Glutamine metabolism is one of the hallmarks of cancers which is described as an essential role in serving as a major energy and building blocks supply to cell proliferation in cancer cells. Many malignant tumor cells always display glutamine addiction. The "kidney-type" glutaminase (GLS1) is a metabolism enzyme which plays a significant part in glutaminolysis. Interestingly, GLS1 is often overexpressed in highly proliferative cancer cells to fulfill enhanced glutamine demand. So far, GLS1 has been proved to be a significant target during the carcinogenesis process, and emerging evidence reveals that its inhibitors could provide a benefit strategy for cancer therapy. Herein, we summarize the prognostic value of GLS1 in multiple cancer type and its related regulatory factors which are associated with antitumor activity. Moreover, this review article highlights the remarkable reform of discovery and development for GLS1 inhibitors. On the basis of case studies, our perspectives for targeting GLS1 and development of GLS1 antagonist are discussed in the final part.

Targeting GLS1 to cancer therapy through glutamine metabolism.

Cancer is a heterogeneous disease characterized by various genetic and phenotypic aberrations. Cancer cells undergo genetic modifications that promote their proliferation, survival, and dissemination as the disease progresses. The unabated proliferation of cancer cells incurs an enormous energy demand that is supplied by metabolic reprogramming. Cancer cells undergo metabolic alterations to provide for increased energy and metabolite requirement; these alterations also help drive the tumor progression. Dysregulation in glucose uptake and increased lactate production via “aerobic glycolysis” were described more than 100 years ago, and since then, the metabolic signature of various cancers has been extensively studied. However, the extensive research in this field has failed to translate into significant therapeutic intervention, except for treating childhood-ALL with amino acid metabolism inhibitor L-asparaginase. Despite the growing understanding of novel metabolic alterations in tumors, the therapeutic targeting of these tumor-specific dysregulations has largely been ineffective in clinical trials. This chapter discusses the major pathways involved in the metabolism of glucose, amino acids, and lipids and highlights the inter-twined nature of metabolic aberrations that promote tumorigenesis in different types of cancer. Finally, we summarise the therapeutic interventions which can be used as a combinational therapy to target metabolic dysregulations that are unique or common in blood, breast, colorectal, lung, and prostate cancer.

/pdf/targeting-cancer-specific-metabolic-pathways-for-developing-4ovc8mcl.pdf

Targeting cancer-specific metabolic pathways for developing novel cancer therapeutics

Screening of Potential Biomarkers for Gastric Cancer with Diagnostic Value Using Label-free Global Proteome Analysis.

Gastric cancer (GC) is the fifth most common cancer and the third deadliest cancer in the world, and the occurrence and development of GC are influenced by epigenetics. Methyltransferase-like 3 (METTL3) is a prominent RNA n6-adenosine methyltransferase (m6A) that plays an important role in tumor growth by controlling the work of RNA. This study aimed to reveal the biological function and molecular mechanism of METTL3 in GC. The expression level of METTL3 in GC tissues and cells was detected by qPCR, Western blot and immunohistochemistry, and the expression level and prognosis of METTL3 were predicted in public databases. CCK-8, colony formation, transwell and wound healing assays were used to study the effect of METTL3 on GC cell proliferation and migration. In addition, the enrichment effect of METTL3 on DEK mRNA was detected by the RIP experiment, the m6A modification effect of METTL3 on DEK was verified by the MeRIP experiment and the mRNA half-life of DEK when METTL3 was overexpressed was detected. The dot blot assay detects m6A modification at the mRNA level. The effect of METTL3 on cell migration ability in vivo was examined by tail vein injection of luciferase-labeled cells. The experimental results showed that METTL3 was highly expressed in GC tissues and cells, and the high expression of METTL3 was associated with a poor prognosis. In addition, the m6A modification level of mRNA was higher in GC tissues and GC cell lines. Overexpression of METTL3 in MGC80-3 cells and AGS promoted cell proliferation and migration, while the knockdown of METTL3 inhibited cell proliferation and migration. The results of in vitro rescue experiments showed that the knockdown of DEK reversed the promoting effects of METTL3 on cell proliferation and migration. In vivo experiments showed that the knockdown of DEK reversed the increase in lung metastases caused by the overexpression of METTL3 in mice. Mechanistically, the results of the RIP experiment showed that METTL3 could enrich DEK mRNA, and the results of the MePIP and RNA half-life experiments indicated that METTL3 binds to the 3’UTR of DEK, participates in the m6A modification of DEK and promotes the stability of DEK mRNA. Ultimately, we concluded that METTL3 promotes GC cell proliferation and migration by stabilizing DEK mRNA expression. Therefore, METTL3 is a potential biomarker for GC prognosis and a therapeutic target.

/pdf/the-m6a-methyltransferase-mettl3-mediated-n6-methyladenosine-2e6whxyk.pdf

The m6A Methyltransferase METTL3-Mediated N6-Methyladenosine Modification of DEK mRNA to Promote Gastric Cancer Cell Growth and Metastasis

Depletion of gamma-glutamylcyclotransferase inhibits cancer cell growth by activating the AMPK-FOXO3a-p21 axis.

Purpose To screen the novel biomarkers for gastric cancer and to determine the values of glutaminase 1 (GLS1) and gamma-glutamylcyclotransferase (GGCT) for detecting gastric cancer. Experimental design A discovery group of four paired gastric cancer tissue samples are labeled with Isobaric tag for relative and absolute quantitation agents and identified with LC-ESI-MS/MS. A validation group of 168 gastric cancer samples and 30 healthy controls are used to validate the expression of GLS1 and GGCT. Results Four hundred and thirty-one proteins are found differentially expressed in gastric cancer tissues. Of these proteins, GLS1 and GGCT are found overexpressed in gastric cancer patients, with sensitivity of 75.6% (95% CI: 69-82.2%) and specificity of 81% (95% CI: 75-87%) for GLS1, and with sensitivity of 63.1% (95% CI: 55.7-71.5%) and specificity of 60.7% (95% CI: 53.3-68.2%) for GGCT. The co-expression of GLS1 and GGCT in gastric cancer tissues has sensitivity of 78.1% (95% CI: 70.1-86.1%) and specificity of 86.5% (95% CI: 79.5-93.4%). Moreover, both GLS1 and GGCT present higher expression of 82.6% (95% CI: 68.5-99.4%) and 73.9% (95% CI: 54.5-93.3%) in lymph node metastasis specimen than those in non-lymph node metastasis specimen. The areas under ROC curves are up to 0.734 for the co-expression of GLS1 and GGCT in gastric cancer. The co-expression of GLS1 and GGCT is strongly associated with histological grade, lymph node metastasis, and TNM stage Ⅲ/Ⅳ. Conclusions and clinical relevance The present study provides the quantitative proteomic analysis of gastric cancer tissues to identify prognostic biomarkers of gastric cancer. The co-expression level of GLS1 and GGCT is of great clinical value to serve as diagnostic and therapeutic biomarkers for early gastric cancer.

iTRAQ‐Based Quantitative Proteomics Approach Identifies Novel Diagnostic Biomarkers That Were Essential for Glutamine Metabolism and Redox Homeostasis for Gastric Cancer

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iTRAQ‐Based Quantitative Proteomics Approach Identifies Novel Diagnostic Biomarkers That Were Essential for Glutamine Metabolism and Redox Homeostasis for Gastric Cancer