bims-glucam 2022-06-05 papers

Mol Biol Rep. 2022 Jun 02.

β-Escin reduces cancer progression in aggressive MDA-MB-231 cells by inhibiting glutamine metabolism through downregulation of c-myc oncogene.

Sakine Akar, Hamiyet Donmez-Altuntas, Zuhal Hamurcu.

BACKGROUND: The c-myc oncogene, which causes glutamine dependence in triple negative breast cancers (TNBC), is also the target of one of the signaling pathways affected by β-Escin.
METHODS AND RESULTS: We sought to determine how c-myc protein affects glutamine metabolism and the proteins, glutamine transporter alanine-serine-cysteine 2 (ASCT2) and glutaminase (GLS1), in β-Escin-treated MDA-MB-231 cells using glutamine uptake and western blot analysis. Cell viability, colony formation, migration and apoptosis were also evaluated in MDA-MB-231 cells in response to β-Escin treatment using MTS, colony forming, wound healing, and Annexin-V assay. We determined that β-Escin decreased glutamine uptake and reduced c-myc and GLS1 protein expressions and increased the expression of ASCT2. In addition, this inhibition of glutamine metabolism decreased cell proliferation, colony formation and migration, and induced apoptosis.
CONCLUSIONS: In this study, it was suggested that β-Escin inhibits glutamine metabolism via c-myc in MDA-MB-231 cells, and it is thought that as a result of interrupting the energy supply in these cells via c-myc, it results in a decrease in the carcinogenic properties of the cells. Consequently, β-Escin may be promising as a therapeutic agent for glutamine-dependent cancers.

Keywords: ASCT2; Apoptosis; Breast cancer; GLS1; Glutamine; MDA-MB-231; Migration; c-myc; β-Escin

DOI: https://doi.org/10.1007/s11033-022-07536-5

Nat Commun. 2022 May 31. 13(1): 3034

Neddylation inhibition induces glutamine uptake and metabolism by targeting CRL3SPOP E3 ligase in cancer cells.

Qiyin Zhou, Wenyu Lin, Chaoqun Wang, Fei Sun, Siwei Ju, Qian Chen, Yi Wang, Yongxia Chen, Haomin Li, Linbo Wang, Zeping Hu, Hongchuan Jin, Xian Wang, Yi Sun.

Abnormal neddylation activation is frequently observed in human cancers and neddylation inhibition has been proposed as a therapy for cancer. Here, we report that MLN4924, a small-molecule inhibitor of neddylation activating enzyme, increases glutamine uptake in breast cancer cells by causing accumulation of glutamine transporter ASCT2/SLC1A5, via inactivation of CRL3-SPOP E3 ligase. We show the E3 ligase SPOP promotes ASCT2 ubiquitylation, whereas SPOP itself is auto-ubiquitylated upon glutamine deprivation. Thus, SPOP and ASCT2 inversely regulate glutamine uptake and metabolism. SPOP knockdown increases ASCT2 levels to promote growth which is rescued by ASCT2 knockdown. Adding ASCT2 inhibitor V-9302 enhances MLN4924 suppression of tumor growth. In human breast cancer specimens, SPOP and ASCT2 levels are inversely correlated, whereas lower SPOP with higher ASCT2 predicts a worse patient survival. Collectively, our study links neddylation to glutamine metabolism via the SPOP-ASCT2 axis and provides a rational drug combination for enhanced cancer therapy.

DOI: https://doi.org/10.1038/s41467-022-30559-2

Front Oncol. 2022 ;12 889826

LKB1: Can We Target an Hidden Target? Focus on NSCLC.

Gloriana Ndembe, Ilenia Intini, Elisa Perin, Mirko Marabese, Elisa Caiola, Paolo Mendogni, Lorenzo Rosso, Massimo Broggini, Marika Colombo.

LKB1 (liver kinase B1) is a master regulator of several processes such as metabolism, proliferation, cell polarity and immunity. About one third of non-small cell lung cancers (NSCLCs) present LKB1 alterations, which almost invariably lead to protein loss, resulting in the absence of a potential druggable target. In addition, LKB1-null tumors are very aggressive and resistant to chemotherapy, targeted therapies and immune checkpoint inhibitors (ICIs). In this review, we report and comment strategies that exploit peculiar co-vulnerabilities to effectively treat this subgroup of NSCLCs. LKB1 loss leads to an enhanced metabolic avidity, and treatments inducing metabolic stress were successful in inhibiting tumor growth in several preclinical models. Biguanides, by compromising mitochondria and reducing systemic glucose availability, and the glutaminase inhibitor telaglenastat (CB-839), inhibiting glutamate production and reducing carbon intermediates essential for TCA cycle progression, have provided the most interesting results and entered different clinical trials enrolling also LKB1-null NSCLC patients. Nutrient deprivation has been investigated as an alternative therapeutic intervention, giving rise to interesting results exploitable to design specific dietetic regimens able to counteract cancer progression. Other strategies aimed at targeting LKB1-null NSCLCs exploit its pivotal role in modulating cell proliferation and cell invasion. Several inhibitors of LKB1 downstream proteins, such as mTOR, MEK, ERK and SRK/FAK, resulted specifically active on LKB1-mutated preclinical models and, being molecules already in clinical experimentation, could be soon proposed as a specific therapy for these patients. In particular, the rational use in combination of these inhibitors represents a very promising strategy to prevent the activation of collateral pathways and possibly avoid the potential emergence of resistance to these drugs. LKB1-null phenotype has been correlated to ICIs resistance but several studies have already proposed the mechanisms involved and potential interventions. Interestingly, emerging data highlighted that LKB1 alterations represent positive determinants to the new KRAS specific inhibitors response in KRAS co-mutated NSCLCs. In conclusion, the absence of the target did not block the development of treatments able to hit LKB1-mutated NSCLCs acting on several fronts. This will give patients a concrete chance to finally benefit from an effective therapy.

Keywords: STK11 (LKB1); metabolism; non-small cell lung cancer; personalized medicine; target

DOI: https://doi.org/10.3389/fonc.2022.889826

Angew Chem Int Ed Engl. 2022 May 30.

A Cobalamin-Dependent Radical SAM Enzyme Catalyzes the Unique Cα-Methylation of Glutamine in Methyl-Coenzyme M Reductase.

Jana Gagsteiger, Sören Jahn, Lorenz Heidinger, Lukas Gericke, Jennifer N Andexer, Thorsten Friedrich, Christoph Loenarz, Gunhild Layer.

Methyl-coenzyme M reductase, which is responsible for the production of the greenhouse gas methane during biological methane formation, carries several unique posttranslational amino acid modifications, inter alia a 2-(S)-methylglutamine. The enzyme responsible for the Cα-methylation of this glutamine is not known. Here, we identify and characterize a cobalamin-dependent Radical SAM enzyme as the glutamine C-methyltransferase. The recombinant protein from Methanoculleus thermophilus binds cobalamin in a base-off, His-off conformation and contains a single [4Fe-4S] cluster. The cobalamin cofactor cycles between the methyl-cob(III)alamin, cob(II)alamin and cob(I)alamin states during catalysis and produces methylated substrate, 5'-deoxyadenosine and S-adenosyl-L-homocysteine in a 1:1:1 ratio. The newly identified glutamine C-methyltransferase belongs to the class B of Radical SAM methyltransferases known to catalyze challenging methylation reactions of sp3-hybridized carbon atoms.

Keywords: MCR modification; Methanogenesis; Radical S-adenosylmethionine; Radical reactions; metalloproteins

DOI: https://doi.org/10.1002/anie.202204198

Antioxid Redox Signal. 2022 Jun 01.

A Metabolic Paradigm for H2S Signaling via ETC Plasticity.

David Hanna, Roshan Kumar, Ruma Banerjee.

SIGNIFICANCE: A burgeoning literature has attributed varied physiological effects to H2S, which is a product of eukaryotic sulfur amino acid metabolism. Protein persulfidation represents a major focus of studies elucidating the mechanism underlying H2S signaling. On the other hand, the capacity of H2S to induce reductive stress by targeting the electron transport chain (ETC), and signal by reprogramming redox metabolism have only recently begun to be elucidated.
RECENT ADVANCES: In contrast to the nonspecific reaction of H2S with oxidized cysteines to form protein persulfides, its inhibition of complex IV represents a specific mechanism of action. Studies on the dual impact of H2S as an ETC substrate and an inhibitor have led to the exciting discovery of ETC plasticity and the use of fumarate as a terminal electron acceptor. H2S oxidation combined with complex IV targeting generate mitochondrial reductive stress, which is signaled through the metabolic network, leading to increased aerobic glycolysis, glutamine-dependent reductive carboxylation and lipogenesis.
CRITICAL ISSUES: Insights into H2S-induced metabolic reprogramming are ushering in a paradigm shift for understanding the mechanism of its cellular action. It will be critical to reevaluate the physiological effects of H2S e.g., cytoprotection against ischemia-reperfusion injury, through the framework of metabolic reprogramming and ETC remodeling by H2S.
FUTURE DIRECTIONS: The metabolic ramifications of H2S in other cellular compartments, e.g., the endoplasmic reticulum and the nucleus, as well as the intersections between hypoxia and H2S signaling are important future directions that merit elucidation.

DOI: https://doi.org/10.1089/ars.2022.0067

World J Clin Cases. 2022 Apr 06. 10(10): 2990-3004

Targeting metabolism: A potential strategy for hematological cancer therapy.

Xue Tang, Fen Chen, Li-Chun Xie, Si-Xi Liu, Hui-Rong Mai.

Most hematological cancer-related relapses and deaths are caused by metastasis; thus, the importance of this process as a target of therapy should be considered. Hematological cancer is a type of cancer in which metabolism plays an essential role in progression. Therefore, we are required to block fundamental metastatic processes and develop specific preclinical and clinical strategies against those biomarkers involved in the metabolic regulation of hematological cancer cells, which do not rely on primary tumor responses. To understand progress in this field, we provide a summary of recent developments in the understanding of metabolism in hematological cancer and a general understanding of biomarkers currently used and under investigation for clinical and preclinical applications involving drug development. The signaling pathways involved in cancer cell metabolism are highlighted and shed light on how we could identify novel biomarkers involved in cancer development and treatment. This review provides new insights into biomolecular carriers that could be targeted as anticancer biomarkers.

Keywords: Anticancer; Biomarker; Cancer; Hematological cancer; Metabolism; Metastasis

DOI: https://doi.org/10.12998/wjcc.v10.i10.2990