bims-glucam 2020-12-27 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2020–12–27
eight papers selected by
Sreeparna Banerjee, Middle East Technical University

Novel Liver X Receptor Ligand GAC0001E5 Disrupts Glutamine Metabolism and Induces Oxidative Stress in Pancreatic Cancer Cells.
In Vivo Evidence for Serine Biosynthesis-Defined Sensitivity of Lung Metastasis, but Not of Primary Breast Tumors, to mTORC1 Inhibition.
Profiling and Targeting of Energy and Redox Metabolism in Grade 2 Bladder Cancer Cells with Different Invasiveness Properties.
Cancer-secreted miRNAs regulate amino-acid-induced mTORC1 signaling and fibroblast protein synthesis.
The pivotal role of MicroRNAs in glucose metabolism in cancer.
Mitochondrial Threonyl-tRNA Synthetase TARS2 Is Required for Threonine-Sensitive mTORC1 Activation.
CC-223, NSC781406, and BGT226 Exerts a Cytotoxic Effect Against Pancreatic Cancer Cells via mTOR Signaling.
Spontaneous protein-protein crosslinking at glutamine and glutamic acid residues in long-lived proteins.

Int J Mol Sci. 2020 Dec 17. pii: E9622. [Epub ahead of print]21(24):

Novel Liver X Receptor Ligand GAC0001E5 Disrupts Glutamine Metabolism and Induces Oxidative Stress in Pancreatic Cancer Cells.

Shivangi Srivastava, Scott Widmann, Charles Ho, Donovan Nguyen, Alexis Nguyen, Asitha Premaratne, Jan-Åke Gustafsson, Chin-Yo Lin.

  Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer with a high mortality rate due to the lack of early detection and effective treatment options for advanced diseases. Metabolic reprogramming, a common hallmark of malignant transformation in pancreatic cancer, is critical for the growth and survival of cancer cells and a potential target mechanism for the treatment of pancreatic cancer. PDAC cells have upregulated glutamine metabolism to meet their biosynthetic and oxidative demands. Liver X receptors (LXRs) are ligand-dependent transcription factors involved in maintaining metabolic homeostasis. LXRs regulate critical cancer-related processes and pathways, including cholesterol, glucose and lipid metabolism, and inflammatory and immune responses. Analysis of transcriptomic data from PDAC clinical samples reveals overexpression of LXRs and their target genes in tumors as compared to normal tissue controls. Targeting LXRs with the novel LXR inverse agonist and degrader GAC0001E5 inhibited PDAC cell proliferation. Using a metabolomics approach, we discovered that 1E5 inhibits glutamine anaplerosis and induces oxidative stress, which are detrimental to PDAC cells. These findings highlight a novel role for LXR in regulating cancer metabolism and the potential application of LXR modulators in targeting cancer metabolism in pancreatic cancer and other malignancies.

Keywords:  glutamine metabolism; ligand; liver X receptor; oxidative stress; pancreatic cancer

DOI:  https://doi.org/10.3390/ijms21249622
Mol Cell. 2020 Dec 15. pii: S1097-2765(20)30827-3. [Epub ahead of print]

In Vivo Evidence for Serine Biosynthesis-Defined Sensitivity of Lung Metastasis, but Not of Primary Breast Tumors, to mTORC1 Inhibition.

Gianmarco Rinaldi, Erica Pranzini, Joke Van Elsen, Dorien Broekaert, Cornelius M Funk, Mélanie Planque, Ginevra Doglioni, Patricia Altea-Manzano, Matteo Rossi, Vincent Geldhof, Shao Thing Teoh, Christina Ross, Kent W Hunter, Sophia Y Lunt, Thomas G P Grünewald, Sarah-Maria Fendt.

  In tumors, nutrient availability and metabolism are known to be important modulators of growth signaling. However, it remains elusive whether cancer cells that are growing out in the metastatic niche rely on the same nutrients and metabolic pathways to activate growth signaling as cancer cells within the primary tumor. We discovered that breast-cancer-derived lung metastases, but not the corresponding primary breast tumors, use the serine biosynthesis pathway to support mTORC1 growth signaling. Mechanistically, pyruvate uptake through Mct2 supported mTORC1 signaling by fueling serine biosynthesis-derived α-ketoglutarate production in breast-cancer-derived lung metastases. Consequently, expression of the serine biosynthesis enzyme PHGDH was required for sensitivity to the mTORC1 inhibitor rapamycin in breast-cancer-derived lung tumors, but not in primary breast tumors. In summary, we provide in vivo evidence that the metabolic and nutrient requirements to activate growth signaling differ between the lung metastatic niche and the primary breast cancer site.

Keywords:  MCT2; PHGDH; breast cancer; lung environment; mTORC1; metastasis formation; pyruvate; serine biosynthesis; α-ketoglutarate

DOI:  https://doi.org/10.1016/j.molcel.2020.11.027
Cells. 2020 12 11. pii: E2669. [Epub ahead of print]9(12):

Profiling and Targeting of Energy and Redox Metabolism in Grade 2 Bladder Cancer Cells with Different Invasiveness Properties.

Valentina Pasquale, Giacomo Ducci, Gloria Campioni, Adria Ventrici, Chiara Assalini, Stefano Busti, Marco Vanoni, Riccardo Vago, Elena Sacco.

  Bladder cancer is one of the most prevalent deadly diseases worldwide. Grade 2 tumors represent a good window of therapeutic intervention, whose optimization requires high resolution biomarker identification. Here we characterize energy metabolism and cellular properties associated with spreading and tumor progression of RT112 and 5637, two Grade 2 cancer cell lines derived from human bladder, representative of luminal-like and basal-like tumors, respectively. The two cell lines have similar proliferation rates, but only 5637 cells show efficient lateral migration. In contrast, RT112 cells are more prone to form spheroids. RT112 cells produce more ATP by glycolysis and OXPHOS, present overall higher metabolic plasticity and are less sensitive than 5637 to nutritional perturbation of cell proliferation and migration induced by treatment with 2-deoxyglucose and metformin. On the contrary, spheroid formation is less sensitive to metabolic perturbations in 5637 than RT112 cells. The ability of metformin to reduce, although with different efficiency, cell proliferation, sphere formation and migration in both cell lines, suggests that OXPHOS targeting could be an effective strategy to reduce the invasiveness of Grade 2 bladder cancer cells.

Keywords:  2D and 3D cultures; Operetta CLS™; Seahorse Extracellular Flux Analyzer; bladder cancer; cellular bioenergetics; energy and redox metabolism; fatty acids oxidation; glycolysis; mitochondrial function; oxidative stress; quantitative imaging

DOI:  https://doi.org/10.3390/cells9122669
EMBO Rep. 2020 Dec 20. e51239

Cancer-secreted miRNAs regulate amino-acid-induced mTORC1 signaling and fibroblast protein synthesis.

Miranda Y Fong, Wei Yan, Majid Ghassemian, Xiwei Wu, Xin Zhou, Minghui Cao, Li Jiang, Jessica Wang, Xuxiang Liu, Jin Zhang, Shizhen Emily Wang.

  Metabolic reprogramming of non-cancer cells residing in a tumor microenvironment, as a result of the adaptations to cancer-derived metabolic and non-metabolic factors, is an emerging aspect of cancer-host interaction. We show that in normal and cancer-associated fibroblasts, breast cancer-secreted extracellular vesicles suppress mTOR signaling upon amino acid stimulation to globally reduce mRNA translation. This is through delivery of cancer-derived miR-105 and miR-204, which target RAGC, a component of Rag GTPases that regulate mTORC1 signaling. Following amino acid starvation and subsequent re-feeding, 13 C-arginine labeling of de novo synthesized proteins shows selective translation of proteins that cluster to specific cellular functional pathways. The repertoire of these newly synthesized proteins is altered in fibroblasts treated with cancer-derived extracellular vesicles, in addition to the overall suppressed protein synthesis. In human breast tumors, RAGC protein levels are inversely correlated with miR-105 in the stroma. Our results suggest that through educating fibroblasts to reduce and re-prioritize mRNA translation, cancer cells rewire the metabolic fluxes of amino acid pool and dynamically regulate stroma-produced proteins during periodic nutrient fluctuations.

Keywords:  breast cancer; extracellular vesicles; mRNA translation; mTORC1; microRNA

DOI:  https://doi.org/10.15252/embr.202051239
Pathol Res Pract. 2020 Dec 04. pii: S0344-0338(20)32169-5. [Epub ahead of print]217 153314

The pivotal role of MicroRNAs in glucose metabolism in cancer.

Sina Taefehshokr, Nima Taefehshokr, Nima Hemmat, Saba Hajazimian, Alireza Isazadeh, Pourya Dadebighlu, Behzad Baradaran.

  Cancer cells are able to undergo aerobic glycolysis and metabolize glucose to lactate instead of oxidative phosphorylation, which is known as Warburg effect. Accumulating evidence has revealed that microRNAs regulate cancer cell metabolism, which manifest a higher rate of glucose metabolism. Various signaling pathways along with glycolytic enzymes are responsible for the emergence of glycolytic dependence. MicroRNAs are a class of non-coding RNAs that are not translated into proteins but regulate target gene expression or in other words function pre-translationally and post-transcriptionally. MicroRNAs have been shown to be involved in various biological processes, including glucose metabolism via targeting major transcription factors, enzymes, oncogenes or tumor suppressors alongside the oncogenic signaling pathways. In this review, we describe the regulatory role of microRNAs of cancer cell glucose metabolism, including in the glucose uptake, glycolysis, tricarboxylic acid cycle and several signaling pathways and further suggest that microRNA-based therapeutics can be used to inhibit the process of glucose metabolism reprogramming in cancer cells and thus suppressing cancer progression.

Keywords:  Cancer; Glucose; Metabolism; MicroRNA

DOI:  https://doi.org/10.1016/j.prp.2020.153314
Mol Cell. 2020 Dec 10. pii: S1097-2765(20)30836-4. [Epub ahead of print]

Mitochondrial Threonyl-tRNA Synthetase TARS2 Is Required for Threonine-Sensitive mTORC1 Activation.

Sung-Hoon Kim, Jung-Hyun Choi, Peng Wang, Christopher D Go, Geoffrey G Hesketh, Anne-Claude Gingras, Seyed Mehdi Jafarnejad, Nahum Sonenberg.

  Mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and proliferation by sensing fluctuations in environmental cues such as nutrients, growth factors, and energy levels. The Rag GTPases (Rags) serve as a critical module that signals amino acid (AA) availability to modulate mTORC1 localization and activity. Recent studies have demonstrated how AAs regulate mTORC1 activity through Rags. Here, we uncover an unconventional pathway that activates mTORC1 in response to variations in threonine (Thr) levels via mitochondrial threonyl-tRNA synthetase TARS2. TARS2 interacts with inactive Rags, particularly GTP-RagC, leading to increased GTP loading of RagA. mTORC1 activity in cells lacking TARS2 is resistant to Thr repletion, showing that TARS2 is necessary for Thr-dependent mTORC1 activation. The requirement of TARS2, but not cytoplasmic threonyl-tRNA synthetase TARS, for this effect demonstrates an additional layer of complexity in the regulation of mTORC1 activity.

Keywords:  Rag GTPases; TARS2; amino acid; aminoacyl-tRNA synthetase; mTORC1; threonine

DOI:  https://doi.org/10.1016/j.molcel.2020.11.036
Front Pharmacol. 2020 ;11 580407

CC-223, NSC781406, and BGT226 Exerts a Cytotoxic Effect Against Pancreatic Cancer Cells via mTOR Signaling.

Yangyang Guo, Hengyue Zhu, Min Weng, Hewei Zhang, Cheng Wang, Linxiao Sun.

  The mTOR signaling pathway is abnormally activated in pancreatic cancer and is related to tumor glucose metabolism. However, its specific regulation mechanism is still unclear. Therefore, this study aims to investigate whether Sestrin2 affects the glucose metabolism of pancreatic cancer by modulating mTOR signal and then affects its biological behavior. We have observed that l-leucine can promote the proliferation of pancreatic cancer cells and increase the expression of Sestrin2 and p-mTOR proteins. In order to further study the role of Sestrin2 and mTOR signaling in pancreatic cancer, we conducted Sestrin2 overexpression and mTOR pharmacological inhibition experiments. We found that Sestrin2 overexpression can increase glycolysis of pancreatic cancer cells and promote their proliferation. This effect can be eliminated by mTOR inhibitors. Finally, we found that Sestrin2 knockdown could inhibit the growth of pancreatic cancer in vivo. In conclusion, these findings suggest that Sestrin2 may promote the occurrence and development of pancreatic cancer through mTOR signaling.

Keywords:  BGT226; CC-223; NSC781406; mTOR; pancreatic cancer

DOI:  https://doi.org/10.3389/fphar.2020.580407
Biochem J. 2020 Dec 21. pii: BCJ20200798. [Epub ahead of print]

Spontaneous protein-protein crosslinking at glutamine and glutamic acid residues in long-lived proteins.

Michael G Friedrich, Zhen Wang, Kevin L Schey, Roger J W Truscott.

  Long-lived proteins (LLPs) are susceptible to the accumulation of both enzymatic and spontaneous post-translational modifications (PTMs). A prominent PTM observed in LLPs is covalent protein-protein crosslinking. In this study we examined aged human lenses and found several proteins to be crosslinked at Glu and Gln residues. This new covalent bond involves the amino group of Lys or an α-amino group. A number of these crosslinks were found in intermediate filament proteins. Such crosslinks could be reproduced experimentally by incubation of Glu- or Gln-containing peptides and their formation were consistent with an amino group attacking a glutarimide intermediate. These findings show that both Gln and Glu residues can act as sites for spontaneous covalent cross-linking in LLPs and they provide a mechanistic explanation for an otherwise puzzling observation, that a major fraction of Aβ in the human brain is crosslinked via Glu 22 and the N-terminal amino group.

Keywords:  Age; Alzheimer's disease; Human lens; Long-lived proteins; Protein crosslinks

DOI:  https://doi.org/10.1042/BCJ20200798