a dose-dependent manner. We found a marked prolonged graft median survival time and significant tumor inhibition for mice that received DON compared to those that received no treatment. These results highlight that targeting glutamine metabolism can promote allograft acceptance in a long tumor-free period.

Keywords: Glutamine; Metabolism; Tolerance; Transplantation; Tumor

DOI: https://doi.org/10.1016/j.trim.2020.101336

Mol Ther. 2020 Sep 02. pii: S1525-0016(20)30457-3. [Epub ahead of print]

xCT: A Critical Molecule That Links Cancer Metabolism to Redox Signaling.

Jinyun Liu, Xiaojun Xia, Peng Huang.

System xc- cystine/glutamate antiporter, composed of a light-chain subunit (xCT, SLC7A11) and a heavy-chain subunit (CD98hc, SLC3A2), is mainly responsible for the cellular uptake of cystine in exchange for intracellular glutamate. In recent years, the xCT molecule has been found to play an important role in tumor growth, progression, metastasis, and multidrug resistance in various types of cancer. Interestingly, xCT also exhibits an essential function in regulating tumor-associated ferroptosis. Despite significant progress in targeting the system xc- transporter in cancer treatment, the underlying mechanisms still remain elusive. It is also unclear why solid tumors are more sensitive to xCT inhibitors such as sulfasalazine, as compared to hematological malignancies. This review mainly focuses on the role of xCT cystine/glutamate transporter in regard to tumor growth, chemoresistance, tumor-selective ferroptosis, and the mechanisms regulating xCT gene expression. The potential therapeutic implications of targeting the system xc- and its combination with chemotherapeutic agents or immunotherapy to suppress tumor growth and overcome drug resistance are also discussed.

Keywords: ROS; ferroptosis; system x(c)(−); xCT

DOI: https://doi.org/10.1016/j.ymthe.2020.08.021