bims-glucam 2023-04-23 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023–04–23
eight papers selected by
Sreeparna Banerjee, Middle East Technical University

Targeting glutamine metabolism with photodynamic immunotherapy for metastatic tumor eradication.
Critical role of 6-phosphogluconate dehydrogenase in TAp73-mediated cancer cell proliferation.
Resistance to energy metabolism - targeted therapy of AML cells residual in the bone marrow microenvironment.
GCN2 kinase-mediated upregulation of ubiquitin C maintains intracellular glutamine level and tRNAGln (CUG) charging under amino acid starvation.
Isocitrate dehydrogenase 1 sustains a hybrid cytoplasmic-mitochondrial tricarboxylic acid cycle that can be targeted for therapeutic purposes in prostate cancer.
The metabolic cross-talk between cancer and T cells.
Warburg Effect Revisited: Embodiment of Classical Biochemistry and Organic Chemistry. Current State and Prospects.
Circular RNA Dipeptidyl Peptidase 4 (circDPP4) Stimulates the Expression of Glutamate Dehydrogenase 1 to Contribute to the Malignant Phenotypes of Prostate Cancer by Sponging miR-497-5p.

J Control Release. 2023 Apr 19. pii: S0168-3659(23)00277-8. [Epub ahead of print]357 460-471

Targeting glutamine metabolism with photodynamic immunotherapy for metastatic tumor eradication.

Linping Zhao, Xiaona Rao, Rongrong Zheng, Chuyu Huang, Renjiang Kong, Xiyong Yu, Hong Cheng, Shiying Li.

  Immune checkpoint blockade (ICB) has shown significant clinical success, yet its responses can vary due to immunosuppressive tumor microenvironments. To enhance antitumor immunity, combining ICB therapy with tumor metabolism reprogramming may be a promising strategy. In this study, we developed a photodynamic immunostimulant called BVC aiming to boost immune recognition and prevent immune escape for metastatic tumor eradication by reprogramming glutamine metabolism. BVC, a carrier free self-assembled nanoparticle, comprises a photosensitizer (chlorin e6), an ASCT2 inhibitor (V9302) and a PD1/PDL1 blocker (BMS-1), offering favorable stability and enhanced drug delivery efficiency. The potent photodynamic therapy (PDT) capability of BVC is attributed to its regulation of glutamine metabolism, which influences the redox microenvironment within tumor tissues. By targeting ASCT2-mediated glutamine metabolism, BVC inhibits glutamine transport and GSH synthesis, leading to the upregulation of Fas and PDL1. Additionally, BVC-mediated PDT induces immunogenic cell death, triggering a cascade of immune responses. Consequently, BVC not only enhances immune recognition between CD8+ T cells and Fas-overexpressing tumor cells but also reduces tumor cell immune escape through PD1/PDL1 blockade, significantly benefiting metastatic tumor eradication. This study paves a novel approach for multi-synergistic tumor treatment.

Keywords:  Glutamine metabolism; Immune checkpoint blockade; Immunogenic cell death; Photodynamic therapy; Self-delivery

DOI:  https://doi.org/10.1016/j.jconrel.2023.04.027
Mol Cancer Res. 2023 Apr 18. pii: MCR-22-0814. [Epub ahead of print]

Critical role of 6-phosphogluconate dehydrogenase in TAp73-mediated cancer cell proliferation.

Rui Qiao, Mengmeng Wei, Hui Chen, Xianhong Zhang, Jie Zhang, Liyang Gao, Haijun Ma, Yujiong Wang, Le Li.

Cancer cells frequently alter their metabolism to support biogenesis and proliferation and survive specific metabolic stressors. The glucose-associated pentose phosphate pathway (PPP) is crucial for cancer cell proliferation. In particular, 6-phosphogluconate dehydrogenase (6PGD), the second dehydrogenase in the PPP, catalyzes the decarboxylation of 6-phosphogluconate into ribulose 5-phosphate (Ru5P). However, the mechanisms controlling 6PGD expression in cancer cells remain unclear. Herein, we show that TAp73 increases Ru5P and NADPH production through 6PGD activation to counteract reactive oxygen species and protects cells from apoptosis. Moreover, 6PGD overexpression rescues the proliferation and tumorigenic ability of TAp73-deficient cells. These findings further establish the critical role of TAp73 on glucose metabolism regulation, demonstrating that TAp73 can activate 6PGD expression to support oncogenic cell growth. Implications: By transcriptional upregulation of 6PGD, TAp73 promotes the generation of Ru5P and NADPH, and enhances tumor cell proliferation.

DOI: https://doi.org/10.1158/1541-7786.MCR-22-0814
Cancer Drug Resist. 2023 ;6(1): 138-150

Resistance to energy metabolism - targeted therapy of AML cells residual in the bone marrow microenvironment.

Yoko Tabe, Marina Konopleva.

  In response to the changing availability of nutrients and oxygen in the bone marrow microenvironment, acute myeloid leukemia (AML) cells continuously adjust their metabolic state. To meet the biochemical demands of their increased proliferation, AML cells strongly depend on mitochondrial oxidative phosphorylation (OXPHOS). Recent data indicate that a subset of AML cells remains quiescent and survives through metabolic activation of fatty acid oxidation (FAO), which causes uncoupling of mitochondrial OXPHOS and facilitates chemoresistance. For targeting these metabolic vulnerabilities of AML cells, inhibitors of OXPHOS and FAO have been developed and investigated for their therapeutic potential. Recent experimental and clinical evidence has revealed that drug-resistant AML cells and leukemic stem cells rewire metabolic pathways through interaction with BM stromal cells, enabling them to acquire resistance against OXPHOS and FAO inhibitors. These acquired resistance mechanisms compensate for the metabolic targeting by inhibitors. Several chemotherapy/targeted therapy regimens in combination with OXPHOS and FAO inhibitors are under development to target these compensatory pathways.

Keywords:  Bone marrow microenvironment; acute myeloid leukemia; energy metabolism; fatty acid oxidation; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.20517/cdr.2022.133
FEBS Lett. 2023 Apr 20.

GCN2 kinase-mediated upregulation of ubiquitin C maintains intracellular glutamine level and tRNAGln (CUG) charging under amino acid starvation.

Yusuke Tsukamoto, Yumi Nakamura, Makoto Hirata, Daisuke Okuzaki, Ryuichi Sakate, Tomonori Kimura.

Each tRNA is aminoacylated (charged) with a genetic codon-specific amino acid. It remains unclear what factors are associated with tRNA charging and how tRNA charging is maintained. By using the individual tRNA acylation PCR (i-tRAP) method, we found that the charging ratio of tRNAGln (CUG) reflects cellular glutamine level. When uncharged tRNAGln (CUG) increased under amino acid starvation, the kinase GCN2, which is a key stimulator of the integrated stress response, was activated. Activation of GCN2 led to the upregulation of ubiquitin C (UBC) expression. Upregulated UBC, in turn, suppressed the further reduction of tRNAGln (CUG) charging levels. Thus, tRNA charging is sensitive to intracellular nutrient status and is an important initiator of intracellular signaling.

DOI: https://doi.org/10.1002/1873-3468.14628
Mol Oncol. 2023 Apr 22.

Isocitrate dehydrogenase 1 sustains a hybrid cytoplasmic-mitochondrial tricarboxylic acid cycle that can be targeted for therapeutic purposes in prostate cancer.

Kevin Gonthier, Cindy Weidmann, Line Berthiaume, Cynthia Jobin, Aurélie Lacouture, Camille Lafront, Mario Harvey, Bertrand Neveu, Jérémy Loehr, Alain Bergeron, Yves Fradet, Louis Lacombe, Julie Riopel, Éva Latulippe, Chantal Atallah, Michael Shum, Jean-Philippe Lambert, Frédéric Pouliot, Martin Pelletier, Étienne Audet-Walsh.

  The androgen receptor (AR) is an established orchestrator of cell metabolism in prostate cancer (PCa), notably by inducing an oxidative mitochondrial program. Intriguingly, AR regulates cytoplasmic isocitrate dehydrogenase 1 (IDH1) but not its mitochondrial counterparts IDH2 and IDH3. Here, we aimed to understand the functional role of IDH1 in PCa. Mouse models, in vitro human PCa cell lines, and human patient-derived organoids (PDOs) were used to study the expression and activity of IDH enzymes in the normal prostate and PCa. Genetic and pharmacological inhibition of IDH1 was then combined with extracellular flux analysis and gas chromatography-mass spectrometry for metabolomic analyses and cancer cell proliferation in vitro and in vivo. In PCa cells, more than 90% of the total IDH activity is mediated through IDH1 rather than its mitochondrial counterparts. This profile seems to originate from the specialized prostate metabolic program, as observed using mouse prostate and PDOs. Pharmacological and genetic inhibition of IDH1 impaired mitochondrial respiration, suggesting that this cytoplasmic enzyme contributes to the mitochondrial tricarboxylic acid cycle (TCA) in PCa. Mass spectrometry-based metabolomics confirmed this hypothesis, showing that inhibition of IDH1 impairs carbon flux into the TCA cycle. Consequently, inhibition of IDH1 decreased PCa cell proliferation in vitro and in vivo. These results demonstrate that PCa cells have a hybrid cytoplasmic-mitochondrial TCA cycle that depends on IDH1. This metabolic enzyme represents a metabolic vulnerability of PCa cells and a potential new therapeutic target.

Keywords:  IDH1; androgen receptor; castration-resistant prostate cancer; citric acid; mitochondria; nuclear receptor

DOI:  https://doi.org/10.1002/1878-0261.13441
Trends Biochem Sci. 2023 Apr 18. pii: S0968-0004(23)00080-4. [Epub ahead of print]

The metabolic cross-talk between cancer and T cells.

Silvia Cadenas-De Miguel, Giulia Lucianer, Ilaria Elia.

  The metabolic cross-talk between cancer cells and T cells dictates cancer formation and progression. These cells possess metabolic plasticity. Thus, they adapt their metabolic profile to meet their phenotypic requirements. However, the nutrient microenvironment of a tumor is a very hostile niche in which these cells are forced to compete for the available nutrients. The hyperactive metabolism of tumor cells often outcompetes the antitumorigenic CD8+ T cells while promoting the protumorigenic exhausted CD8+ T cells and T regulatory (Treg) cells. Thus, cancer cells elude the immune response and spread in an uncontrolled manner. Identifying the metabolic pathways necessary to shift the balance from a protumorigenic to an antitumorigenic immune phenotype is essential to potentiate antitumor immunity.

Keywords:  antitumorigenic T cells; immunometabolism; protumorigenic T cells; tumor microenvironment

DOI:  https://doi.org/10.1016/j.tibs.2023.03.004
Biochemistry (Mosc). 2023 Jan;88(Suppl 1): S1-S20

Warburg Effect Revisited: Embodiment of Classical Biochemistry and Organic Chemistry. Current State and Prospects.

Leonid G Menchikov, Alexander A Shestov, Anatoliy V Popov.

  The Nobel Prize Winner (1931) Dr. Otto H. Warburg had established that the primary energy source of the cancer cell is aerobic glycolysis (the Warburg effect). He also postulated the hypothesis about "the prime cause of cancer", which is a matter of debate nowadays. Contrary to the hypothesis, his discovery was recognized entirely. However, the discovery had almost vanished in the heat of battle about the hypothesis. The prime cause of cancer is essential for the prevention and diagnosis, yet the effects that influence tumor growth are more important for cancer treatment. Due to the Warburg effect, a large amount of data has been accumulated on biochemical changes in the cell and the organism as a whole. Due to the Warburg effect, the recovery of normal biochemistry and oxygen respiration and the restoration of the work of mitochondria of cancer cells can inhibit tumor growth and lead to remission. Here, we review the current knowledge on the inhibition of abnormal glycolysis, neutralization of its consequences, and normalization of biochemical parameters, as well as recovery of oxygen respiration of a cancer cell and mitochondrial function from the point of view of classical biochemistry and organic chemistry.

Keywords:  biochemistry; glycolysis; mitochondria; oncology; oxygen respiration; the Warburg effect

DOI:  https://doi.org/10.1134/S0006297923140018
Mol Biotechnol. 2023 Apr 20.

Circular RNA Dipeptidyl Peptidase 4 (circDPP4) Stimulates the Expression of Glutamate Dehydrogenase 1 to Contribute to the Malignant Phenotypes of Prostate Cancer by Sponging miR-497-5p.

Long Pei, Xiaosen Song, Xiangdong Liang, Ming Li, Aili Zhang, Xiaoliang Tan.

  Circular RNA dipeptidyl peptidase 4 (circDPP4) has been confirmed as a novel oncogene in prostate cancer (PCa). In this study, we aimed to explore the underlying mechanism of circDPP4 in PCa progression. Levels of circDPP4, microRNA (miR)-497-5p, glutamate dehydrogenase 1 (GLUD1), proliferating cell nuclear antigen (PCNA), BCL2 associated X, apoptosis regulator (Bax), E-cadherin and Ki67 were gauged by a quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, or immunohistochemical method. We assessed the roles of variables in PCa cell phenotypes by measuring cell growth, apoptosis, motility and invasiveness. We performed RNA immunoprecipitation (RIP) and dual-luciferase reporter assays to confirm the interactions of circDPP4/miR-497-5p and miR-497-5p/GLUD1. A xenograft model was established to gauge the effect of circDPP4 in the tumorigenicity of PCa cells. PCa tumor tissues and cell lines revealed higher levels of circDPP4 and GLUD1 and a lower expression of miR-497-5p than controls. CircDPP4 silencing hindered the growth, motility and invasiveness of PCa cells. Conversely, silencing circDPP4 enhanced PCa cell apoptosis. Mechanistic analysis showed that circDPP4 functioned as a miR-497-5p sponge to reduce the suppressive action of miR-497-5p on GLUD1, which was validated as a direct miR-497-5p target. Furthermore, circDPP4 knockdown weakened the tumorigenicity of PCa cells. CircDPP4 facilitated PCa process by mediating the miR-497-5p/GLUD1 axis, providing a possible therapy target for PCa.

Keywords:  GLUD1; Prostate cancer; circDPP4; miR-497-5p

DOI:  https://doi.org/10.1007/s12033-023-00750-x