bims-glucam 2022-02-20 papers

Cancers (Basel). 2022 Jan 22. pii: 553. [Epub ahead of print]14(3):

Advancing Cancer Treatment by Targeting Glutamine Metabolism-A Roadmap.

Tumor growth and metastasis strongly depend on adapted cell metabolism. Cancer cells adjust their metabolic program to their specific energy needs and in response to an often challenging tumor microenvironment. Glutamine metabolism is one of the metabolic pathways that can be successfully targeted in cancer treatment. The dependence of many hematological and solid tumors on glutamine is associated with mitochondrial glutaminase (GLS) activity that enables channeling of glutamine into the tricarboxylic acid (TCA) cycle, generation of ATP and NADPH, and regulation of glutathione homeostasis and reactive oxygen species (ROS). Small molecules that target glutamine metabolism through inhibition of GLS therefore simultaneously limit energy availability and increase oxidative stress. However, some cancers can reprogram their metabolism to evade this metabolic trap. Therefore, the effectiveness of treatment strategies that rely solely on glutamine inhibition is limited. In this review, we discuss the metabolic and molecular pathways that are linked to dysregulated glutamine metabolism in multiple cancer types. We further summarize and review current clinical trials of glutaminolysis inhibition in cancer patients. Finally, we put into perspective strategies that deploy a combined treatment targeting glutamine metabolism along with other molecular or metabolic pathways and discuss their potential for clinical applications.

Keywords: cancer; cancer treatment; drug resistance; glutamine metabolism; glutaminolysis inhibition; metabolism

DOI: https://doi.org/10.3390/cancers14030553

Int J Mol Sci. 2022 Jan 21. pii: 1155. [Epub ahead of print]23(3):

Cancer as a Metabolic Disorder.

Jones Gyamfi, Jinyoung Kim, Junjeong Choi.

Cancer has long been considered a genetic disease characterized by a myriad of mutations that drive cancer progression. Recent accumulating evidence indicates that the dysregulated metabolism in cancer cells is more than a hallmark of cancer but may be the underlying cause of the tumor. Most of the well-characterized oncogenes or tumor suppressor genes function to sustain the altered metabolic state in cancer. Here, we review evidence supporting the altered metabolic state in cancer including key alterations in glucose, glutamine, and fatty acid metabolism. Unlike genetic alterations that do not occur in all cancer types, metabolic alterations are more common among cancer subtypes and across cancers. Recognizing cancer as a metabolic disorder could unravel key diagnostic and treatments markers that can impact approaches used in cancer management.

Keywords: cancer; fatty acids; glucose; glutamine; metabolism

DOI: https://doi.org/10.3390/ijms23031155

J Cancer. 2022 ;13(3): 1061-1072

Glutamate dehydrogenase 1 mediated glutaminolysis sustains HCC cells survival under glucose deprivation.

Yujiao Zhou, Haibo Yu, Shengtao Cheng, Yao Chen, Lin He, Jihua Ren, Xin He, Juan Chen, Lu Zheng, Fan Li.

Besides aerobic glycolysis, glutaminolysis has also become a hot spot in the field of tumor research because of its important role in regulating cell proliferation, apoptosis, and migration and invasion. Meanwhile, it is generally believed that tumor cells could sustain its proliferation and survival according to a so-called metabolic flexibility. How the metabolic flexibility of HCC cells behaves has not yet been fully elucidated. In this study, we validated the glutamine addiction of HCC cells, and identified that the glutaminolysis pathway of HCC cells altered in response to different glucose conditions. That is, glutamate transaminases GOT1 pathway played a dominant role in regulating cell growth when glucose was sufficient, yet deaminase GDH1 mediated metabolic pathway became dominant when glucose was limited, for the reason that GDH1 could drive the TCA cycle in response to glucose deprivation. Additionally, we further uncovered an negative relationship between GDH1 and GOT1 in low-glucose HCC tissues. Together, our study provided a new insight into the metabolic flexibility of glutaminolysis related enzymes in HCC, and highlighted the crucial role of GDH1 on HCC cells proliferation and survival in glucose starvation.

Keywords: GDH1; Glutaminolysis; HCC; TCA cycle

DOI: https://doi.org/10.7150/jca.64195

Front Oncol. 2022 ;12 820173

Targeting Nutrient Dependency in Cancer Treatment.

Kexin Fan, Zhan Liu, Min Gao, Kangsheng Tu, Qiuran Xu, Yilei Zhang.

Metabolic reprogramming is one of the hallmarks of tumor. Growing evidence suggests metabolic changes that support oncogenic progression may cause selective vulnerabilities that can be exploited for cancer treatment. Increasing demands for certain nutrients under genetic determination or environmental challenge enhance dependency of tumor cells on specific nutrient, which could be therapeutically developed through targeting such nutrient dependency. Various nutrients including several amino acids and glucose have been found to induce dependency in genetic alteration- or context-dependent manners. In this review, we discuss the extensively studied nutrient dependency and the biological mechanisms behind such vulnerabilities. Besides, existing applications and strategies to target nutrient dependency in different cancer types, accompanied with remaining challenges to further exploit these metabolic vulnerabilities to improve cancer therapies, are reviewed.

Keywords: cancer; dependency; metabolism; nutrient; therapy

DOI: https://doi.org/10.3389/fonc.2022.820173

Endocr Regul. 2022 Feb 18. 56(1): 38-47

The impact of glutamine deprivation on the expression of MEIS3, SPAG4, LHX1, LHX2, and LHX6 genes in ERN1 knockdown U87 glioma cells.

Dariia A Krasnytska, Olena O Khita, Dariia O Tsymbal, Olha Y Luzina, Anastasiia A Cherednychenko, Halyna E Kozynkevich, Borys H Bezrodny, Dmytro O Minchenko.

Objective. The aim of the current study was to investigate the expression of genes encoded homeobox proteins such as MEIS3 (Meis homeobox 3), SPAG4 (sperm associated antigen 4), LHX1 (LIM homeobox 1), LHX2, and LHX6 in U87 glioma cells in response to glutamine deprivation in control glioma cells and cells with knockdown of ERN1 (endoplasmic reticulum to nucleus signaling 1), the major pathway of the endoplasmic reticulum stress signaling, for evaluation of a possible dependence on the expression of these important regulatory genes from glutamine supply and ERN1 signaling. Methods. The expression level of MEIS3, SPAG4, LHX, LHX2, and LHX6 genes was studied by real-time quantitative polymerase chain reaction in control U87 glioma cells (transfected by vector) and cells with ERN1 knockdown after exposure to glutamine deprivation. Results. It was shown that the expression level of MEIS3 and LHX1 genes was up-regulated in control glioma cells treated by glutamine deprivation. At the same time, the expression level of three other genes (LHX2, LHX6, and SPAG4) was down-regulated. Furthermore, ERN1 knockdown significantly modified the effect of glutamine deprivation on LHX1 gene expression in glioma cells, but did not change significantly the sensitivity of all other genes expression to this experimental condition. Conclusion. The results of this investigation demonstrate that the exposure of U87 glioma cells under glutamine deprivation significantly affected the expression of all genes studied encoding the homeobox proteins and that this effect of glutamine deprivation was independent of the endoplasmic reticulum stress signaling mediated by ERN1, except LHX1 gene.

Keywords: ERN1 knockdown; U87 glioma cells; glutamine deprivation; homeobox genes; mRNA expression

DOI: https://doi.org/10.2478/enr-2022-0005

Semin Cancer Biol. 2022 Feb 10. pii: S1044-579X(22)00031-1. [Epub ahead of print]

Metabolic modulation of immune checkpoints and novel therapeutic strategies in cancer.

Yi Wang, Yuya Wang, Yifei Ren, Qi Zhang, Ping Yi, Chunming Cheng.

Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) or programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1)-based immune checkpoint inhibitors (ICIs) have led to significant improvements in the overall survival of patients with certain cancers and are expected to benefit patients by achieving complete, long-lasting remissions and cure. However, some patients who receive ICIs either fail treatment or eventually develop immunotherapy resistance. The existence of such patients necessitates a deeper understanding of cancer progression, specifically nutrient regulation in the tumor microenvironment (TME), which includes both metabolic cross-talk between metabolites and tumor cells, and intracellular metabolism in immune and cancer cells. Here we review the features and behaviors of the TME and discuss the recently identified major immune checkpoints. We comprehensively and systematically summarize the metabolic modulation of tumor immunity and immune checkpoints in the TME, including glycolysis, amino acid metabolism, lipid metabolism, and other metabolic pathways, and further discuss the potential metabolism-based therapeutic strategies tested in preclinical and clinical settings. These findings will help to determine the existence of a link or crosstalk between tumor metabolism and immunotherapy, which will provide an important insight into cancer treatment and cancer research.

Keywords: Amine acid metabolism; Fatty acid synthesis; Glycolysis; Immune checkpoint; Immunotherapy; Lipid metabolism; Tumor metabolism; Tumor microenvironment

DOI: https://doi.org/10.1016/j.semcancer.2022.02.010