bims-glucam 2022-07-17 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022–07–17
eight papers selected by
Sreeparna Banerjee, Middle East Technical University

Circ_0067717 promotes colorectal cancer cell growth, invasion and glutamine metabolism by serving as a miR-497-5p sponge to upregulate SLC7A5.
Tumor metabolic reprogramming in lung cancer progression.
Metabolic requirement for GOT2 in pancreatic cancer depends on environmental context.
Antitumor activity of mianserin (a tetracyclic antidepressant) primarily driven by the inhibition of SLC1A5-mediated glutamine transport.
Low-dose exposure to phytosynthesized gold nanoparticles combined with glutamine deprivation enhances cell death in the cancer cell line HeLa via oxidative stress-mediated mitochondrial dysfunction and G0/G1 cell cycle arrest.
Targeting mitochondrial metabolism for precision medicine in cancer.
Biomimetic Nanoplatform Loading Type I Aggregation-Induced Emission Photosensitizer and Glutamine Blockade to Regulate Nutrient Partitioning for Enhancing Antitumor Immunotherapy.
The discovery of a non-competitive GOT1 inhibitor, hydralazine hydrochloride, via a coupling reaction-based high-throughput screening assay.

Histol Histopathol. 2022 Jul 12. 18494

Circ_0067717 promotes colorectal cancer cell growth, invasion and glutamine metabolism by serving as a miR-497-5p sponge to upregulate SLC7A5.

Mo Song, Jipan Liu.

BACKGROUND: Circular RNAs (circRNAs) have been shown to exert vital functions in colorectal cancer (CRC) development. However, the role of circ_0067717 in CRC progression remains to be elucidated.
METHODS: The expression of circ_0067717, microRNA (miR)-497-5p and solute carrier family 7 member 5 (SLC7A5) was analyzed by quantitative real-time PCR. Cell proliferation, apoptosis and invasion were determined by cell counting kit 8 assay, EdU assay, flow cytometry and transwell assay. Protein expression was examined using western blot analysis. Glutamine metabolism was assessed by measuring glutamine consumption, α-ketoglutarate production and glutamate production. The interaction between miR-497-5p and circ_0067717 or SLC7A5 was identified by dual-luciferase reporter assay. Xenograft tumor models were constructed to confirm the role of circ_0067717 in CRC tumorigenesis in vivo.
RESULTS: Our data revealed that circ_0067717 was upregulated in CRC tissues and cells, and its knockdown restrained CRC cell proliferation, invasion, glutamine metabolism, and promoted apoptosis. MiR-497-5p was lowly expressed in CRC and it could be sponged by circ_0067717. MiR-497-5p inhibitor eliminated the regulation of circ_0067717 knockdown on CRC cell function. SLC7A5 was targeted by miR-497-5p and was positively regulated by circ_0067717. MiR-497-5p overexpression suppressed CRC cell growth, invasion and glutamine metabolism, and SLC7A5 was able to revoke this effect. Animal experiments showed that interference of circ_0067717 reduced CRC tumor growth.
CONCLUSION: Our research pointed out that circ_0067717 facilitated CRC development depending on the regulation of the miR-497-5p/SLC7A5 axis, providing a novel insight into CRC treatment.

DOI: https://doi.org/10.14670/HH-18-494
Oncol Lett. 2022 Aug;24(2): 287

Tumor metabolic reprogramming in lung cancer progression.

Xin Li, Minghui Liu, Hongyu Liu, Jun Chen.

  Metabolic reprogramming is an important characteristic of tumor cells. Tumor cells reprogram their metabolic pathways to meet the material, energy and redox force needs for rapid proliferation. Metabolic reprogramming changes the level or type of specific metabolites inside and outside cells, and promotes tumor growth by affecting gene expression, cell state and the tumor microenvironment. Glucose metabolism, glutamine metabolism and lipid metabolism are significant metabolic pathways in tumors. Targeting metabolic reprogramming can significantly inhibit tumor growth and induce apoptosis. Metabolic reprogramming also plays an important role in maintaining the growth advantage of tumor cells and enhancing the chemotherapy tolerance of lung cancer. This review summarizes abnormal changes in the metabolism of glucose, fat and amino acids in lung cancer, and the underlying molecular mechanism, with the aim of providing novel ideas for the prevention, early diagnosis and treatment of lung cancer.

Keywords:  lung cancer; metabolic reprogramming

DOI:  https://doi.org/10.3892/ol.2022.13407
Elife. 2022 Jul 11. pii: e73245. [Epub ahead of print]11

Metabolic requirement for GOT2 in pancreatic cancer depends on environmental context.

Samuel Kerk, Lin Lin, Amy L Myers, Damien J Sutton, Anthony Andren, Peter Sajjakulnukit, Li Zhang, Yaqing Zhang, Jennifer A Jiménez, Barbara S Nelson, Brandon Chen, Anthony Robinson, Galloway Thurston, Samantha B Kemp, Nina G Steele, Megan T Hoffman, Hui-Ju Wen, Daniel Long, Sarah E Ackenhusen, Johanna Ramos, Xiaohua Gao, Zeribe C Nwosu, Stefanie Galban, Christopher J Halbrook, David B Lombard, David R Piwnica-Worms, Haoqiang Ying, Marina Pasca di Magliano, Howard C Crawford, Yatrik M Shah, Costas A Lyssiotis.

  Mitochondrial glutamate-oxaloacetate (GOT2) is part of the malate-aspartate shuttle (MAS), a mechanism by which cells transfer reducing equivalents from the cytosol to the mitochondria. GOT2 is a key component of mutant KRAS (KRAS*)-mediated rewiring of glutamine metabolism in pancreatic ductal adenocarcinoma (PDA). Here, we demonstrate that the loss of GOT2 disturbs redox homeostasis and halts proliferation of PDA cells in vitro. GOT2 knockdown (KD) in PDA cell lines in vitro induced NADH accumulation, decreased Asp and α-ketoglutarate (αKG) production, stalled glycolysis, disrupted the TCA cycle, and impaired proliferation. Oxidizing NADH through chemical or genetic means resolved the redox imbalance induced by GOT2 KD, permitting sustained proliferation. Despite a strong in vitro inhibitory phenotype, loss of GOT2 had no effect on tumor growth in xenograft PDA or autochthonous mouse models. We show that cancer-associated fibroblasts (CAFs), a major component of the pancreatic tumor microenvironment (TME), release the redox active metabolite pyruvate, and culturing GOT2 KD cells in CAF conditioned media (CM) rescued proliferation in vitro. Furthermore, blocking pyruvate import or pyruvate-to-lactate reduction prevented rescue of GOT2 KD in vitro by exogenous pyruvate or CAF CM. However, these interventions failed to sensitize xenografts to GOT2 KD in vivo, demonstrating the remarkable plasticity and differential metabolism deployed by PDA cells in vitro and in vivo. This emphasizes how the environmental context of distinct pre-clinical models impacts both cell-intrinsic metabolic rewiring and metabolic crosstalk with the tumor microenvironment (TME).

Keywords:  biochemistry; cancer biology; chemical biology; human; mouse

DOI:  https://doi.org/10.7554/eLife.73245
Invest New Drugs. 2022 Jul 14.

Antitumor activity of mianserin (a tetracyclic antidepressant) primarily driven by the inhibition of SLC1A5-mediated glutamine transport.

Zelin Duan, Zhiyun Zhou, Feifei Lu, Yawen Zhang, Xvqin Guo, Chunshan Gui, Hongjian Zhang.

  Targeting tumor metabolic vulnerabilities such as "glutamine addiction" has become an attractive approach for the discovery of novel antitumor agents. Among various mechanisms explored, SLC1A5, a membrane transporter that plays an important role in glutamine cellular uptake, represents a viable target to interfere with tumor's ability to acquire critical nutrients during proliferation. In the present study, a stably transfected HEK293 cell line with human SLC1A5 (HEK293-SLC1A5) was established for the screening and identification of small molecule SLC1A5 inhibitors. This in vitro system, in conjunction with direct measurement of SLC1A5-mediated L-glutamine-2,3,3,4,4-D5 (substrate) uptake, was practical and efficient in ensuring the specificity of SLC1A5 inhibition. Among a group of diverse compounds tested, mianserin (a tetracyclic antidepressant) demonstrated a marked inhibition of SLC1A5-mediated glutamine uptake. Subsequent investigations using SW480 cells demonstrated that mianserin was capable of inhibiting SW480 tumor growth both in vitro and in vivo, and the in vivo antitumor efficacy was correlated to the reduction of glutamine concentrations in tumor tissues. Computational analysis revealed that hydrophobic interactions between SLC1A5 and its inhibitors could be a critical factor in drug design. Taken together, the current findings confirmed the feasibility of targeting SLC1A5-mediated glutamine uptake as a novel approach for antitumor intervention. It is anticipated that structural insights obtained based on homology modeling would lead to the discovery of more potent and specific SLC1A5 inhibitors for clinical development.

Keywords:  Antitumor activity; Glutamine; Mianserin; SLC1A5; Solute carrier proteins

DOI:  https://doi.org/10.1007/s10637-022-01284-w
Nanoscale. 2022 Jul 12.

Low-dose exposure to phytosynthesized gold nanoparticles combined with glutamine deprivation enhances cell death in the cancer cell line HeLa via oxidative stress-mediated mitochondrial dysfunction and G0/G1 cell cycle arrest.

Abhinav Prasad, Ashapurna Khatua, Yugal Kishore Mohanta, Muthupandian Saravanan, Ramovatar Meena, Ilora Ghosh.

Cancer cells use nutrients like D-glucose (Glc) and L-glutamine (Q) more efficiently for their development. This increased nutritional dependency of malignant cells has been commonly employed in various in vitro and in vivo models of anticancer therapies. This study utilized a combination of a low dose (25 μg mL-1) of S2, a phytosynthesized gold nanoparticle (AuNP) that was previously proven to be non-toxic, and deprivation of extracellular glutamine as an anticancer strategy in the human cervical cancer cell line HeLa. We discovered that 24 h Q deprivation led to a less significant decrease in the viability of HeLa cells while a low dose of S2 caused a non-significant reduction in the viability of HeLa cells. However, combining these two treatments resulted in highly significant inhibition of cell growth, as measured by the MTT test and morphological examination. Glutamine starvation in HeLa cells was found to induce cellular uptake of S2 via clathrin-mediated endocytosis, thus facilitating the improved antitumor effects of the combined treatment. Flow cytometry-based assays using fluorescent probes H2DCFDA and MitoSOX Red confirmed that this combination therapy involved the development of oxidative stress conditions owing to a surplus of cytosolic reactive oxygen species (cytoROS) and mitochondrial superoxide (mtSOX) generation. Furthermore, the investigated combinatorial treatment also indicated mitochondrial inactivity and disintegration, as evidenced by the drop in the mitochondrial membrane potential (Δψm) and the decrease in the mitochondrial mass (mtMass) in a flow-cytometric assay utilizing the probes. Tetramethylrhodamine ethyl ester and MitoTracker Green FM, respectively. Cell cycle arrest in the G0/G1 phase, induction of cell death via apoptosis/necrosis, and inhibition of migration capacities of HeLa cells were also seen after the combined treatment. Thus, this research provides insight into a new combinatorial approach for reducing the dose of nanoparticles and increasing their efficacy to better inhibit the growth of human cervical cancer cells by leveraging their extracellular glutamine dependence.

DOI: https://doi.org/10.1039/d2nr02150a
Cell Death Differ. 2022 Jul;29(7): 1304-1317

Targeting mitochondrial metabolism for precision medicine in cancer.

Lourdes Sainero-Alcolado, Judit Liaño-Pons, María Victoria Ruiz-Pérez, Marie Arsenian-Henriksson.

During decades, the research field of cancer metabolism was based on the Warburg effect, described almost one century ago. Lately, the key role of mitochondria in cancer development has been demonstrated. Many mitochondrial pathways including oxidative phosphorylation, fatty acid, glutamine, and one carbon metabolism are altered in tumors, due to mutations in oncogenes and tumor suppressor genes, as well as in metabolic enzymes. This results in metabolic reprogramming that sustains rapid cell proliferation and can lead to an increase in reactive oxygen species used by cancer cells to maintain pro-tumorigenic signaling pathways while avoiding cellular death. The knowledge acquired on the importance of mitochondrial cancer metabolism is now being translated into clinical practice. Detailed genomic, transcriptomic, and metabolomic analysis of tumors are necessary to develop more precise treatments. The successful use of drugs targeting metabolic mitochondrial enzymes has highlighted the potential for their use in precision medicine and many therapeutic candidates are in clinical trials. However, development of efficient personalized drugs has proved challenging and the combination with other strategies such as chemocytotoxic drugs, immunotherapy, and ketogenic or calorie restriction diets is likely necessary to boost their potential. In this review, we summarize the main mitochondrial features, metabolic pathways, and their alterations in different cancer types. We also present an overview of current inhibitors, highlight enzymes that are attractive targets, and discuss challenges with translation of these approaches into clinical practice. The role of mitochondria in cancer is indisputable and presents several attractive targets for both tailored and personalized cancer therapy.

DOI: https://doi.org/10.1038/s41418-022-01022-y
ACS Nano. 2022 Jul 13.

Biomimetic Nanoplatform Loading Type I Aggregation-Induced Emission Photosensitizer and Glutamine Blockade to Regulate Nutrient Partitioning for Enhancing Antitumor Immunotherapy.

Wei Xie, Bei Chen, Haifei Wen, Peihong Xiao, Lei Wang, Wei Liu, Dong Wang, Ben Zhong Tang.

  The intense metabolism of cancer cells leads to hypoxia and lack of crucial nutrients in the tumor microenvironment, which hinders the function of immune cells. We designed a biomimetic immune metabolic nanoplatform, in which a type I aggregation-induced emission photosensitizer and a glutamine antagonist are encapsulated into a cancer cell membrane for achieving specific delivery in vivo. This approach greatly satisfies the glucose and glutamine required by T cells, significantly improves the tumor hypoxic environment, enables the reprogramming of tumor and immune cell metabolism, induces immunogenic cell death, promotes dendritic cell maturation, and effectively inhibits tumor proliferation. Strong tumor-specific immune responses are further triggered, and the tumor immune-suppressing microenvironment is modulated, by decreasing the number of immunosuppressive cells. Moreover, subsequent combination with anti-PD-1 is able to generate strong abscopal effects to prevent tumor distant metastasis and provide long-term immune memory against tumor recurrence.

Keywords:  aggregation-induced emission; distant metastasis; glutamine blockade; nutrient partitioning; tumor recurrence

DOI:  https://doi.org/10.1021/acsnano.2c02605
Bioorg Med Chem Lett. 2022 Jul 09. pii: S0960-894X(22)00359-6. [Epub ahead of print] 128883

The discovery of a non-competitive GOT1 inhibitor, hydralazine hydrochloride, via a coupling reaction-based high-throughput screening assay.

Qiqi Wu, Zhongya Sun, Zhifeng Chen, Jingqiu Liu, Hong Ding, Cheng Luo, Mingliang Wang, Daohai Du.

  Glutamate oxaloacetate transaminase 1 (GOT1) plays a key role in aberrant glutamine metabolism. GOT1 suppression can arrest tumor growth and prevent the development of cancer, indicating GOT1 as a potential anticancer target. Reported GOT1 inhibitors, on the other hand, are quite restricted. Here, we developed and optimized a coupling reaction-based high-throughput screening assay for the discovery of GOT1 inhibitors. By using this screening assay, we found that the cardiovascular drug hydralazine hydrochloride inhibited GOT1 catalytic activity, with an IC50 of 26.62 ± 7.45 μM, in a non-competitive and partial-reversible manner. In addition, we determined the binding affinity of hydralazine hydrochloride to GOT1, with a Kd of 16.54 ± 8.59 μM, using a microscale thermophoresis assay. According to structure-activity relationship analysis, the inhibitory activity of hydralazine hydrochloride is mainly derived from its hydrazine group. Furthermore, it inhibits the proliferation of cancer cells MCF-7 and MDA-MB-468 with a slight inhibitory effect compared to other tested cancer cells, highlighting GOT1 as a promising therapeutic target for the treatment of breast cancer.

Keywords:  Glutamate oxaloacetate transaminase 1; High-throughput screening; Hydralazine hydrochloride; Inhibitor

DOI:  https://doi.org/10.1016/j.bmcl.2022.128883