bims-glucam 2022-05-22 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022–05–22
ten papers selected by
Sreeparna Banerjee, Middle East Technical University

NEDD4L inhibits cell viability, cell cycle progression, and glutamine metabolism in esophageal squamous cell carcinoma via ubiquitination of c-Myc.
Metabolic Reprogramming in Cholangiocarcinoma.
Polystyrene micro and nano-particles induce metabolic rewiring in normal human colon cells: A risk factor for human health.
Amino acid metabolism: challenges and opportunities for the therapeutic treatment of leukemia and lymphoma.
The Glutaminase Inhibitor Compound 968 Exhibits Potent in vitro and in vivo Anti-tumor Effects in Endometrial Cancer.
Inhibition of Glutamine Cellular Uptake Contributes to the Cytotoxic Effect of Xanthohumol in Triple-Negative Breast Cancer Cells.
Telaglenastat Plus Everolimus in Advanced Renal Cell Carcinoma: A Randomized, Double-Blinded, Placebo-Controlled, Phase 2 ENTRATA Trial.
Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia.
L-glutamine for sickle cell disease: more than reducing redox.
Advanced nanomedicines for the regulation of cancer metabolism.

Acta Biochim Biophys Sin (Shanghai). 2022 May 25.

NEDD4L inhibits cell viability, cell cycle progression, and glutamine metabolism in esophageal squamous cell carcinoma via ubiquitination of c-Myc.

Wei Cheng, Guiyuan Li, Zhou Ye, Jun Hu, Lixia Gao, Xiaoling Jia, Suping Zhao, Yan Wang, Qin Zhou.

  Esophageal squamous cell carcinoma (ESCC) is a common subtype of esophageal cancer with high incidence. Surgery remains the main strategy for treatment of ESCC at early stage. However, the treatment outcome is unsatisfactory. Therefore, finding new therapeutics is of great importance. In the present study, we measured the level of NEDD4L, an ubiquitin protein ligase, in clinical samples and investigated the effects of NEDD4L on cell viability, cell cycle progression, and glutamine metabolism in TE14 cells determined by CCK-8 assay, flow cytometry and biochemical analysis, respectively. The results show that NEDD4L is significantly decreased in ESCC specimens, and its decreased expression is associated with a poor clinical outcome. Overexpression of NEDD4L significantly inhibits cell viability, cell cycle progression, and glutamine metabolism in TE14 cells. Mechanistic study indicates that NEDD4L regulates tumor progression through ubiquitination of c-Myc and modulation of glutamine metabolism. NEDD4L inhibits cell viability, cell cycle progression, and glutamine metabolism in ESCC by ubiquitination of to decrease the expressions of GLS1 and SLC1A5. Our findings highlight the importance of NEDD4L/c-Myc signaling in ESCC.

Keywords:  NEDD4L; esophageal squamous cell carcinoma; glutamine metabolism; ubiquitination

DOI:  https://doi.org/10.3724/abbs.2022048
J Hepatol. 2022 May 17. pii: S0168-8278(22)00314-2. [Epub ahead of print]

Metabolic Reprogramming in Cholangiocarcinoma.

Chiara Raggi, Maria Letizia Taddei, Colin Rae, Chiara Braconi, Fabio Marra.

  Metabolic reprogramming is a hallmark of cancer and allows tumor cells to meet the increased energy demands required for rapid proliferation, invasion, and metastasis. Indeed, many tumor cells acquire distinctive metabolic and bioenergetic features to survive under conditions of limited resources, mainly using alternative nutrients. Several recent studies have explored the metabolic plasticity of cancer cells with the aim to identify new druggable targets, and therapeutic strategies aimed to limit the access to nutrients have been successfully applied to the treatment of some tumors. Cholangiocarcinoma (CCA), a highly heterogeneous tumor, is the second most common form of primary liver cancer. It is characterized by resistance to chemotherapy and poor prognosis, with 5-year survival lower than 20%. Deregulation of metabolic pathways has been described during the onset and progression of CCA. Increased aerobic glycolysis and glutamine anaplerosis provide CCA cells with the ability to generate biosynthetic intermediates. Other metabolic alterations involving carbohydrates, amino acids and lipids have been shown to sustain cancer cell growth and dissemination. In this review, we discuss the complex metabolic rewiring taking place during CCA development, leading to unique nutrient addiction. The possible role of therapeutic interventions based on metabolic changes is also thoroughly discussed.

Keywords:  CD36; IDH1/2; PGC1α; cancer stem cells; fatty acids; fatty-acid synthase; glutamine; glycolysis; mTOR; methionine adenosyltransferases; mitochondria; oxidative metabolism

DOI:  https://doi.org/10.1016/j.jhep.2022.04.038
Chemosphere. 2022 May 14. pii: S0045-6535(22)01440-0. [Epub ahead of print] 134947

Polystyrene micro and nano-particles induce metabolic rewiring in normal human colon cells: A risk factor for human health.

Marcella Bonanomi, Noemi Salmistraro, Danilo Porro, Annalisa Pinsino, Anna Maria Colangelo, Daniela Gaglio.

  Polystyrene is a thermoplastic polymer widely used in commercial products. Like all plastics, polystyrene can be degraded into microplastic and nanoplastic particles and ingested via food chain contamination. Although the ecological impact due to plastic contamination is well known, there are no studies indicating a carcinogenic potential of polystyrene microplastics (MPs) and nanoplastics (NPs). Here, we evaluated the effects of the MPs and NPs on normal human intestinal CCD-18Co cells. Our results show that internalization of NPs and MPs induces metabolic changes under both acute and chronic exposure by inducing oxidative stress, increasing glycolysis via lactate to sustain energy metabolism and glutamine metabolism to sustain anabolic processes. We also show that this decoupling of nutrients mirrors the effect of the potent carcinogenic agent azoxymethane and HCT15 colon cancer cells, carrying out the typical strategy of cancer cells to optimize nutrients utilization and allowing metabolic adaptation to environmental stress conditions. Taken together our data provide new evidence that chronic NPs and MPs exposure could act as cancer risk factor for human health.

Keywords:  Metabolomics; Plastic pollution; Risk factor

DOI:  https://doi.org/10.1016/j.chemosphere.2022.134947
Immunol Cell Biol. 2022 May 16.

Amino acid metabolism: challenges and opportunities for the therapeutic treatment of leukemia and lymphoma.

Peiyun Liao, Ning Chang, Binyan Xu, Yingqi Qiu, Sheng Wang, Lijuan Zhou, Yanjie He, Xiaoling Xie, Yuhua Li.

  Leukemia and lymphoma-the most common hematological malignant diseases-are often accompanied by complications such as drug resistance, refractory diseases, and relapse. Amino acids are important energy sources for malignant cells. Tumor-mediated amino acid metabolism is associated with the immunosuppressive properties of the tumor microenvironment, thereby assisting malignant cells to evade immune surveillance. Targeting abnormal amino acid metabolism in the tumor microenvironment may be an effective therapeutic approach to address the therapeutic challenges of leukemia and lymphoma. Here, we review the effects of glutamine, arginine, and tryptophan metabolism on tumorigenesis and immunomodulation, and define the differences between tumor cells and immune effector cells. We also comment on treatments targeting these amino acid metabolism pathways in lymphoma and leukemia and discuss how these treatments have profound adverse effects on tumor cells, but leave the immune cells unaffected or mildly affected.

Keywords:  amino acid metabolism; immunomodulation; leukemia; lymphoma; tumor microenvironment

DOI:  https://doi.org/10.1111/imcb.12557
Anticancer Agents Med Chem. 2022 May 13.

The Glutaminase Inhibitor Compound 968 Exhibits Potent in vitro and in vivo Anti-tumor Effects in Endometrial Cancer.

Hui Guo, Wanhu Li, Guoyou Pan, Cong Wang, Dapeng Li, Naifu Liu, Xiugui Sheng, Lingqin Yuan.

   BACKGROUND: Glutamine is one of the primary nutrients utilized by cancer cells for energy production and biosynthesis. Hence, interfering with glutamine metabolism may impose anti-tumor effects.
OBJECTIVE: In this study, we assessed the anti-tumorigenic effects of glutaminase-1 enzyme (GLS1) inhibition in endometrial cancer in vitro and in vivo.
METHODS: The human endometrial cancer cell lines Ishikawa and HEC-1B were used. The effects of compound 968 on cell proliferation, cell cycle, apoptosis, cellular stress, and AKT/mTOR pathway inhibition were assessed. The synergistic effects of compound 968 and paclitaxel was also analyzed. The in vivo effect of compound 968 was evaluated using tumor xenografts.
RESULTS: We found that the GLS1-targeting compound 968 was able to reduce cancer cell proliferation in a dose- and time-dependent manner. Compound 968 combined with low concentration of paclitaxel showed stronger inhibitory effects. Further analyses indicated that compound 968 induced cell cycle arrest at the G1 phase, as well as increased the production of cellular reactive oxygen species (ROS) and promoted cellular stress and cancer cell apoptosis. Additionally, the treatment of endometrial cancer with compound 968 downregulated the expression of GLS1 and cyclin D1, and upregulated the expression of P21 and E-cadherin. Moreover, the treatment of endometrial cancer cells with compound 968 significantly reduced levels of phospho-S6 ribosomal protein and phospho-AKT (Ser473), indicative of AKT/mTOR/S6 signaling pathway inhibition. In xenograft mouse models of endometrial cancer, compound 968 significantly suppressed tumor growth. In addition, western blotting analysis indicated that GLS1 expression was upregulated in human endometrial cancer tissues.
CONCLUSION: Compound 968 may be a promising approach for the management of human endometrial cancer.

Keywords:  Compound 968; Endometrial cancer; Glutaminase-1 enzyme (GLS1); Glutamine; Inhibitor; phospho-S6

DOI:  https://doi.org/10.2174/1871520622666220513163341
Nutr Cancer. 2022 May 20. 1-18

Inhibition of Glutamine Cellular Uptake Contributes to the Cytotoxic Effect of Xanthohumol in Triple-Negative Breast Cancer Cells.

F Carmo, C Silva, F Martel.

Breast cancer constitutes the most incident cancer and one of the most common causes of cancer-related death. "Glutamine addiction", an important metabolic feature of cancer cells, is dependent on supply of this amino acid from external sources. In this study, the effect of several polyphenols (catechin, epicatechin, EGCG, catechin:lysine, naringenin, hesperidin, malvidin, delphinidin, kaempferol, quercetin, rutin, myricetin, resveratrol, xanthohumol, and chrysin) upon glutamine (3H-GLN) uptake by human breast epithelial adenocarcinoma cell lines with distinct characteristics (MCF-7 and MDA-MB-231) was assessed.Several polyphenols interfere with 3H-GLN uptake by both cell lines. Xanthohumol markedly decreases total and Na+-dependent 3H-GLN uptake and showed a cytotoxic and anti-proliferative effect in MDA-MB-231 cells. Xanthohumol is as an uncompetitive inhibitor of Na+-dependent 3H-GLN uptake and inhibits GPNA (L-γ-glutamyl-p-nitroanilide)-sensitive, both ASCT2 (alanine, serine, cysteine transporter 2)-mediated and non-ASCT2-mediated 3H-GLN uptake. Xanthohumol does not interfere with the transcription rates of ASCT2. The cytotoxic effect of xanthohumol, but not its anti-proliferative effect, is GPNA-sensitive and related to ASCT2 inhibition. Combination of xanthohumol with the breast cancer chemotherapeutic agent doxorubicin results in an additive anti-proliferative, but not cytotoxic effect.We conclude that targeting glutamine uptake might constitute a potential interesting strategy for triple-negative breast cancer.

DOI: https://doi.org/10.1080/01635581.2022.2076889
Clin Cancer Res. 2022 May 16. pii: clincanres.0061.2022. [Epub ahead of print]

Telaglenastat Plus Everolimus in Advanced Renal Cell Carcinoma: A Randomized, Double-Blinded, Placebo-Controlled, Phase 2 ENTRATA Trial.

Chung-Han Lee, Robert Motzer, Hamid Emamekhoo, Marc Matrana, Ivor Percent, James J Hsieh, Arif Hussain, Ulka Vaishampayan, Sandy Liu, Steven McCune, Vijay Patel, Montaser Shaheen, Johanna Bendell, Alice C Fan, Benjamin A Gartrell, Oscar B Goodman, Petros G Nikolinakos, Arash Rezazadeh Kalebasty, Yousef Zakharia, Zhentao Zhang, Hema Parmar, Lalith Akella, Keith Orford, Nizar M Tannir.

PURPOSE: Glutaminase is a key enzyme that supports elevated dependency of tumors on glutamine-dependent biosynthesis of metabolic intermediates. Dual targeting of glucose and glutamine metabolism by the mTOR inhibitor everolimus plus the oral glutaminase inhibitor telaglenastat showed preclinical synergistic anticancer effects which translated to encouraging safety and efficacy findings in a phase 1 trial of 2L+ renal cell carcinoma (RCC). This study evaluated telaglenastat plus everolimus (TelaE) versus placebo plus everolimus (PboE) in patients with advanced/metastatic RCC (mRCC) in the 3L+ setting (NCT03163667).
EXPERIMENTAL DESIGN: Eligible patients with mRCC, previously treated with at least 2 prior lines of therapy (including {greater than or equal to}1 VEGFR-targeted tyrosine kinase inhibitor [TKI]) were randomized 2:1 to receive E, plus Tela or Pbo, until disease progression or unacceptable toxicity. Primary endpoint was investigator-assessed progression-free survival (PFS; 1-sided alpha <0.2).
RESULTS: 69 patients were randomized (46 TelaE, 23 PboE). Patients had a median 3 prior lines of therapy, including TKIs (100%) and checkpoint inhibitors (88%). At median follow-up of 7.5 months, median PFS was 3.8 months for TelaE vs 1.9 months for PboE (hazard ratio [HR]=0.64; 95% confidence interval [CI]: 0.34, 1.20; 1-sided P=0.079). One TelaE patient had a partial response (PR) and 26 had stable disease (SD). Eleven patients on PboE had SD. Treatment-emergent adverse events included fatigue, anemia, cough, dyspnea, elevated serum creatinine, and diarrhea; Grade 3-4 events occurred in 74% TelaE patients vs. 61% PboE.
CONCLUSIONS: TelaE was well tolerated and improved PFS vs PboE in patients with mRCC previously treated with TKIs and checkpoint inhibitors.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-0061
Nat Commun. 2022 May 19. 13(1): 2801

Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia.

Natalia Baran, Alessia Lodi, Yogesh Dhungana, Shelley Herbrich, Meghan Collins, Shannon Sweeney, Renu Pandey, Anna Skwarska, Shraddha Patel, Mathieu Tremblay, Vinitha Mary Kuruvilla, Antonio Cavazos, Mecit Kaplan, Marc O Warmoes, Diogo Troggian Veiga, Ken Furudate, Shanti Rojas-Sutterin, Andre Haman, Yves Gareau, Anne Marinier, Helen Ma, Karine Harutyunyan, May Daher, Luciana Melo Garcia, Gheath Al-Atrash, Sujan Piya, Vivian Ruvolo, Wentao Yang, Sriram Saravanan Shanmugavelandy, Ningping Feng, Jason Gay, Di Du, Jun J Yang, Fieke W Hoff, Marcin Kaminski, Katarzyna Tomczak, R Eric Davis, Daniel Herranz, Adolfo Ferrando, Elias J Jabbour, M Emilia Di Francesco, David T Teachey, Terzah M Horton, Steven Kornblau, Katayoun Rezvani, Guy Sauvageau, Mihai Gagea, Michael Andreeff, Koichi Takahashi, Joseph R Marszalek, Philip L Lorenzi, Jiyang Yu, Stefano Tiziani, Trang Hoang, Marina Konopleva.

T-cell acute lymphoblastic leukemia (T-ALL) is commonly driven by activating mutations in NOTCH1 that facilitate glutamine oxidation. Here we identify oxidative phosphorylation (OxPhos) as a critical pathway for leukemia cell survival and demonstrate a direct relationship between NOTCH1, elevated OxPhos gene expression, and acquired chemoresistance in pre-leukemic and leukemic models. Disrupting OxPhos with IACS-010759, an inhibitor of mitochondrial complex I, causes potent growth inhibition through induction of metabolic shut-down and redox imbalance in NOTCH1-mutated and less so in NOTCH1-wt T-ALL cells. Mechanistically, inhibition of OxPhos induces a metabolic reprogramming into glutaminolysis. We show that pharmacological blockade of OxPhos combined with inducible knock-down of glutaminase, the key glutamine enzyme, confers synthetic lethality in mice harboring NOTCH1-mutated T-ALL. We leverage on this synthetic lethal interaction to demonstrate that IACS-010759 in combination with chemotherapy containing L-asparaginase, an enzyme that uncovers the glutamine dependency of leukemic cells, causes reduced glutaminolysis and profound tumor reduction in pre-clinical models of human T-ALL. In summary, this metabolic dependency of T-ALL on OxPhos provides a rational therapeutic target.

DOI: https://doi.org/10.1038/s41467-022-30396-3
Ann Hematol. 2022 May 14.

L-glutamine for sickle cell disease: more than reducing redox.

Firas Jafri, Gyuhee Seong, Tim Jang, Emanuela Cimpeanu, Maria Poplawska, Dibyendu Dutta, Seah H Lim.

  Oxidative stress is a major contributor to the pathophysiology of sickle cell disease (SCD) including hemolysis and vaso-occlusive crisis (VOC). L-glutamine is a conditionally essential amino acid with important roles, including the synthesis of antioxidants, such as reduced glutathione and the cofactors NAD(H) and NADP(H), as well as nitric oxide. Given the increased levels of oxidative stress and lower (NADH):(NAD + + NADH) ratio in sickle erythrocytes that adversely affects the blood rheology compared to normal red blood cells, L-glutamine was investigated for its therapeutic potential to reduce VOC. While L-glutamine was approved by the United States (US) Food and Drug Administration to treat SCD, its impact on the redox environment in sickle erythrocytes is not fully understood. The mechanism through which L-glutamine reduces VOC in SCD is also not clear. In this paper, we will summarize the results of the Phase 3 study that led to the approval of L-glutamine for treating SCD and discuss its assumed mechanisms of action. We will examine the role of L-glutamine in health and propose how the extra-erythrocytic functions of L-glutamine might contribute to its beneficial effects in SCD. Further research into the role of L-glutamine on extra-erythrocyte functions might help the development of an improved formulation with more efficacy.

Keywords:  Antioxidant; Extra-erythrocytic functions; L-glutamine; Mechanisms of action; Sickle cell disease

DOI:  https://doi.org/10.1007/s00277-022-04867-y
Biomaterials. 2022 May 07. pii: S0142-9612(22)00205-8. [Epub ahead of print]286 121565

Advanced nanomedicines for the regulation of cancer metabolism.

Jiaying Yang, Yu Zhao, Yanyan Zhou, Xiaolu Wei, Hongjie Wang, Nan Si, Jian Yang, Qinghe Zhao, Baolin Bian, Haiyu Zhao.

  Cancer cells can reprogram metabolic pathways to facilitate proliferation, metastasis, biosynthesis, and chemoresistance. Metabolic reprogramming is currently considered as a hallmark of tumors and is recognized as a promising therapeutic strategy. The recent progress in nanomedicine has greatly improved the therapeutic effect of conventional therapeutic modalities such as surgical treatment, radiotherapy, chemical drug therapy. However, nanomedicine engineering still fails to achieve satisfactory therapeutic effects due to the metabolic reprogramming of tumor cells. The targeted delivery and development of precise therapeutic strategies are the latest focus in tumor metabolism to design nanomedicines according to the characteristics of cancer metabolic reprogramming. Therefore, this review focuses mainly on metabolic pathways of tumors. Pathways such as glycolysis, aerobic respiration, lipid metabolism, nucleotide metabolism, and glutathione metabolism are reviewed in detail. The latest advances are summarized in the design and combined treatment of smart nanomedicines that can regulate cancer metabolism to provide an emerging cancer therapeutic model. The challenges and future developments of this cancer therapeutic model are discussed in detail to understand as much as possible the prospects of this field. Designing nanomedicine therapy strategies by targeting tumor metabolic characteristics will provide a novel approach for the application of personalized biomedicine of tumors.

Keywords:  Metabolic reprogramming; Metabolism regulation; Nanomedicine; Synergistic therapy; Tumors metabolism

DOI:  https://doi.org/10.1016/j.biomaterials.2022.121565