Targeting Cellular Metabolism Modulates Head and Neck Oncogenesis

Considering the great energy and biomass demand for cell survival, cancer cells exhibit unique metabolic signatures compared to normal cells. Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent neoplasms worldwide. Recent findings have shown that environmental challenges, as well as intrinsic metabolic manipulations, could modulate HNSCC experimentally and serve as clinic prognostic indicators, suggesting that a better understanding of dynamic metabolic changes during HNSCC development could be of great benefit for developing adjuvant anti-cancer schemes other than conventional therapies. However, the following questions are still poorly understood: (i) how does metabolic reprogramming occur during HNSCC development? (ii) how does the tumorous milieu contribute to HNSCC tumourigenesis? and (iii) at the molecular level, how do various metabolic cues interact with each other to control the oncogenicity and therapeutic sensitivity of HNSCC? In this review article, the regulatory roles of different metabolic pathways in HNSCC and its microenvironment in controlling the malignancy are therefore discussed in the hope of providing a systemic overview regarding what we knew and how cancer metabolism could be translated for the development of anti-cancer therapeutic reagents.

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Phytochemicals targeting metabolic reprogramming in cancer: an assessment of role, mechanisms, pathways and therapeutic relevance

10.22541/au.160684227.70170021/v1 ◽

2020 ◽

Author(s):

Asifa Khan ◽

Shumaila Siddiqui ◽

Syed Husain ◽

Sybille Mazurek ◽

Mohammad Askandar Iqbal

Keyword(s):

Metabolic Pathways ◽

Cancer Metabolism ◽

Therapeutic Benefit ◽

Metabolic Reprogramming ◽

Normal Cells ◽

Cancer Hallmarks ◽

Metabolic Transformation ◽

Regulation Of Growth ◽

Diverse Plant

The metabolism of cancer is remarkably different from that of normal cells and confers variety of benefits including the promotion of other cancer hallmarks. As the rewired metabolism is a near-universal property of cancer cells, efforts are underway to exploit metabolic vulnerabilities for therapeutic benefit. In the continued search for a safer and effective ways of cancer treatment, structurally diverse plant-based compounds have gained substantial attention. Here, we present an extensive assessment of the role of phytocompounds in modulating cancer metabolism and make a case for the use of plant-based compounds in targeting metabolic vulnerabilities of cancer. We discuss the interactions of phytocompounds with major metabolic pathways and evaluate the role of phytochemicals in the regulation of growth signaling and transcriptional programs involved in metabolic transformation of cancer. Lastly, we examine the potential of these compounds in clinical management of cancer along with limitations and challenges

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Metabolic Anti-Cancer Effects of Melatonin: Clinically Relevant Prospects

Cancers ◽

10.3390/cancers13123018 ◽

2021 ◽

Vol 13 (12) ◽

pp. 3018

Author(s):

Marek Samec ◽

Alena Liskova ◽

Lenka Koklesova ◽

Kevin Zhai ◽

Elizabeth Varghese ◽

...

Keyword(s):

Cancer Metabolism ◽

Glucose Transporter ◽

Aerobic Glycolysis ◽

Cell Metabolism ◽

Lactate Production ◽

Pentose Phosphate ◽

Metabolic Reprogramming ◽

Effective Prevention ◽

Anti Cancer ◽

Glucose 6 Phosphate Dehydrogenase

Metabolic reprogramming characterized by alterations in nutrient uptake and critical molecular pathways associated with cancer cell metabolism represents a fundamental process of malignant transformation. Melatonin (N-acetyl-5-methoxytryptamine) is a hormone secreted by the pineal gland. Melatonin primarily regulates circadian rhythms but also exerts anti-inflammatory, anti-depressant, antioxidant and anti-tumor activities. Concerning cancer metabolism, melatonin displays significant anticancer effects via the regulation of key components of aerobic glycolysis, gluconeogenesis, the pentose phosphate pathway (PPP) and lipid metabolism. Melatonin treatment affects glucose transporter (GLUT) expression, glucose-6-phosphate dehydrogenase (G6PDH) activity, lactate production and other metabolic contributors. Moreover, melatonin modulates critical players in cancer development, such as HIF-1 and p53. Taken together, melatonin has notable anti-cancer effects at malignancy initiation, progression and metastasing. Further investigations of melatonin impacts relevant for cancer metabolism are expected to create innovative approaches supportive for the effective prevention and targeted therapy of cancers.

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Targeting Cancer Metabolism to Resensitize Chemotherapy: Potential Development of Cancer Chemosensitizers from Traditional Chinese Medicines

Cancers ◽

10.3390/cancers12020404 ◽

2020 ◽

Vol 12 (2) ◽

pp. 404 ◽

Cited By ~ 6

Author(s):

Guo ◽

Tan ◽

Chen ◽

Wang ◽

Feng

Keyword(s):

Chinese Medicine ◽

Cancer Therapy ◽

Traditional Chinese Medicine ◽

Cancer Cells ◽

Metabolic Pathways ◽

Cancer Metabolism ◽

Metabolic Reprogramming ◽

Traditional Chinese Medicines ◽

Chinese Medicines ◽

Incidence And Mortality

Cancer is a common and complex disease with high incidence and mortality rates, which causes a severe public health problem worldwide. As one of the standard therapeutic approaches for cancer therapy, the prognosis and outcome of chemotherapy are still far from satisfactory due to the severe side effects and increasingly acquired resistance. The development of novel and effective treatment strategies to overcome chemoresistance is urgent for cancer therapy. Metabolic reprogramming is one of the hallmarks of cancer. Cancer cells could rewire metabolic pathways to facilitate tumorigenesis, tumor progression, and metastasis, as well as chemoresistance. The metabolic reprogramming may serve as a promising therapeutic strategy and rekindle the research enthusiasm for overcoming chemoresistance. This review focuses on emerging mechanisms underlying rewired metabolic pathways for cancer chemoresistance in terms of glucose and energy, lipid, amino acid, and nucleotide metabolisms, as well as other related metabolisms. In particular, we highlight the potential of traditional Chinese medicine as a chemosensitizer for cancer chemotherapy from the metabolic perspective. The perspectives of metabolic targeting to chemoresistance are also discussed. In conclusion, the elucidation of the underlying metabolic reprogramming mechanisms by which cancer cells develop chemoresistance and traditional Chinese medicines resensitize chemotherapy would provide us a new insight into developing promising therapeutics and scientific evidence for clinical use of traditional Chinese medicine as a chemosensitizer for cancer therapy.

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Targeting T cell metabolism in the tumor microenvironment: an anti-cancer therapeutic strategy

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1409-3 ◽

2019 ◽

Vol 38 (1) ◽

Cited By ~ 18

Author(s):

Zhongping Yin ◽

Ling Bai ◽

Wei Li ◽

Tanlun Zeng ◽

Huimin Tian ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Microenvironment ◽

Metabolic Pathways ◽

Cell Metabolism ◽

Basic Research ◽

Metabolic Reprogramming ◽

Activated T Cells ◽

Cell Functions ◽

Anti Cancer

Abstract T cells play important roles in anti-tumor immunity. Emerging evidence has revealed that distinct metabolic changes impact the activation and differentiation of T cells. Tailoring immune responses by manipulating cellular metabolic pathways and the identification of new targets may provide new options for cancer immunotherapy. In this review, we focus on recent advances in the metabolic reprogramming of different subtypes of T cells and T cell functions. We summarize how metabolic pathways accurately regulate T cell development, differentiation, and function in the tumor microenvironment. Because of the similar metabolism in activated T cells and tumor cells, we also describe the effect of the tumor microenvironment on T cell metabolism reprogramming, which may provide strategies for maximal anti-cancer effects and enhancing the immunity of T cells. Thus, studies of T lymphocyte metabolism can not only facilitate the basic research of immune metabolism, but also provide potential targets for drug development and new strategies for clinical treatment of cancer.

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Wnt Signaling in Cancer Metabolism and Immunity

Cancers ◽

10.3390/cancers11070904 ◽

2019 ◽

Vol 11 (7) ◽

pp. 904 ◽

Cited By ~ 23

Author(s):

Sara El-Sahli ◽

Ying Xie ◽

Lisheng Wang ◽

Sheng Liu

Keyword(s):

Wnt Signaling ◽

Cancer Cells ◽

Cancer Metabolism ◽

Metabolic Reprogramming ◽

Tumor Initiating Cells ◽

Tumor Plasticity ◽

Anti Cancer ◽

Wnt Ligands ◽

Canonical Wnt

The Wingless (Wnt)/β-catenin pathway has long been associated with tumorigenesis, tumor plasticity, and tumor-initiating cells called cancer stem cells (CSCs). Wnt signaling has recently been implicated in the metabolic reprogramming of cancer cells. Aberrant Wnt signaling is considered to be a driver of metabolic alterations of glycolysis, glutaminolysis, and lipogenesis, processes essential to the survival of bulk and CSC populations. Over the past decade, the Wnt pathway has also been shown to regulate the tumor microenvironment (TME) and anti-cancer immunity. Wnt ligands released by tumor cells in the TME facilitate the immune evasion of cancer cells and hamper immunotherapy. In this review, we illustrate the role of the canonical Wnt/β-catenin pathway in cancer metabolism and immunity to explore the potential therapeutic approach of targeting Wnt signaling from a metabolic and immunological perspective.

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Systematic investigation of metabolic reprogramming in different cancers based on tissue-specific metabolic models

Journal of Bioinformatics and Computational Biology ◽

10.1142/s0219720016440017 ◽

2016 ◽

Vol 14 (05) ◽

pp. 1644001 ◽

Cited By ~ 3

Author(s):

Fangzhou Shen ◽

Jian Li ◽

Ying Zhu ◽

Zhuo Wang

Keyword(s):

Renal Cancer ◽

Drug Targets ◽

Metabolic Flux ◽

Cancer Metabolism ◽

Metabolic Model ◽

Systematic Investigation ◽

Metabolic Reprogramming ◽

Measurement Technology ◽

Normal Cells ◽

Tissue Specific

Cancer cells have different metabolism in contrast to normal cells. The advancement in omics measurement technology enables the genome-wide characterization of altered cellular processes in cancers, but the metabolic flux landscape of cancer is still far from understood. In this study, we compared the well-reconstructed tissue-specific models of five cancers, including breast, liver, lung, renal, and urothelial cancer, and their corresponding normal cells. There are similar patterns in majority of significantly regulated pathways and enriched pathways in correlated reaction sets. But the differences among cancers are also explicit. The renal cancer demonstrates more dramatic difference with other cancer models, including the smallest number of reactions, flux distribution patterns, and specifically correlated pathways. We also validated the predicted essential genes and revealed the Warburg effect by in silico simulation in renal cancer, which are consistent with the measurements for renal cancer. In conclusion, the tissue-specific metabolic model is more suitable to investigate the cancer metabolism. The similarity and heterogenicity of metabolic reprogramming in different cancers are crucial for understanding the aberrant mechanisms of cancer proliferation, which is fundamental for identifying drug targets and biomarkers.

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Macrosphelide A Exhibits a Specific Anti-Cancer Effect by Simultaneously Inactivating ENO1, ALDOA, and FH

Pharmaceuticals ◽

10.3390/ph14101060 ◽

2021 ◽

Vol 14 (10) ◽

pp. 1060

Author(s):

Kyoung Song ◽

Nirmal Rajasekaran ◽

Chaithanya Chelakkot ◽

Hunseok Lee ◽

Seungmann Paek ◽

...

Keyword(s):

Cancer Cells ◽

Warburg Effect ◽

Cancer Metabolism ◽

Aerobic Glycolysis ◽

Fumarate Hydratase ◽

Metabolic Adaptation ◽

Normal Cells ◽

Target Proteins ◽

Anti Cancer ◽

The Warburg Effect

Aerobic glycolysis in cancer cells, also known as the Warburg effect, is an indispensable hallmark of cancer. This metabolic adaptation of cancer cells makes them remarkably different from normal cells; thus, inhibiting aerobic glycolysis is an attractive strategy to specifically target tumor cells while sparing normal cells. Macrosphelide A (MSPA), an organic small molecule, is a potential lead compound for the design of anti-cancer drugs. However, its role in modulating cancer metabolism remains poorly understood. MSPA target proteins were screened using mass spectrometry proteomics combined with affinity chromatography. Direct and specific interactions of MSPA with its candidate target proteins were confirmed by in vitro binding assays, competition assays, and simulation modeling. The siRNA-based knockdown of MSPA target proteins indirectly confirmed the cytotoxic effect of MSPA in HepG2 and MCF-7 cancer cells. In addition, we showed that MSPA treatment in the HEPG2 cell line significantly reduced glucose consumption and lactate release. MSPA also inhibited cancer cell proliferation and induced apoptosis by inhibiting critical enzymes involved in the Warburg effect: aldolase A (ALDOA), enolase 1 (ENO1), and fumarate hydratase (FH). Among these enzymes, the purified ENO1 inhibitory potency of MSPA was further confirmed to demonstrate the direct inhibition of enzyme activity to exclude indirect/secondary factors. In summary, MSPA exhibits anti-cancer effects by simultaneously targeting ENO1, ALDOA, and FH.

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Metabolic Reprogramming of Cancer by Chemicals that Target Glutaminase Isoenzymes

Current Medicinal Chemistry ◽

10.2174/0929867326666190416165004 ◽

2020 ◽

Vol 27 (32) ◽

pp. 5317-5339 ◽

Cited By ~ 3

Author(s):

José M. Matés ◽

José A. Campos-Sandoval ◽

Juan de los Santos-Jiménez ◽

Juan A. Segura ◽

Francisco J. Alonso ◽

...

Keyword(s):

Metabolic Pathways ◽

Cancer Metabolism ◽

Expression Patterns ◽

Therapeutic Agents ◽

Tumour Suppressor ◽

Metabolic Reprogramming ◽

Glutamine Metabolism ◽

Tumour Suppressor Genes ◽

Suppressor Factor ◽

Functional Roles

Background: Metabolic reprogramming of tumours is a hallmark of cancer. Among the changes in the metabolic network of cancer cells, glutaminolysis is a key reaction altered in neoplasms. Glutaminase proteins control the first step in glutamine metabolism and their expression correlates with malignancy and growth rate of a great variety of cancers. The two types of glutaminase isoenzymes, GLS and GLS2, differ in their expression patterns and functional roles: GLS has oncogenic properties and GLS2 has been described as a tumour suppressor factor. Results: We have focused on glutaminase connections with key oncogenes and tumour suppressor genes. Targeting glutaminase isoenzymes includes different strategies aimed at deactivating the rewiring of cancer metabolism. In addition, we found a long list of metabolic enzymes, transcription factors and signalling pathways dealing with glutaminase. On the other hand, a number of chemicals have been described as isoenzyme-specific inhibitors of GLS and/or GLS2 isoforms. These molecules are being characterized as synergic and therapeutic agents in many types of tumours. Conclusion: This review states the metabolic pathways that are rewired in cancer, the roles of glutaminase isoforms in cancer, as well as the metabolic circuits regulated by glutaminases. We also show the plethora of anticancer drugs that specifically inhibit glutaminase isoenzymes for treating several sets of cancer.

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Glucose Metabolism and Oxidative Stress in Hepatocellular Carcinoma: Role and Possible Implications in Novel Therapeutic Strategies

Cancers ◽

10.3390/cancers12061668 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1668 ◽

Cited By ~ 3

Author(s):

Monica Mossenta ◽

Davide Busato ◽

Michele Dal Bo ◽

Giuseppe Toffoli

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Cells ◽

Metabolic Pathways ◽

Metabolic Reprogramming ◽

Related Factor ◽

Anti Cancer ◽

Innovative Therapies ◽

Novel Therapeutic Strategies ◽

And Oxidative Stress ◽

Glycolytic Rate

Hepatocellular carcinoma (HCC) metabolism is redirected to glycolysis to enhance the production of metabolic compounds employed by cancer cells to produce proteins, lipids, and nucleotides in order to maintain a high proliferative rate. This mechanism drives towards uncontrolled growth and causes a further increase in reactive oxygen species (ROS), which could lead to cell death. HCC overcomes the problem generated by ROS increase by increasing the antioxidant machinery, in which key mechanisms involve glutathione, nuclear factor erythroid 2-related factor 2 (Nrf2), and hypoxia-inducible transcription factor (HIF-1α). These mechanisms could represent optimal targets for innovative therapies. The tumor microenvironment (TME) exerts a key role in HCC pathogenesis and progression. Various metabolic machineries modulate the activity of immune cells in the TME. The deregulated metabolic activity of tumor cells could impair antitumor response. Lactic acid–lactate, derived from the anaerobic glycolytic rate of tumor cells, as well as adenosine, derived from the catabolism of ATP, have an immunosuppressive activity. Metabolic reprogramming of the TME via targeted therapies could enhance the treatment efficacy of anti-cancer immunotherapy. This review describes the metabolic pathways mainly involved in the HCC pathogenesis and progression. The potential targets for HCC treatment involved in these pathways are also discussed.

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The Crosstalk Between Signaling Pathways and Cancer Metabolism in Colorectal Cancer

Frontiers in Pharmacology ◽

10.3389/fphar.2021.768861 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kha Wai Hon ◽

Syafiq Asnawi Zainal Abidin ◽

Iekhsan Othman ◽

Rakesh Naidu

Keyword(s):

Colorectal Cancer ◽

Signaling Pathways ◽

Metabolic Pathways ◽

Cancer Metabolism ◽

Kinase Inhibitors ◽

Protein Kinase Inhibitors ◽

Metabolic Reprogramming ◽

Metabolic Inhibitors ◽

Downstream Signaling ◽

Insight Into

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. Metabolic reprogramming represents an important cancer hallmark in CRC. Reprogramming core metabolic pathways in cancer cells, such as glycolysis, glutaminolysis, oxidative phosphorylation, and lipid metabolism, is essential to increase energy production and biosynthesis of precursors required to support tumor initiation and progression. Accumulating evidence demonstrates that activation of oncogenes and loss of tumor suppressor genes regulate metabolic reprogramming through the downstream signaling pathways. Protein kinases, such as AKT and c-MYC, are the integral components that facilitate the crosstalk between signaling pathways and metabolic pathways in CRC. This review provides an insight into the crosstalk between signaling pathways and metabolic reprogramming in CRC. Targeting CRC metabolism could open a new avenue for developing CRC therapy by discovering metabolic inhibitors and repurposing protein kinase inhibitors/monoclonal antibodies.

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