Glutamine Metabolism Regulators Associated with Cancer Development and the Tumor Microenvironment: A Pan-Cancer Multi-Omics Analysis

Abstract

Background: In recent years, metabolic reprogramming has been identified as a hallmark of cancer. Accumulating evidence suggests that glutamine metabolism plays a crucial role in oncogenesis and the tumor microenvironment. In this study, we aimed to perform a systematic and comprehensive analysis of six key metabolic node genes involved in the dynamic regulation of glutamine metabolism (referred to as GLNM regulators) across 33 types of cancer. Methods: We analyzed the gene expression, epigenetic regulation, and genomic alterations of six key GLNM regulators, including SLC1A5, SLC7A5, SLC3A2, SLC7A11, GLS, and GLS2, in pan-cancer using several open-source platforms and databases. Additionally, we investigated the impacts of these gene expression changes on clinical outcomes, drug sensitivity, and the tumor microenvironment. We also attempted to investigate the upstream microRNA–mRNA molecular networks and the downstream signaling pathways involved in order to uncover the potential molecular mechanisms behind metabolic reprogramming. Results: We found that the expression levels of GLNM regulators varied across cancer types and were related to several genomic and immunological characteristics. While the immune scores were generally lower in the tumors with higher gene expression, the types of immune cell infiltration showed significantly different correlations among cancer types, dividing them into two clusters. Furthermore, we showed that elevated GLNM regulators expression was associated with poor overall survival in the majority of cancer types. Lastly, the expression of GLNM regulators was significantly associated with PD-L1 expression and drug sensitivity. Conclusions: The elevated expression of GLNM regulators was associated with poorer cancer prognoses and a cold tumor microenvironment, providing novel insights into cancer treatment and possibly offering alternative options for the treatment of clinically refractory cancers.

A Metabolism-Related Gene Prognostic Index Bridging Metabolic Signatures and Antitumor Immune Cycling in Head and Neck Squamous Cell Carcinoma

“…The enhanced glutamine in cancer cells activates mTOR signal transduction, inhibits endoplasmic reticulum stress, and promotes protein synthesis, thereby promoting tumor growth and proliferation (88)(89)(90). Moreover, our previous research revealed that glutamine metabolism regulators were associated with poorer cancer prognoses and an immunosuppressive TME (91). In the TME under hypoxic conditions, Glucose metabolism is the most common metabolic reprogramming of tumors that plays a major role in cancer survival, proliferation, metastasis, and treatment resistance (92)(93)(94)(95)(96).…”

The ferroptosis signature predicts the prognosis and immune microenvironment of nasopharyngeal carcinoma

“…A few studies have suggested that GLS2 expression is associated with good prognosis; for example, high expression of GLS2 in HCC is associated with a long survival time of patients 37 . However, most studies have shown that overexpression or amplification of GLS2 was associated with poor survival prognosis, such as in breast cancer 38,39 , glioblastoma 40 , ovarian cancer 41 , and lung cancer 34,42 . In addition, GLS2 was more highly expressed and regulated by METTL3 by m6A modification, which was significantly associated with poor prognosis in esophageal squamous cell carcinoma 43 .…”

Inhibition of glutaminase suppresses the proliferation and invasion of esophageal squamous cancer cells via TGF-β/Smad and MAPK signaling pathways

“…The enzyme kidneytype glutaminase (GLS or GLS1) participates in the catabolism of glutamine into glutamate in the mitochondria. This process is particularly crucial for highly proliferative cancer cells, as they often overexpress GLS to meet elevated energy and raw material requirements [19]. GLS is crucial for providing energy through α-ketoglutarate in the tricarboxylic acid (TCA) cycle [18].…”