bims-glucam 2021-11-14 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2021–11–14
sixteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Development of simultaneous quantitative analysis of tricarboxylic acid cycle metabolites to identify specific metabolites in cancer cells by targeted metabolomic approach.
Molecular aspects of pancreatic cancer: focus on reprogrammed metabolism in a nutrient-deficient environment and potential therapeutic targets.
The expression of glutamate metabolism modulators in the intracranial tumors and glioblastoma cell line.
Alternative Energy: Breaking Down the Diverse Metabolic Features of Lung Cancers.
Fibroblast pyruvate carboxylase is required for collagen production in the tumour microenvironment.
MTHFD2 is a metabolic checkpoint controlling effector and regulatory T cell fate and function.
A comprehensive tool for accurate identification of methyl-Glutamine sites.
PIK3CA mutation affects the proliferation of colorectal cancer cells through the PI3K-MEK/PDK1-GPT2 pathway.
The biological role of metabolic reprogramming in pancreatic cancer.
Unfolding the role of autophagy in the cancer metabolism.
Metabolic therapy and bioenergetic analysis: the missing piece of the puzzle.
The predictive role of preoperative serum glutamate dehydrogenase levels in microvascular invasion and hepatocellular carcinoma prognosis following liver transplantation-a single center retrospective study.
The Neglected Liaison: Targeting Cancer Cell Metabolic Reprogramming Modifies the Composition of Non-Malignant Populations of the Tumor Microenvironment.
Functional Amino Acids and Autophagy: Diverse Signal Transduction and Application.
Autophagy in Cancer Therapy-Molecular Mechanisms and Current Clinical Advances.
The Key Role of the WNT/β-Catenin Pathway in Metabolic Reprogramming in Cancers under Normoxic Conditions.

Biochem Biophys Res Commun. 2021 Nov 05. pii: S0006-291X(21)01495-9. [Epub ahead of print]584 53-59

Development of simultaneous quantitative analysis of tricarboxylic acid cycle metabolites to identify specific metabolites in cancer cells by targeted metabolomic approach.

Tetsushi Yamamoto, Kanta Sato, Masafumi Yamaguchi, Kuniko Mitamura, Atsushi Taga.

  The tricarboxylic acid (TCA) cycle is one of the most important pathways of energy metabolism, and the profiles of its components are influenced by factors such as diseases and diets. Therefore, the differences in metabolic profile of TCA cycle between healthy and cancer cells have been the focus of studies to understand pathological conditions. In this study, we developed a quantitative method to measure TCA cycle metabolites using LC-MS/MS to obtain useful metabolic profiles for development of diagnostic and therapeutic methods for cancer. We successfully analyzed 11 TCA cycle metabolites by LC MS/MS with high reproducibility by using a PFP column with 0.5% formic acid as a mobile phase. Next, we analyzed the concentration of TCA cycle metabolites in human cell lines (HaCaT: normal skin keratinocytes; A431: skin squamous carcinoma cells; SW480: colorectal cancer cells). We observed reduced concentration of succinate and increased concentration of citrate, 2-hydroxyglutarate, and glutamine in A431 cells as compared with HaCaT cells. On the other hand, decreased concentration of isocitrate, fumarate, and α-ketoglutarate and increased concentration of malate, glutamine, and glutamate in A431 cells were observed in comparison with SW480 cells. These findings suggested the possibility of identifying disease-specific metabolites and/or organ-specific metabolites by using this targeted metabolomic analysis.

Keywords:  Cancer; Energy metabolism; LC-MS; TCA cycle; Targeted metabolomics

DOI:  https://doi.org/10.1016/j.bbrc.2021.10.072
Cent Eur J Immunol. 2021 ;46(2): 258-263

Molecular aspects of pancreatic cancer: focus on reprogrammed metabolism in a nutrient-deficient environment and potential therapeutic targets.

Robert Słotwiński, Gustaw Lech, Sylwia Małgorzata Słotwińska.

  Pancreatic ductal adenocarcinoma (PDAC) is still burdened with high mortality (5-year survival rate < 9%) due to late diagnosis, aggressiveness, and a lack of more effective treatment methods. Early diagnosis and new therapeutic approaches based on the reprogrammed metabolism of the tumor in a nutrient-deficient environment are expected to improve the future treatment of PDAC patients. Research results suggest that genetic and metabolic disorders may precede the onset of neoplastic changes, which should allow for earlier appropriate treatment. Glycolysis and glutaminolysis are the most investigated pathways associated with the highest aggressiveness of pancreatic tumors. Blocking of selected metabolic pathways related to the local adaptive metabolic activity of pancreatic cancer cells improving nutrient acquisition and metabolic crosstalk within the microenvironment to sustain proliferation may inhibit cancer development, increase cancer cells death, and increase sensitivity to other forms of treatment (e.g., chemotherapy). Depriving cancer cells of important nutrients (glucose, glutamine) revealed tumor "checkpoints" for the mechanisms that drive cell proliferation and metastasis formation in order to determine its accuracy for individualization of the therapeutic approach. The present review highlights selected metabolic signaling pathways and their regulators aimed at inhibiting the neoplastic process. Particular attention has been paid to the adaptive metabolism of pancreatic cancer, which promotes its development in an oxygen-deficient and nutrient-poor environment.

Keywords:  pancreatic carcinoma; reprogrammed metabolism; therapeutic targets

DOI:  https://doi.org/10.5114/ceji.2021.107027
Mol Biol Rep. 2021 Nov 13.

The expression of glutamate metabolism modulators in the intracranial tumors and glioblastoma cell line.

Aysenur Akkulak, Düriye Nur Dağdelen, Abdullah Yalçın, Esin Oktay, Gülden Diniz, Dudu Solakoğlu Kahraman, Mehmet Şenoğlu, Gizem Donmez Yalcin.

   BACKGROUND: The accumulation of excess glutamate in the synapse leads to excitotoxicity, which is the underlying reason of neuronal death in intracranial tumors.
METHODS AND RESULTS: We identified the expression levels of glutamate dehydrogenase, glutamine synthetase and sirtuin 4 in U87 cell line and various intracranial tumors. mRNA expressions of glutamate dehydrogenase (GDH), glutamine synthetase (GS) and sirtuin 4 (SIRT4) were analyzed in various intracranial tumors using qPCR. GDH, GS and SIRT4 protein expressions were analyzed in glioblastoma (U87) and glial (IHA-immortalized human astrocytes) cell lines via western blotting. The protein expressions of SIRT4 and GS were shown to be elevated and GDH protein expression was reduced in U87 cells in comparison to IHA cells. All types of intracranial tumors displayed lower GS mRNA expressions compared to controls. SIRT4 mRNA expressions were also shown to be lower in all the tumors and grades, although not significantly. GDH mRNA expression was found to be similar in all groups.
CONCLUSION: The molecular mechanisms of glutamate metabolism and excitotoxicity should be discovered to develop therapies against intracranial tumors.

Keywords:  Excitotoxicity; Glioblastoma; Glutamate; Tumor

DOI:  https://doi.org/10.1007/s11033-021-06931-8
Front Oncol. 2021 ;11 757323

Alternative Energy: Breaking Down the Diverse Metabolic Features of Lung Cancers.

Kasey R Cargill, William L Hasken, Carl M Gay, Lauren A Byers.

  Metabolic reprogramming is a hallmark of cancer initiation, progression, and relapse. From the initial observation that cancer cells preferentially ferment glucose to lactate, termed the Warburg effect, to emerging evidence indicating that metabolic heterogeneity and mitochondrial metabolism are also important for tumor growth, the complex mechanisms driving cancer metabolism remain vastly unknown. These unique shifts in metabolism must be further investigated in order to identify unique therapeutic targets for individuals afflicted by this aggressive disease. Although novel therapies have been developed to target metabolic vulnerabilities in a variety of cancer models, only limited efficacy has been achieved. In particular, lung cancer metabolism has remained relatively understudied and underutilized for the advancement of therapeutic strategies, however recent evidence suggests that lung cancers have unique metabolic preferences of their own. This review aims to provide an overview of essential metabolic mechanisms and potential therapeutic agents in order to increase evidence of targeted metabolic inhibition for the treatment of lung cancer, where novel therapeutics are desperately needed.

Keywords:  glycolysis (Warburg effect); lung cancer; metabolic inhibitors; metabolism; oxidative phosphorylation

DOI:  https://doi.org/10.3389/fonc.2021.757323
Nat Metab. 2021 Nov 11.

Fibroblast pyruvate carboxylase is required for collagen production in the tumour microenvironment.

Simon Schwörer, Natalya N Pavlova, Francesco V Cimino, Bryan King, Xin Cai, Gina M Sizemore, Craig B Thompson.

The aberrant production of collagen by fibroblasts is a hallmark of many solid tumours and can influence cancer progression. How the mesenchymal cells in the tumour microenvironment maintain their production of extracellular matrix proteins as the vascular delivery of glutamine and glucose becomes compromised remains unclear. Here we show that pyruvate carboxylase (PC)-mediated anaplerosis in tumour-associated fibroblasts contributes to tumour fibrosis and growth. Using cultured mesenchymal and cancer cells, as well as mouse allograft models, we provide evidence that extracellular lactate can be utilized by fibroblasts to maintain tricarboxylic acid (TCA) cycle anaplerosis and non-essential amino acid biosynthesis through PC activity. Furthermore, we show that fibroblast PC is required for collagen production in the tumour microenvironment. These results establish TCA cycle anaplerosis as a determinant of extracellular matrix collagen production, and identify PC as a potential target to inhibit tumour desmoplasia.

DOI: https://doi.org/10.1038/s42255-021-00480-x
Immunity. 2021 Nov 03. pii: S1074-7613(21)00448-9. [Epub ahead of print]

MTHFD2 is a metabolic checkpoint controlling effector and regulatory T cell fate and function.

Ayaka Sugiura, Gabriela Andrejeva, Kelsey Voss, Darren R Heintzman, Xincheng Xu, Matthew Z Madden, Xiang Ye, Katherine L Beier, Nowrin U Chowdhury, Melissa M Wolf, Arissa C Young, Dalton L Greenwood, Allison E Sewell, Shailesh K Shahi, Samantha N Freedman, Alanna M Cameron, Patrik Foerch, Tim Bourne, Juan C Garcia-Canaveras, John Karijolich, Dawn C Newcomb, Ashutosh K Mangalam, Joshua D Rabinowitz, Jeffrey C Rathmell.

  Antigenic stimulation promotes T cell metabolic reprogramming to meet increased biosynthetic, bioenergetic, and signaling demands. We show that the one-carbon (1C) metabolism enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) regulates de novo purine synthesis and signaling in activated T cells to promote proliferation and inflammatory cytokine production. In pathogenic T helper-17 (Th17) cells, MTHFD2 prevented aberrant upregulation of the transcription factor FoxP3 along with inappropriate gain of suppressive capacity. MTHFD2 deficiency also promoted regulatory T (Treg) cell differentiation. Mechanistically, MTHFD2 inhibition led to depletion of purine pools, accumulation of purine biosynthetic intermediates, and decreased nutrient sensor mTORC1 signaling. MTHFD2 was also critical to regulate DNA and histone methylation in Th17 cells. Importantly, MTHFD2 deficiency reduced disease severity in multiple in vivo inflammatory disease models. MTHFD2 is thus a metabolic checkpoint to integrate purine metabolism with pathogenic effector cell signaling and is a potential therapeutic target within 1C metabolism pathways.

Keywords:  CD4(+) T cells; CRISPR screen; MTHFD2; T cell differentiation; inflammation; mTORC1; metabolic checkpoint; methylation; one carbon metabolism; purine metabolism

DOI:  https://doi.org/10.1016/j.immuni.2021.10.011
J Mol Graph Model. 2021 Nov 06. pii: S1093-3263(21)00245-X. [Epub ahead of print]110 108074

A comprehensive tool for accurate identification of methyl-Glutamine sites.

Sharaf J Malebary, Ebraheem Alzahrani, Yaser Daanial Khan.

  Methylation is a biochemical process involved in nearly all of the human body functions. Glutamine is considered an indispensable amino acid that is susceptible to methylation via post-translational modification (PTM). Modern research has proved that methylation plays a momentous role in the progression of most types of cancers. Therefore, there is a need for an effective method to predict glutamine sites vulnerable to methylation accurately and inexpensively. The motive of this study is the formulation of an accurate method that could predict such sites with high accuracy. Various computationally intelligent classifiers were employed for their formulation and evaluation. Rigorous validations prove that deep learning performs best as compared to other classifiers. The accuracy (ACC) and the area under the receiver operating curve (AUC) obtained by 10-fold cross-validation was 0.962 and 0.981, while with the jackknife testing, it was 0.968 and 0.980, respectively. From these results, it is concluded that the proposed methodology works sufficiently well for the prediction of methyl-glutamine sites. The webserver's code, developed for the prediction of methyl-glutamine sites, is freely available at https://github.com/s20181080001/WebServer.git. The code can easily be set up by any intermediate-level Python user.

Keywords:  Cross-validation; Jackknife testing; Methyl-glutamine; Methylation; Post-translational modification; Random forest; Statistical moments

DOI:  https://doi.org/10.1016/j.jmgm.2021.108074
Oncol Rep. 2022 Jan;pii: 11. [Epub ahead of print]47(1):

PIK3CA mutation affects the proliferation of colorectal cancer cells through the PI3K-MEK/PDK1-GPT2 pathway.

Wenli Chen, Guangli Dai, Yike Qian, Lian Wen, Xueqing He, Hui Liu, Yunxing Gao, Xingli Tang, Bohan Dong.

  The phosphatidylinositol‑3‑kinase catalytic subunit α (PIK3CA) gene is mutated in numerous human cancers. This mutation promotes the proliferation of tumor cells; however, the underlying mechanism is still not clear. In the present study, it was revealed that the PIK3CA mutation in colorectal cancer (CRC) HCT116 (MUT) rendered the cells more dependent on glutamine by regulating the glutamic‑pyruvate transaminase 2 (GPT2). The dependence of glutamine increased the proliferation of cells in a normal environment and resistance to a suboptimal environment. Further study revealed that the mutated PIK3CA could regulate GPT2 expression not only through signal transduction molecule 3‑phosphoinositide‑dependent kinase (PDK1) but also through mitogen‑activated protein kinase (MEK) molecules. In HCT116 cells, MEK inhibitor treatment could reduce the expression of GPT2 signaling molecules, thereby inhibiting the proliferation of CRC cells. A new signal transduction pathway, the PI3K/MEK/GPT2 pathway was identified. Based on these findings, MEK and PDK1 inhibitors were combined to inhibit the aforementioned pathway. It was revealed that the combined application of MEK and PDK1 inhibitors could promisingly inhibit the proliferation of MUT compared with the application of PI3K inhibitors, PDK1 inhibitors, or MEK inhibitors alone. In vivo, MEK inhibitors alone and combined inhibitors had stronger tumor‑suppressing effects. There was no significant difference between the PDK1‑inhibitor group and normal group in vivo. Thus, these results indicated that mutated PI3K affected GPT2 mediated by the MEK/PDK1 dual pathway, and that the PI3K/MEK/GPT2 pathway was more important in vivo. Inhibiting MEK and PDK1 concurrently could effectively inhibit the proliferation of CRC cells. Targeting the MEK and PDK1 signaling pathway may provide a novel strategy for the treatment of PIK3CA‑mutated CRC.

Keywords:  colorectal cancer; glutamine transaminase 2; mitogen‑activated protein kinase; mutation; phosphatidylinositol‑3‑kinase catalytic subunit α; proliferation

DOI:  https://doi.org/10.3892/or.2021.8222
MedComm (Beijing). 2020 Dec;1(3): 302-310

The biological role of metabolic reprogramming in pancreatic cancer.

Tatsunori Suzuki, Motoyuki Otsuka, Takahiro Seimiya, Takuma Iwata, Takahiro Kishikawa, Kazuhiko Koike.

  Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease and highly resistant to all forms of therapy. PDAC cells reprogram their metabolism extensively to promote their survival and growth. Reflecting the vital role of altered metabolism, experimental and clinical trials targeting the rewired metabolism are currently underway. In this review, we summarize the vital role of metabolic reprogramming in the development of PDAC and the future of novel therapeutic applications.

Keywords:  autophagy; macropinocytosis; metabolism; pancreatic cancer; tumor microenvironment

DOI:  https://doi.org/10.1002/mco2.37
Biochem Biophys Rep. 2021 Dec;28 101158

Unfolding the role of autophagy in the cancer metabolism.

Anchala Pandey, Pooja Yadav, Sanjeev Shukla.

  Autophagy is considered an indispensable process that scavenges toxins, recycles complex macromolecules, and sustains the essential cellular functions. In addition to its housekeeping role, autophagy plays a substantial role in many pathophysiological processes such as cancer. Certainly, it adapts cancer cells to thrive in the stress conditions such as hypoxia and starvation. Cancer cells indeed have also evolved by exploiting the autophagy process to fulfill energy requirements through the production of metabolic fuel sources and fundamentally altered metabolic pathways. Occasionally autophagy as a foe impedes tumorigenesis and promotes cell death. The complex role of autophagy in cancer makes it a potent therapeutic target and has been actively tested in clinical trials. Moreover, the versatility of autophagy has opened new avenues of effective combinatorial therapeutic strategies. Thereby, it is imperative to comprehend the specificity of autophagy in cancer-metabolism. This review summarizes the recent research and conceptual framework on the regulation of autophagy by various metabolic pathways, enzymes, and their cross-talk in the cancer milieu, including the implementation of altered metabolism and autophagy in clinically approved and experimental therapeutics.

Keywords:  Autophagy; Cancer; Hypoxia; Metabolism; Starvation; Therapeutics

DOI:  https://doi.org/10.1016/j.bbrep.2021.101158
Mol Metab. 2021 Nov 05. pii: S2212-8778(21)00240-4. [Epub ahead of print] 101389

Metabolic therapy and bioenergetic analysis: the missing piece of the puzzle.

Tomás Duraj, Josefa Carrión-Navarro, Thomas N Seyfried, Noemí García-Romero, Angel Ayuso-Sacido.

   BACKGROUND: Aberrant metabolism is recognized as a hallmark of cancer, a pillar necessary for proliferation. Regarding bioenergetics (ATP-generation), most cancers display a preference towards aerobic glycolysis ("Warburg effect") and glutaminolysis (mitochondrial substrate level-phosphorylation), but also other metabolites such as lactate, pyruvate, and fat-derived sources. These secondary metabolites can assist in proliferation but cannot fully cover ATP demands.
SCOPE OF REVIEW: The concept of a static metabolic profile is challenged by instances of heterogeneity and flexibility to meet fuel/anaplerotic demands. Although metabolic therapies are a promising tool to improve therapeutic outcomes, either via pharmacological targets or press-pulse interventions, metabolic plasticity is rarely considered. Lack of bioenergetic analysis in vitro and patient-derived models is hindering translational potential. Here, we review the bioenergetics of cancer and propose a simple analysis of major metabolic pathways, encompassing both affordable and advanced techniques. A comprehensive compendium of Seahorse XF bioenergetic measurements is presented for the first time.
MAJOR CONCLUSIONS: Standardization of principal readouts might help researchers collect a complete metabolic picture of cancer using the most appropriate methods depending on the sample of interest.

Keywords:  Cancer; Energy Metabolism; Glycolysis; Oxidative Phosphorylation; Research Design

DOI:  https://doi.org/10.1016/j.molmet.2021.101389
PeerJ. 2021 ;9 e12420

The predictive role of preoperative serum glutamate dehydrogenase levels in microvascular invasion and hepatocellular carcinoma prognosis following liver transplantation-a single center retrospective study.

Jinlong Gong, Yaxiong Li, Jia Yu, Tielong Wang, Jinliang Duan, Anbin Hu, Xiaoshun He, Xiaofeng Zhu.

   Background: As a critical metabolic substrate, glutamine is not only involved in the progression of many cancers but is also related to angiogenesis. Glutamate dehydrogenase (GLDH), a key enzyme in glutamine metabolism, has been reported to regulate tumor proliferation; however, its relationship with microvascular invasion (MVI) is unclear. This study evaluated the ability of preoperative serum GLDH levels to predict MVI and the long-term survival of hepatocellular carcinoma (HCC) patients after liver transplantation (LT).
Methods: HCC patients that underwent LT from January 2015 to May 2020 at the First Affiliated Hospital of Sun Yat-Sen University were enrolled in our retrospective analysis. Clinicopathological variables were extracted from medical records. A receiver operating characteristic curve was created to determine the optimal cut-off value of GLDH for MVI.
Results: Preoperative GLDH was significantly elevated in the MVI-positive group (U = 454.00, p = 0.000). The optimal cut-off value of GLDH for MVI was 7.45 U/L, with an area under the curve of 0.747 (95% CI [0.639-0.856], p = 0.000). The sensitivity was 79.3%, while the specificity was 64.5%. GLDH > 7.45 U/L (p = 0.023) and maximum diameter >5 cm (p = 0.001) were independent risk factors for the presence of MVI. Patients with GLDH > 7.45 U/L had significantly poorer overall survival (p = 0.001) and recurrence-free survival (p = 0.001) after LT than patients with GLDH ≤ 7.45 U/L. Similarly, patients with MVI were associated with poor survival (p = 0.000).
Conclusions: Preoperative elevated serum GLDH levels predict MVI and poorer long-term survival for HCC after LT.

Keywords:  Hepatocellular carcinoma; Liver transplantation; Microvascular invasion; glutamate dehydrogenase

DOI:  https://doi.org/10.7717/peerj.12420
Cancers (Basel). 2021 Oct 29. pii: 5447. [Epub ahead of print]13(21):

The Neglected Liaison: Targeting Cancer Cell Metabolic Reprogramming Modifies the Composition of Non-Malignant Populations of the Tumor Microenvironment.

Maria Iorio, Nikkitha Umesh Ganesh, Monica De Luise, Anna Maria Porcelli, Giuseppe Gasparre, Ivana Kurelac.

  Metabolic reprogramming is a well-known hallmark of cancer, whereby the development of drugs that target cancer cell metabolism is gaining momentum. However, when establishing preclinical studies and clinical trials, it is often neglected that a tumor mass is a complex system in which cancer cells coexist and interact with several types of microenvironment populations, including endothelial cells, fibroblasts and immune cells. We are just starting to understand how such populations are affected by the metabolic changes occurring in a transformed cell and little is known about the impact of metabolism-targeting drugs on the non-malignant tumor components. Here we provide a general overview of the links between cancer cell metabolism and tumor microenvironment (TME), particularly focusing on the emerging literature reporting TME-specific effects of metabolic therapies.

Keywords:  cancer metabolism; cancer-associated fibroblasts; metabolic reprogramming; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3390/cancers13215447
Int J Mol Sci. 2021 Oct 22. pii: 11427. [Epub ahead of print]22(21):

Functional Amino Acids and Autophagy: Diverse Signal Transduction and Application.

Chunchen Liu, Linbao Ji, Jinhua Hu, Ying Zhao, Lee J Johnston, Xiujun Zhang, Xi Ma.

  Functional amino acids provide great potential for treating autophagy-related diseases by regulating autophagy. The purpose of the autophagy process is to remove unwanted cellular contents and to recycle nutrients, which is controlled by many factors. Disordered autophagy has been reported to be associated with various diseases, such as cancer, neurodegeneration, aging, and obesity. Autophagy cannot be directly controlled and dynamic amino acid levels are sufficient to regulate autophagy. To date, arginine, leucine, glutamine, and methionine are widely reported functional amino acids that regulate autophagy. As a signal relay station, mammalian target of rapamycin complex 1 (mTORC1) turns various amino acid signals into autophagy signaling pathways for functional amino acids. Deficiency or supplementation of functional amino acids can immediately regulate autophagy and is associated with autophagy-related disease. This review summarizes the mechanisms currently involved in autophagy and amino acid sensing, diverse signal transduction among functional amino acids and autophagy, and the therapeutic appeal of amino acids to autophagy-related diseases. We aim to provide a comprehensive overview of the mechanisms of amino acid regulation of autophagy and the role of functional amino acids in clinical autophagy-related diseases and to further convert these mechanisms into feasible therapeutic applications.

Keywords:  autophagy; autophagy-related diseases; functional amino acids; mTORC1; signal transduction

DOI:  https://doi.org/10.3390/ijms222111427
Cancers (Basel). 2021 Nov 08. pii: 5575. [Epub ahead of print]13(21):

Autophagy in Cancer Therapy-Molecular Mechanisms and Current Clinical Advances.

Ingo Ganzleben, Markus F Neurath, Christoph Becker.

  Autophagy is a crucial general survival tactic of mammalian cells. It describes the capability of cells to disassemble and partially recycle cellular components (e.g., mitochondria) in case they are damaged and pose a risk to cell survival or simply if their resources are urgently needed elsewhere at the time. Autophagy-associated pathomechanisms have been increasingly recognized as important disease mechanisms in non-malignant (neurodegeneration, diffuse parenchymal lung disease) and malignant conditions alike. However, the overall consequences of autophagy for the organism depend particularly on the greater context in which autophagy occurs, such as the cell type or whether the cell is proliferating. In cancer, autophagy sustains cancer cell survival under challenging, i.e., resource-depleted, conditions. However, this leads to situations in which cancer cells are completely dependent on autophagy. Accordingly, autophagy represents a promising yet complex target in cancer treatment with therapeutically induced increase and decrease of autophagic flux as important therapeutic principles.

Keywords:  autophagy; cancer; glutamine; hydroxychloroquine; mitophagy; reverse Warburg effect

DOI:  https://doi.org/10.3390/cancers13215575
Cancers (Basel). 2021 Nov 05. pii: 5557. [Epub ahead of print]13(21):

The Key Role of the WNT/β-Catenin Pathway in Metabolic Reprogramming in Cancers under Normoxic Conditions.

Alexandre Vallée, Yves Lecarpentier, Jean-Noël Vallée.

  The canonical WNT/β-catenin pathway is upregulated in cancers and plays a major role in proliferation, invasion, apoptosis and angiogenesis. Nuclear β-catenin accumulation is associated with cancer. Hypoxic mechanisms lead to the activation of the hypoxia-inducible factor (HIF)-1α, promoting glycolytic and energetic metabolism and angiogenesis. However, HIF-1α is degraded by the HIF prolyl hydroxylase under normoxia, conditions under which the WNT/β-catenin pathway can activate HIF-1α. This review is therefore focused on the interaction between the upregulated WNT/β-catenin pathway and the metabolic processes underlying cancer mechanisms under normoxic conditions. The WNT pathway stimulates the PI3K/Akt pathway, the STAT3 pathway and the transduction of WNT/β-catenin target genes (such as c-Myc) to activate HIF-1α activity in a hypoxia-independent manner. In cancers, stimulation of the WNT/β-catenin pathway induces many glycolytic enzymes, which in turn induce metabolic reprogramming, known as the Warburg effect or aerobic glycolysis, leading to lactate overproduction. The activation of the Wnt/β-catenin pathway induces gene transactivation via WNT target genes, c-Myc and cyclin D1, or via HIF-1α. This in turn encodes aerobic glycolysis enzymes, including glucose transporter, hexokinase 2, pyruvate kinase M2, pyruvate dehydrogenase kinase 1 and lactate dehydrogenase-A, leading to lactate production. The increase in lactate production is associated with modifications to the tumor microenvironment and tumor growth under normoxic conditions. Moreover, increased lactate production is associated with overexpression of VEGF, a key inducer of angiogenesis. Thus, under normoxic conditions, overstimulation of the WNT/β-catenin pathway leads to modifications of the tumor microenvironment and activation of the Warburg effect, autophagy and glutaminolysis, which in turn participate in tumor growth.

Keywords:  HIF-1α; VEGF; WNT/β-catenin pathway; Warburg effect; aerobic glycolysis; angiogenesis; autophagy; cancer; glutaminolysis; lactate; metabolic reprogramming; normoxia

DOI:  https://doi.org/10.3390/cancers13215557