Wnt Signaling in Cancer Metabolism and Immunity

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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Extracellular Vesicles in Cancer Metabolism: Implications for Cancer Diagnosis and Treatment

Technology in Cancer Research & Treatment ◽

10.1177/15330338211037821 ◽

2021 ◽

Vol 20 ◽

pp. 153303382110378

Author(s):

Qian Zhang ◽

Xiangling Yang ◽

Huanliang Liu

Keyword(s):

Cancer Cells ◽

Extracellular Vesicles ◽

Cancer Diagnosis ◽

Cancer Metabolism ◽

Metabolic Reprogramming ◽

Bioactive Molecules ◽

Diagnosis And Treatment ◽

Existing Problems ◽

Non Coding Rnas

Metabolic reprogramming is one of the most common characteristics of cancer cells. The metabolic alterations of glucose, amino acids and lipids can support the aggressive phenotype of cancer cells. Exosomes, a kind of extracellular vesicles, participate in the intercellular communication through transferring bioactive molecules. Increasing evidence has demonstrated that enzymes, metabolites and non-coding RNAs in exosomes are responsible for the metabolic alteration of cancer cells. In this review, we summarize the past and recent findings of exosomes in altering cancer metabolism and elaborate on the role of the specific enzymes, metabolites and non-coding RNAs transferred by exosomes. Moreover, we give evidence of the role of exosomes in cancer diagnosis and treatment. Finally, we discuss the existing problems in the study and application of exosomes in cancer diagnosis and treatment.

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Cancer Stem Cell-Associated Pathways in the Metabolic Reprogramming of Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms21239125 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9125

Author(s):

Sara El-Sahli ◽

Lisheng Wang

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Malignant Tumors ◽

Metabolic Reprogramming ◽

Metabolic Adaptation ◽

Metabolic Flexibility ◽

Tumor Initiating Cells ◽

Metabolic Adaptations

Metabolic reprogramming of cancer is now considered a hallmark of many malignant tumors, including breast cancer, which remains the most commonly diagnosed cancer in women all over the world. One of the main challenges for the effective treatment of breast cancer emanates from the existence of a subpopulation of tumor-initiating cells, known as cancer stem cells (CSCs). Over the years, several pathways involved in the regulation of CSCs have been identified and characterized. Recent research has also shown that CSCs are capable of adopting a metabolic flexibility to survive under various stressors, contributing to chemo-resistance, metastasis, and disease relapse. This review summarizes the links between the metabolic adaptations of breast cancer cells and CSC-associated pathways. Identification of the drivers capable of the metabolic rewiring in breast cancer cells and CSCs and the signaling pathways contributing to metabolic flexibility may lead to the development of effective therapeutic strategies. This review also covers the role of these metabolic adaptation in conferring drug resistance and metastasis in breast CSCs.

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mTOR Complexes as a Nutrient Sensor for Driving Cancer Progression

International Journal of Molecular Sciences ◽

10.3390/ijms19103267 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3267 ◽

Cited By ~ 16

Author(s):

Mio Harachi ◽

Kenta Masui ◽

Yukinori Okamura ◽

Ryota Tsukui ◽

Paul Mischel ◽

...

Keyword(s):

Amino Acid ◽

Cell Survival ◽

Cancer Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Cancer Metabolism ◽

Metabolic Reprogramming ◽

Cancer Cell Survival

Recent advancement in the field of molecular cancer research has clearly revealed that abnormality of oncogenes or tumor suppressor genes causes tumor progression thorough the promotion of intracellular metabolism. Metabolic reprogramming is one of the strategies for cancer cells to ensure their survival by enabling cancer cells to obtain the macromolecular precursors and energy needed for the rapid growth. However, an orchestration of appropriate metabolic reactions for the cancer cell survival requires the precise mechanism to sense and harness the nutrient in the microenvironment. Mammalian/mechanistic target of rapamycin (mTOR) complexes are known downstream effectors of many cancer-causing mutations, which are thought to regulate cancer cell survival and growth. Recent studies demonstrate the intriguing role of mTOR to achieve the feat through metabolic reprogramming in cancer. Importantly, not only mTORC1, a well-known regulator of metabolism both in normal and cancer cell, but mTORC2, an essential partner of mTORC1 downstream of growth factor receptor signaling, controls cooperatively specific metabolism, which nominates them as an essential regulator of cancer metabolism as well as a promising candidate to garner and convey the nutrient information from the surrounding environment. In this article, we depict the recent findings on the role of mTOR complexes in cancer as a master regulator of cancer metabolism and a potential sensor of nutrients, especially focusing on glucose and amino acid sensing in cancer. Novel and detailed molecular mechanisms that amino acids activate mTOR complexes signaling have been identified. We would also like to mention the intricate crosstalk between glucose and amino acid metabolism that ensures the survival of cancer cells, but at the same time it could be exploitable for the novel intervention to target the metabolic vulnerabilities of cancer cells.

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The Anti-Cancer Effect of Quercetin: Molecular Implications in Cancer Metabolism

International Journal of Molecular Sciences ◽

10.3390/ijms20133177 ◽

2019 ◽

Vol 20 (13) ◽

pp. 3177 ◽

Cited By ~ 28

Author(s):

Marjorie Reyes-Farias ◽

Catalina Carrasco-Pozo

Keyword(s):

Glucose Metabolism ◽

Mitochondrial Function ◽

Normal Cell ◽

Fruits And Vegetables ◽

Cancer Metabolism ◽

Biological Process ◽

Metabolic Reprogramming ◽

Molecular Pathways ◽

Anti Cancer

Cancer is a problem with worldwide importance and is the second leading cause of death globally. Cancer cells reprogram their metabolism to support their uncontrolled expansion by increasing biomass (anabolic metabolism—glycolysis) at the expense of their energy (bioenergetics-mitochondrial function) requirements. In this aspect, metabolic reprogramming stands out as a key biological process in understanding the conversion of a normal cell into a neoplastic precursor. Quercetin is the major representative of the flavonoid subclass of flavonols. Quercetin is ubiquitously present in fruits and vegetables, being one of the most common dietary flavonols in the western diet. The anti-cancer effects of quercetin include its ability to promote the loss of cell viability, apoptosis and autophagy through the modulation of PI3K/Akt/mTOR, Wnt/β-catenin, and MAPK/ERK1/2 pathways. In this review, we discuss the role of quercetin in cancer metabolism, addressing specifically its ability to target molecular pathways involved in glucose metabolism and mitochondrial function.

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Iron: An Essential Element of Cancer Metabolism

Cells ◽

10.3390/cells9122591 ◽

2020 ◽

Vol 9 (12) ◽

pp. 2591

Author(s):

Myriam Y. Hsu ◽

Erica Mina ◽

Antonella Roetto ◽

Paolo E. Porporato

Keyword(s):

Tumor Growth ◽

Cancer Cells ◽

Iron Metabolism ◽

Cancer Metabolism ◽

Essential Element ◽

Iron Bioavailability ◽

Metabolic Reprogramming ◽

The Common ◽

Antioxidant Mechanisms

Cancer cells undergo considerable metabolic changes to foster uncontrolled proliferation in a hostile environment characterized by nutrient deprivation, poor vascularization and immune infiltration. While metabolic reprogramming has been recognized as a hallmark of cancer, the role of micronutrients in shaping these adaptations remains scarcely investigated. In particular, the broad electron-transferring abilities of iron make it a versatile cofactor that is involved in a myriad of biochemical reactions vital to cellular homeostasis, including cell respiration and DNA replication. In cancer patients, systemic iron metabolism is commonly altered. Moreover, cancer cells deploy diverse mechanisms to increase iron bioavailability to fuel tumor growth. Although iron itself can readily participate in redox reactions enabling vital processes, its reactivity also gives rise to reactive oxygen species (ROS). Hence, cancer cells further rely on antioxidant mechanisms to withstand such stress. The present review provides an overview of the common alterations of iron metabolism occurring in cancer and the mechanisms through which iron promotes tumor growth.

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The Dual-Role of Methylglyoxal in Tumor Progression – Novel Therapeutic Approaches

Frontiers in Oncology ◽

10.3389/fonc.2021.645686 ◽

2021 ◽

Vol 11 ◽

Author(s):

Alessia Leone ◽

Cecilia Nigro ◽

Antonella Nicolò ◽

Immacolata Prevenzano ◽

Pietro Formisano ◽

...

Keyword(s):

Tumor Progression ◽

Cancer Cells ◽

Cancer Progression ◽

Metabolic Reprogramming ◽

Therapeutic Approaches ◽

Hallmarks Of Cancer ◽

Anti Cancer ◽

Cellular Apoptosis ◽

Higher Doses

One of the hallmarks of cancer cells is their metabolic reprogramming, which includes the preference for the use of anaerobic glycolysis to produce energy, even in presence of normal oxygen levels. This phenomenon, known as “Warburg effect”, leads to the increased production of reactive intermediates. Among these Methylglyoxal (MGO), a reactive dicarbonyl known as the major precursor of the advanced glycated end products (AGEs), is attracting great attention. It has been well established that endogenous MGO levels are increased in several types of cancer, however the MGO contribution in tumor progression is still debated. Although an anti-cancer role was initially attributed to MGO due to its cytotoxicity, emerging evidence has highlighted its pro-tumorigenic role in several types of cancer. These apparently conflicting results are explained by the hormetic potential of MGO, in which lower doses of MGO are able to establish an adaptive response in cancer cells while higher doses cause cellular apoptosis. Therefore, the extent of MGO accumulation and the tumor context are crucial to establish MGO contribution to cancer progression. Several therapeutic approaches have been proposed and are currently under investigation to inhibit the pro-tumorigenic action of MGO. In this review, we provide an overview of the early and latest evidence regarding the role of MGO in cancer, in order to define its contribution in tumor progression, and the therapeutic strategies aimed to counteract the tumor growth.

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Potential of Mesenchymal Stem Cells in Anti-Cancer Therapies

Current Stem Cell Research & Therapy ◽

10.2174/1574888x15666200310171547 ◽

2020 ◽

Vol 15 (6) ◽

pp. 482-491 ◽

Cited By ~ 1

Author(s):

Milena Kostadinova ◽

Milena Mourdjeva

Keyword(s):

Cancer Cells ◽

Small Population ◽

Tumor Formation ◽

Bioactive Molecules ◽

Cancer Therapies ◽

New Methods ◽

Cycle Arrest ◽

Anti Cancer ◽

Blocking Mechanisms

Mesenchymal stem/stromal cells (MSCs) are localized throughout the adult body as a small population in the stroma of the tissue concerned. In injury, tissue damage, or tumor formation, they are activated and leave their niche to migrate to the site of injury, where they release a plethora of growth factors, cytokines, and other bioactive molecules. With the accumulation of data about the interaction between MSCs and tumor cells, the dualistic role of MSCs remains unclear. However, a large number of studies have demonstrated the natural anti-tumor properties inherent in MSCs, so this is the basis for intensive research for new methods using MSCs as a tool to suppress cancer cell development. This review focuses specifically on advanced approaches in modifying MSCs to become a powerful, precision- targeted tool for killing cancer cells, but not normal healthy cells. Suppression of tumor growth by MSCs can be accomplished by inducing apoptosis or cell cycle arrest, suppressing tumor angiogenesis, or blocking mechanisms mediating metastasis. In addition, the chemosensitivity of cancer cells may be increased so that the dose of the chemotherapeutic agent used could be significantly reduced.

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The Engaged Role of Tumor Microenvironment in Cancer Metabolism: Focusing on Cancer-Associated Fibroblast and Exosome Mediators

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200910123428 ◽

2020 ◽

Vol 21 (2) ◽

pp. 254-266 ◽

Cited By ~ 1

Author(s):

Khandan Ilkhani ◽

Milad Bastami ◽

Soheila Delgir ◽

Asma Safi ◽

Shahrzad Talebian ◽

...

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Cancer Metabolism ◽

Krebs Cycle ◽

Metabolic Reprogramming ◽

Cancer Management ◽

Cancer Associated Fibroblast ◽

Potential Biomarker ◽

Close Relationship ◽

Microenvironmental Factors

: Metabolic reprogramming is a significant property of various cancer cells, which most commonly arises from the Tumor Microenvironment (TME). The events of metabolic pathways include the Warburg effect, shifting in Krebs cycle metabolites, and the rate of oxidative phosphorylation, potentially providing energy and structural requirements for the development and invasiveness of cancer cells. TME and tumor metabolism shifting have a close relationship through bidirectional signaling pathways between stromal and tumor cells. Cancer- Associated Fibroblasts (CAFs), as the most dominant cells of TME, play a crucial role in the aberrant metabolism of cancer. Furthermore, the stated relationship can affect survival, progression, and metastasis in cancer development. Recently, exosomes are considered one of the most prominent factors in cellular communications considering effective content and bidirectional mediatory effect between tumor and stromal cells. In this regard, CAF-Derived Exosomes (CDE) exhibit an efficient obligation to induce metabolic reprogramming for promoting growth and metastasis of cancer cells. The understanding of cancer metabolism, including factors related to TME, could lead to the discovery of a potential biomarker for diagnostic and therapeutic approaches in cancer management. This review focuses on the association between metabolic reprogramming and engaged microenvironmental, factors such as CAFs, and the associated derived exosomes.

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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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Lobetyolin inhibits the proliferation of breast cancer cells via ASCT2 down-regulation-induced apoptosis

Human & Experimental Toxicology ◽

10.1177/09603271211021476 ◽

2021 ◽

pp. 096032712110214

Author(s):

Yansong Chen ◽

Ye Tian ◽

Gongsheng Jin ◽

Zhen Cui ◽

Wei Guo ◽

...

Keyword(s):

Breast Cancer ◽

Mrna Expression ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Glutamine Metabolism ◽

Down Regulation ◽

Anti Cancer ◽

Induced Apoptosis ◽

Glutamine Uptake

This study aimed to investigate the anti-cancer effect of lobetyolin on breast cancer cells. Lobetyolin was incubated with MDA-MB-231 and MDA-MB-468 breast cancer cells for 24 h. Glucose uptake and the mRNA expression of GLUT4 ( SLC2A4), HK2 and PKM2 were detected to assess the effect of lobetyolin on glucose metabolism. Glutamine uptake and the mRNA expression of ASCT2 ( SLC1A5), GLS1, GDH and GLUL were measured to assess the effect of lobetyolin on glutamine metabolism. Annexin V/PI double staining and Hoechst 33342 staining were used to investigate the effect of lobetyolin on cell apoptosis. Immunoblot was employed to estimate the effect of lobetyolin on the expression of proliferation-related markers and apoptosis-related markers. SLC1A5 knockdown with specific siRNA was performed to study the role of ASCT2 played in the anti-cancer effect of lobetyolin on MDA-MB-231 and MDA-MB-468 breast cancer cells. C-MYC knockdown with specific siRNA was performed to study the role of c-Myc played in lobetyolin-induced ASCT2 down-regulation. Myr-AKT overexpression was performed to investigate the role of AKT/GSK3β signaling played in lobetyolin-induced down-regulation of c-Myc and ASCT2. The results showed that lobetyolin inhibited the proliferation of both MDA-MB-231 and MDA-MB-468 breast cancer cells. Lobetyolin disrupted glutamine uptake via down-regulating ASCT2. SLC1A5 knockdown attenuated the anti-cancer effect of lobetyolin. C-MYC knockdown attenuated lobetyolin-caused down-regulation of ASCT2 and Myr-AKT overexpression reversed lobetyolin-caused down-regulation of both c-Myc and ASCT2. In conclusion, the present work suggested that lobetyolin exerted anti-cancer effect via ASCT2 down-regulation-induced apoptosis in breast cancer cells.

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