Metabolic Reprogramming in Gastric Cancer: Trojan Horse Effect

Worldwide, gastric cancer (GC) represents the fifth most common cancer for incidence and the third leading cause of death in developed countries. Despite the development of combination chemotherapies, the survival rates of GC patients remain unsatisfactory. The reprogramming of energy metabolism is a hallmark of cancer, especially increased dependence on aerobic glycolysis. In the present review, we summarized current evidence on how metabolic reprogramming in GC targets the tumor microenvironment, modulates metabolic networks and overcomes drug resistance. Preclinical and clinical studies on the combination of metabolic reprogramming targeted agents and conventional chemotherapeutics or molecularly targeted treatments [including vascular endothelial growth factor receptor (VEGFR) and HER2] and the value of biomarkers are examined. This deeper understanding of the molecular mechanisms underlying successful pharmacological combinations is crucial in finding the best-personalized treatment regimens for cancer patients.

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Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer

Cells ◽

10.3390/cells10071715 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1715

Author(s):

Macus Hao-Ran Bao ◽

Carmen Chak-Lui Wong

Keyword(s):

Hepatocellular Carcinoma ◽

Drug Resistance ◽

Liver Cancer ◽

Effective Treatment ◽

Molecular Mechanisms ◽

Hypoxia Inducible Factor ◽

Metabolic Reprogramming ◽

Combination Therapies ◽

Low Oxygen ◽

Treatment Regimens

Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.

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A Metabolic Choreography of Maize Plants Treated with a Humic Substance-Based Biostimulant under Normal and Starved Conditions

Metabolites ◽

10.3390/metabo11060403 ◽

2021 ◽

Vol 11 (6) ◽

pp. 403

Author(s):

Kgalaletso Othibeng ◽

Lerato Nephali ◽

Anza-Tshilidzi Ramabulana ◽

Paul Steenkamp ◽

Daniel Petras ◽

...

Keyword(s):

Humic Substance ◽

Metabolic Networks ◽

Molecular Mechanisms ◽

Plant Cell Wall ◽

Growth Promotion ◽

Redox Homeostasis ◽

Metabolic Reprogramming ◽

Sustainable Food ◽

Crop Development ◽

Maize Plants

Humic substance (HS)-based biostimulants show potentials as sustainable strategies for improved crop development and stress resilience. However, cellular and molecular mechanisms governing the agronomically observed effects of HS on plants remain enigmatic. Here, we report a global metabolic reprogramming of maize leaves induced by a humic biostimulant under normal and nutrient starvation conditions. This reconfiguration of the maize metabolism spanned chemical constellations, as revealed by molecular networking approaches. Plant growth and development under normal conditions were characterized by key differential metabolic changes such as increased levels of amino acids, oxylipins and the tricarboxylic acid (TCA) intermediate, isocitric acid. Furthermore, under starvation, the humic biostimulant significantly impacted pathways that are involved in stress-alleviating mechanisms such as redox homeostasis, strengthening of the plant cell wall, osmoregulation, energy production and membrane remodelling. Thus, this study reveals that the humic biostimulant induces a remodelling of inter-compartmental metabolic networks in maize, subsequently readjusting the plant physiology towards growth promotion and stress alleviation. Such insights contribute to ongoing efforts in elucidating modes of action of biostimulants, generating fundamental scientific knowledge that is necessary for development of the biostimulant industry, for sustainable food security.

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PKM2 Is the Target of a Multi-Herb-Combined Decoction During the Inhibition of Gastric Cancer Progression

Frontiers in Oncology ◽

10.3389/fonc.2021.767116 ◽

2021 ◽

Vol 11 ◽

Author(s):

Qingmin Sun ◽

Mengyun Yuan ◽

Hongxing Wang ◽

Xingxing Zhang ◽

Ruijuan Zhang ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Cancer Metastasis ◽

Nuclear Translocation ◽

Aerobic Glycolysis ◽

Metabolic Reprogramming ◽

Migration And Invasion ◽

Dependent Manner ◽

Gastric Cancer Cells ◽

Mesenchymal Transition

Gastric cancer is the third leading cause of cancer death worldwide. Traditional Chinese medicine (TCM) is increasingly extensively applied as a complementary therapy for gastric cancer (GC) in China, which shows unique advantages in preventing gastric cancer metastasis. Previous study indicates modified Jian-pi-yang-zheng (mJPYZ) decoction inhibit the progression of gastric cancer by regulating tumor-associated macrophages (TAM). However, it is unclear whether mJPYZ can affect metabolic reprogramming of gastric cancer cells. Here, we showed that mJPYZ effectively attenuated GC cells proliferation, migration and invasion. Meantime, mJPYZ reduced the aerobic glycolysis level of GC cells in vivo and in vitro by regulating the expression and nuclear translocation of PKM2. Overexpression of PKM2 that could reverse the inhibitory effect of mJPYZ, migration and epithelial to mesenchymal transition (EMT). Our results showed PKM2/HIF-1α signaling was the key metabolic regulator of mJPYZ in GC cells. In summary, our present study suggested that abnormal PKM2 is required for maintaining the malignant phenotype of GC cells. The TCM decoction mJPYZ inhibited GC cells growth and EMT by reducing of glycolysis in PKM2 dependent manner. This evidence expanded our understanding of the anti-tumor mechanism of mJPYZ and further indicated mJPYZ a potential anti-tumor agent for GC patients.Chemical Compounds Studied in this ArticleRutin (PubChem CID: 5280805); Lobetyolin (PubChem CID: 53486204); Calycosin-7-glucoside (PubChem CID: 71571502); Formononetin (PubChem CID: 5280378); Calycosin (PubChem CID: 5280448); Ononin (PubChem CID: 442813); P-Coumaric Acid (PubChem CID: 637542).

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Study of Human Epidermal Growth Factor Receptor 2 (HER2) Expression in Gastric Carcinoma

Journal of Evidence Based Medicine and Healthcare ◽

10.18410/jebmh/2020/564 ◽

2020 ◽

Vol 7 (47) ◽

pp. 2747-2751

Author(s):

Lekshmi Vijayakumaran Nair Lilly ◽

Geetha Sukumaran

Keyword(s):

Gastric Cancer ◽

Growth Factor ◽

Gastric Carcinoma ◽

Survival Rates ◽

Growth Factor Receptor ◽

Intestinal Type ◽

Treatment Modalities ◽

Her2 Overexpression ◽

Her2 Expression ◽

Her2 Positive

BACKGROUND Gastric carcinoma is an important cause of cancer related mortality worldwide. Majority of the patients are diagnosed in the advanced stage of the disease. The main treatment modalities are surgery and chemotherapy, but the survival rate of patients with advanced resectable gastric cancer remains poor. For patients with unresectable gastric cancer, chemotherapy remains the treatment of choice. Into this scenario comes the importance of newer targeted therapeutic agents which improve survival rates with acceptable toxicity effects. HER2 is a growth factor implicated in disease initiation and progression, and its expression is associated with a poor prognosis. The aim of this study is detection of HER2 expression in gastric carcinoma and evaluate its relationship with the histopathological characteristics. This would be the stepping stone for patients with tumours that are HER2 positive who could benefit from targeted therapeutical agents like Trastuzumab. METHODS Gastrectomy specimens which were diagnosed as Gastric Carcinoma in the Department of Pathology, Government Medical College, Trivandrum, during a period of two years were included in this study. Routine Haematoxylin and Eosin staining and immunohistochemistry for HER2 were done. RESULTS Thirty eight cases of gastric carcinoma were received during the study period. Intestinal type adenocarcinoma formed the bulk of the tumours (68.42 %), followed by the diffuse type adenocarcinoma (18.42 %). Of the 38 cases, 10 cases showed HER2 positivity. All the positive cases were intestinal type of adenocarcinomas. CONCLUSIONS Our study concluded that 26 % of gastric carcinomas showed positive immunoreaction for HER2 and HER2 overexpression was more in intestinal type adenocarcinomas. HER2 overexpression was also associated with higher stage tumours. There was no association with the patient’s age, gender, location of tumour and tumour differentiation. KEYWORDS Gastric Carcinoma, HER2 expression, Immunohistochemistry, Lauren Classification

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Linking Cancer Stem Cell Plasticity to Therapeutic Resistance-Mechanism and Novel Therapeutic Strategies in Esophageal Cancer

Cells ◽

10.3390/cells9061481 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1481

Author(s):

Chenghui Zhou ◽

Ningbo Fan ◽

Fanyu Liu ◽

Nan Fang ◽

Patrick S. Plum ◽

...

Keyword(s):

Esophageal Cancer ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Resistance Mechanism ◽

Therapy Resistance ◽

Metabolic Reprogramming ◽

Current Evidence ◽

Mesenchymal Transition ◽

Therapeutic Implications

Esophageal cancer (EC) is an aggressive form of cancer, including squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) as two predominant histological subtypes. Accumulating evidence supports the existence of cancer stem cells (CSCs) able to initiate and maintain EAC or ESCC. In this review, we aim to collect the current evidence on CSCs in esophageal cancer, including the biomarkers/characterization strategies of CSCs, heterogeneity of CSCs, and the key signaling pathways (Wnt/β-catenin, Notch, Hedgehog, YAP, JAK/STAT3) in modulating CSCs during esophageal cancer progression. Exploring the molecular mechanisms of therapy resistance in EC highlights DNA damage response (DDR), metabolic reprogramming, epithelial mesenchymal transition (EMT), and the role of the crosstalk of CSCs and their niche in the tumor progression. According to these molecular findings, potential therapeutic implications of targeting esophageal CSCs may provide novel strategies for the clinical management of esophageal cancer.

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Prospects for NK Cell Therapy of Sarcoma

Cancers ◽

10.3390/cancers12123719 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3719

Author(s):

Mieszko Lachota ◽

Marianna Vincenti ◽

Magdalena Winiarska ◽

Kjetil Boye ◽

Radosław Zagożdżon ◽

...

Keyword(s):

Nk Cells ◽

Molecular Mechanisms ◽

Cell Function ◽

Nk Cell ◽

Immune Surveillance ◽

Current Treatment ◽

Lymphoid Cells ◽

Current Evidence ◽

Treatment Regimens ◽

Novel Therapeutic Strategies

Natural killer (NK) cells are innate lymphoid cells with potent antitumor activity. One of the most NK cell cytotoxicity-sensitive tumor types is sarcoma, an aggressive mesenchyme-derived neoplasm. While a combination of radical surgery and radio- and chemotherapy can successfully control local disease, patients with advanced sarcomas remain refractory to current treatment regimens, calling for novel therapeutic strategies. There is accumulating evidence for NK cell-mediated immunosurveillance of sarcoma cells during all stages of the disease, highlighting the potential of using NK cells as a therapeutic tool. However, sarcomas display multiple immunoevasion mechanisms that can suppress NK cell function leading to an uncontrolled tumor outgrowth. Here, we review the current evidence for NK cells’ role in immune surveillance of sarcoma during disease initiation, promotion, progression, and metastasis, as well as the molecular mechanisms behind sarcoma-mediated NK cell suppression. Further, we apply this basic understanding of NK–sarcoma crosstalk in order to identify and summarize the most promising candidates for NK cell-based sarcoma immunotherapy.

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MiR-365a-3p-Mediated Regulation of HELLS/GLUT1 Axis Suppresses Aerobic Glycolysis and Gastric Cancer Growth

Frontiers in Oncology ◽

10.3389/fonc.2021.616390 ◽

2021 ◽

Vol 11 ◽

Author(s):

Rui Yang ◽

Gen Liu ◽

Limin Han ◽

Yuheng Qiu ◽

Lulin Wang ◽

...

Keyword(s):

Gastric Cancer ◽

Poor Prognosis ◽

Bioinformatics Analysis ◽

Aerobic Glycolysis ◽

Metabolic Reprogramming ◽

Cancer Growth ◽

The Novel ◽

The Third ◽

Cycle Arrest ◽

Glycolytic Activity

Gastric cancer (GC) is a common and invasive malignancy, which lacks effective treatment and is the third main reason of cancer death. Metabolic reprogramming is one of the main reasons that GC is difficult to treat in various environments. Particularly, abnormal glycolytic activity is the most common way of metabolism reprogramming in cancer cells. Numerous studies have shown that microRNAs play important roles in reprogramming glucose metabolism. Here, we found a microRNA-miR-365a-3p, was significantly downregulated in GC according to bioinformatics analysis. Low expression of miR-365a-3p correlated with poor prognosis of GC patients. Overexpression of miR-365a-3p in GC cells significantly inhibited cell proliferation by inducing cell cycle arrest at G1 phase. Notably, miR-365a-3p induced downregulation of HELLS through binding to its 3′ untranslated region (UTR). Additionally, we found that miR-365a-3p suppressed aerobic glycolysis by inhibiting HELLS/GLUT1 axis. Lastly, we shown that overexpression of miR-365a-3p significantly inhibited tumor growth in nude mice. Conversely, Reconstituted the expression of HELLS rescued the suppressive effects of miR-365a-3p. Our data collectively indicated that miR-365a-3p functioned as a tumor suppressor in GC through downregulating HELLS. Therefore, targeting of the novel miR-365a-3p/HELLS axis could be a potentially effective therapeutic approach for GC.

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Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells

Cells ◽

10.3390/cells9112423 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2423

Author(s):

Jacopo Albanesi ◽

Nelida Ines Noguera ◽

Cristina Banella ◽

Tommaso Colangelo ◽

Elisabetta De Marinis ◽

...

Keyword(s):

Acute Promyelocytic Leukemia ◽

Molecular Mechanisms ◽

Immune Cell ◽

Aerobic Glycolysis ◽

Therapy Resistance ◽

Therapeutic Strategies ◽

Promyelocytic Leukemia ◽

Metabolic Reprogramming ◽

Granulocytic Differentiation ◽

Nb4 Cells

Acute promyelocytic leukemia (APL) is a hematological disease characterized by a balanced reciprocal translocation that leads to the synthesis of the oncogenic fusion protein PML-RARα. APL is mainly managed by a differentiation therapy based on the administration of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, therapy resistance, differentiation syndrome, and relapses require the development of new low-toxicity therapies based on the induction of blasts differentiation. In keeping with this, we reasoned that a better understanding of the molecular mechanisms pivotal for ATRA-driven differentiation could definitely bolster the identification of new therapeutic strategies in APL patients. We thus performed an in-depth high-throughput transcriptional profile analysis and metabolic characterization of a well-established APL experimental model based on NB4 cells that represent an unevaluable tool to dissect the complex mechanism associated with ATRA-induced granulocytic differentiation. Pathway-reconstruction analysis using genome-wide transcriptional data has allowed us to identify the activation/inhibition of several cancer signaling pathways (e.g., inflammation, immune cell response, DNA repair, and cell proliferation) and master regulators (e.g., transcription factors, epigenetic regulators, and ligand-dependent nuclear receptors). Furthermore, we provide evidence of the regulation of a considerable set of metabolic genes involved in cancer metabolic reprogramming. Consistently, we found that ATRA treatment of NB4 cells drives the activation of aerobic glycolysis pathway and the reduction of OXPHOS-dependent ATP production. Overall, this study represents an important resource in understanding the molecular “portfolio” pivotal for APL differentiation, which can be explored for developing new therapeutic strategies.

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Saponin-Rich Extracts and Their Acid Hydrolysates Differentially Target Colorectal Cancer Metabolism in the Frame of Precision Nutrition

Cancers ◽

10.3390/cancers12113399 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3399

Author(s):

Marta Gómez de Cedrón ◽

Joaquín Navarro del Hierro ◽

Marina Reguero ◽

Sonia Wagner ◽

Adrián Bouzas ◽

...

Keyword(s):

Colorectal Cancer ◽

Lipid Metabolism ◽

Molecular Mechanisms ◽

Cancer Metabolism ◽

Therapeutic Potential ◽

Biological Activities ◽

Aerobic Glycolysis ◽

Metabolic Reprogramming ◽

Specific Subgroup ◽

Bioactive Agents

Saponins or their aglycone form, sapogenin, have recently gained interest as bioactive agents due to their biological activities, their antitumoral effects being among them. Metabolic reprogramming has been recognized as a hallmark of cancer and, together with the increased aerobic glycolysis and glutaminolysis, the altered lipid metabolism is considered crucial to support cancer initiation and progression. The purpose of this study was to assess and compare the inhibitory effects on colorectal cancer cell lines of saponin-rich extracts from fenugreek and quinoa (FE and QE, respectively) and their hydrolyzed extracts as sapogenin-rich extracts (HFE and HQE, respectively). By mean of the latest technology in the analysis of cell bioenergetics, we demonstrate that FE and HFE diminished mitochondrial oxidative phosphorylation and aerobic glycolysis; meanwhile, quinoa extracts did not show relevant activities. Distinct molecular mechanisms were identified for fenugreek: FE inhibited the expression of TYMS1 and TK1, synergizing with the chemotherapeutic drug 5-fluorouracil (5-FU); meanwhile, HFE inhibited lipid metabolism targets, leading to diminished intracellular lipid content. The relevance of considering the coexisting compounds of the extracts or their hydrolysis transformation as innovative strategies to augment the therapeutic potential of the extracts, and the specific subgroup of patients where each extract would be more beneficial, are discussed in the frame of precision nutrition.

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Regulation of Immune Cell Functions by Metabolic Reprogramming

Journal of Immunology Research ◽

10.1155/2018/8605471 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 16

Author(s):

Jaehong Kim

Keyword(s):

T Cells ◽

Immune Cells ◽

Molecular Mechanisms ◽

Immune Cell ◽

Aerobic Glycolysis ◽

Metabolic Changes ◽

Metabolic Reprogramming ◽

Functional Plasticity ◽

Inflammatory Reactions ◽

Cell Functions

Recent findings show that the metabolic status of immune cells can determine immune responses. Metabolic reprogramming between aerobic glycolysis and oxidative phosphorylation, previously speculated as exclusively observable in cancer cells, exists in various types of immune and stromal cells in many different pathological conditions other than cancer. The microenvironments of cancer, obese adipose, and wound-repairing tissues share common features of inflammatory reactions. In addition, the metabolic changes in macrophages and T cells are now regarded as crucial for the functional plasticity of the immune cells and responsible for the progression and regression of many pathological processes, notably cancer. It is possible that metabolic changes in the microenvironment induced by other cellular components are responsible for the functional plasticity of immune cells. This review explores the molecular mechanisms responsible for metabolic reprogramming in macrophages and T cells and also provides a summary of recent updates with regard to the functional modulation of the immune cells by metabolic changes in the microenvironment, notably the tumor microenvironment.

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