Metabolic Reprogramming and Molecular Rewiring in Cancer: Therapeutic Opportunities

BACKGROUND: A lot of contemporary cancer research has concentrated on genetic influence. However, cancer also involves biochemical changes, such as metabolic adaptation to support the aberrant cell proliferation.CONTENT: The fast cell proliferation in cancer cells enforce a metabolic re-arrangement to promote their long-term survival. The increased glucose uptake and fermentation of glucose to lactate are common features of this altered metabolism known as “the Warburg effect”. These metabolic pathways regulation enable cancer cells to produce adenosine triphosphate (ATP) in an efficient way. Epigenetic and metabolic changes also both affect molecular rewiring in cancer cells and promote cancer development and progression.SUMMARY: Metabolic rewiring and epigenetic remodeling establishing a direct link between metabolism and nuclear transcription to promote the survival of tumor cells. A further understanding of how metabolic remodeling can result in epigenetic changes in tumors, affecting cancer cell differentiation, proliferation, and/or apoptosis, will lead to a new strategy for cancer therapy.KEYWORDS: cancer metabolism, epigenetics, metabolic reprogramming, molecular rewiring

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The Role of Sodium Hydrogen Exchanger 1 in Dysregulation of Proton Dynamics and Reprogramming of Cancer Metabolism as a Sequela

International Journal of Molecular Sciences ◽

10.3390/ijms20153694 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3694 ◽

Cited By ~ 9

Author(s):

Rosa Cardone ◽

Khalid Alfarouk ◽

Robert Elliott ◽

Saad Alqahtani ◽

Samrein Ahmed ◽

...

Keyword(s):

Cancer Cells ◽

Cell Biology ◽

Cancer Metabolism ◽

Cellular Proliferation ◽

Cell Metabolism ◽

Krebs Cycle ◽

Building Blocks ◽

Metabolic Reprogramming ◽

Metabolic Adaptation ◽

Sodium Hydrogen Exchanger

Cancer cells have an unusual regulation of hydrogen ion dynamics that are driven by poor vascularity perfusion, regional hypoxia, and increased glycolysis. All these forces synergize/orchestrate together to create extracellular acidity and intracellular alkalinity. Precisely, they lead to extracellular pH (pHe) values as low as 6.2 and intracellular pH values as high as 8. This unique pH gradient (∆pHi to ∆pHe) across the cell membrane increases as the tumor progresses, and is markedly displaced from the electrochemical equilibrium of protons. These unusual pH dynamics influence cancer cell biology, including proliferation, metastasis, and metabolic adaptation. Warburg metabolism with increased glycolysis, even in the presence of Oxygen with the subsequent reduction in Krebs’ cycle, is a common feature of most cancers. This metabolic reprogramming confers evolutionary advantages to cancer cells by enhancing their resistance to hypoxia, to chemotherapy or radiotherapy, allowing rapid production of biological building blocks that support cellular proliferation, and shielding against damaging mitochondrial free radicals. In this article, we highlight the interconnected roles of dysregulated pH dynamics in cancer initiation, progression, adaptation, and in determining the programming and re-programming of tumor cell metabolism.

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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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The Role of PKM2 in Metabolic Reprogramming: Insights into the Regulatory Roles of Non-Coding RNAs

International Journal of Molecular Sciences ◽

10.3390/ijms22031171 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1171

Author(s):

Dexter L. Puckett ◽

Mohammed Alquraishi ◽

Winyoo Chowanadisai ◽

Ahmed Bettaieb

Keyword(s):

Cancer Cells ◽

Pyruvate Kinase ◽

Cancer Metabolism ◽

Cell Metabolism ◽

Metabolic Reprogramming ◽

Circular Rnas ◽

Tissue Specific ◽

Cell Progression ◽

Non Coding Rnas ◽

Regulatory Effects

Pyruvate kinase is a key regulator in glycolysis through the conversion of phosphoenolpyruvate (PEP) into pyruvate. Pyruvate kinase exists in various isoforms that can exhibit diverse biological functions and outcomes. The pyruvate kinase isoenzyme type M2 (PKM2) controls cell progression and survival through the regulation of key signaling pathways. In cancer cells, the dimer form of PKM2 predominates and plays an integral role in cancer metabolism. This predominance of the inactive dimeric form promotes the accumulation of phosphometabolites, allowing cancer cells to engage in high levels of synthetic processing to enhance their proliferative capacity. PKM2 has been recognized for its role in regulating gene expression and transcription factors critical for health and disease. This role enables PKM2 to exert profound regulatory effects that promote cancer cell metabolism, proliferation, and migration. In addition to its role in cancer, PKM2 regulates aspects essential to cellular homeostasis in non-cancer tissues and, in some cases, promotes tissue-specific pathways in health and diseases. In pursuit of understanding the diverse tissue-specific roles of PKM2, investigations targeting tissues such as the kidney, liver, adipose, and pancreas have been conducted. Findings from these studies enhance our understanding of PKM2 functions in various diseases beyond cancer. Therefore, there is substantial interest in PKM2 modulation as a potential therapeutic target for the treatment of multiple conditions. Indeed, a vast plethora of research has focused on identifying therapeutic strategies for targeting PKM2. Recently, targeting PKM2 through its regulatory microRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) has gathered increasing interest. Thus, the goal of this review is to highlight recent advancements in PKM2 research, with a focus on PKM2 regulatory microRNAs and lncRNAs and their subsequent physiological significance.

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The metabolic adaptation mechanism of metastatic organotropism

Experimental Hematology and Oncology ◽

10.1186/s40164-021-00223-4 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Chao Wang ◽

Daya Luo

Keyword(s):

Cancer Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Cancer Metabolism ◽

Cancer Metastasis ◽

Tumour Microenvironment ◽

Metabolic Adaptation ◽

Adaptation Mechanism ◽

Metastatic Sites ◽

The Impact

AbstractMetastasis is a complex multistep cascade of cancer cell extravasation and invasion, in which metabolism plays an important role. Recently, a metabolic adaptation mechanism of cancer metastasis has been proposed as an emerging model of the interaction between cancer cells and the host microenvironment, revealing a deep and extensive relationship between cancer metabolism and cancer metastasis. However, research on how the host microenvironment affects cancer metabolism is mostly limited to the impact of the local tumour microenvironment at the primary site. There are few studies on how differences between the primary and secondary microenvironments promote metabolic changes during cancer progression or how secondary microenvironments affect cancer cell metastasis preference. Hence, we discuss how cancer cells adapt to and colonize in the metabolic microenvironments of different metastatic sites to establish a metastatic organotropism phenotype. The mechanism is expected to accelerate the research of cancer metabolism in the secondary microenvironment, and provides theoretical support for the generation of innovative therapeutic targets for clinical metastatic diseases.

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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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Metabolic Reprogramming in Breast Cancer and Its Therapeutic Implications

Cells ◽

10.3390/cells8020089 ◽

2019 ◽

Vol 8 (2) ◽

pp. 89 ◽

Cited By ~ 29

Author(s):

Nishant Gandhi ◽

Gokul Das

Keyword(s):

Breast Cancer ◽

Estrogen Receptor Alpha ◽

Cancer Metabolism ◽

Growth Factor Receptor ◽

Standard Of Care ◽

Metabolic Reprogramming ◽

Metabolic Phenotype ◽

Current Standard ◽

Therapeutic Implications ◽

Altered Metabolism

Current standard-of-care (SOC) therapy for breast cancer includes targeted therapies such as endocrine therapy for estrogen receptor-alpha (ERα) positive; anti-HER2 monoclonal antibodies for human epidermal growth factor receptor-2 (HER2)-enriched; and general chemotherapy for triple negative breast cancer (TNBC) subtypes. These therapies frequently fail due to acquired or inherent resistance. Altered metabolism has been recognized as one of the major mechanisms underlying therapeutic resistance. There are several cues that dictate metabolic reprogramming that also account for the tumors’ metabolic plasticity. For metabolic therapy to be efficacious there is a need to understand the metabolic underpinnings of the different subtypes of breast cancer as well as the role the SOC treatments play in targeting the metabolic phenotype. Understanding the mechanism will allow us to identify potential therapeutic vulnerabilities. There are some very interesting questions being tackled by researchers today as they pertain to altered metabolism in breast cancer. What are the metabolic differences between the different subtypes of breast cancer? Do cancer cells have a metabolic pathway preference based on the site and stage of metastasis? How do the cell-intrinsic and -extrinsic cues dictate the metabolic phenotype? How do the nucleus and mitochondria coordinately regulate metabolism? How does sensitivity or resistance to SOC affect metabolic reprogramming and vice-versa? This review addresses these issues along with the latest updates in the field of breast cancer metabolism.

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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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Metabolic cooperation between cancer and non-cancerous stromal cells is pivotal in cancer progression

Tumor Biology ◽

10.1177/1010428318756203 ◽

2018 ◽

Vol 40 (2) ◽

pp. 101042831875620 ◽

Cited By ~ 11

Author(s):

Filipa Lopes-Coelho ◽

Sofia Gouveia-Fernandes ◽

Jacinta Serpa

Keyword(s):

Cancer Cells ◽

Cancer Progression ◽

Stromal Cells ◽

Inflammatory Cells ◽

Metabolic Adaptation ◽

Metabolic Cooperation ◽

Metabolic Remodeling ◽

Organ Tissue ◽

Cancerous Cells

The way cancer cells adapt to microenvironment is crucial for the success of carcinogenesis, and metabolic fitness is essential for a cancer cell to survive and proliferate in a certain organ/tissue. The metabolic remodeling in a tumor niche is endured not only by cancer cells but also by non-cancerous cells that share the same microenvironment. For this reason, tumor cells and stromal cells constitute a complex network of signal and organic compound transfer that supports cellular viability and proliferation. The intensive dual-address cooperation of all components of a tumor sustains disease progression and metastasis. Herein, we will detail the role of cancer-associated fibroblasts, cancer-associated adipocytes, and inflammatory cells, mainly monocytes/macrophages (tumor-associated macrophages), in the remodeling and metabolic adaptation of tumors.

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Mitochondrial Metabolism in PDAC: From Better Knowledge to New Targeting Strategies

Biomedicines ◽

10.3390/biomedicines8080270 ◽

2020 ◽

Vol 8 (8) ◽

pp. 270 ◽

Cited By ~ 2

Author(s):

Gabriela Reyes-Castellanos ◽

Rawand Masoud ◽

Alice Carrier

Keyword(s):

Cancer Therapy ◽

Cancer Cells ◽

Cancer Progression ◽

Cancer Metabolism ◽

Aerobic Glycolysis ◽

Mitochondrial Metabolism ◽

Metabolic Reprogramming ◽

Ductal Adenocarcinoma ◽

Current View ◽

Pancreatic Cancer Cells

Cancer cells reprogram their metabolism to meet bioenergetics and biosynthetic demands. The first observation of metabolic reprogramming in cancer cells was made a century ago (“Warburg effect” or aerobic glycolysis), leading to the classical view that cancer metabolism relies on a glycolytic phenotype. There is now accumulating evidence that most cancers also rely on mitochondria to satisfy their metabolic needs. Indeed, the current view of cancer metabolism places mitochondria as key actors in all facets of cancer progression. Importantly, mitochondrial metabolism has become a very promising target in cancer therapy, including for refractory cancers such as Pancreatic Ductal AdenoCarcinoma (PDAC). In particular, mitochondrial oxidative phosphorylation (OXPHOS) is an important target in cancer therapy. Other therapeutic strategies include the targeting of glutamine and fatty acids metabolism, as well as the inhibition of the TriCarboxylic Acid (TCA) cycle intermediates. A better knowledge of how pancreatic cancer cells regulate mitochondrial metabolism will allow the identification of metabolic vulnerabilities and thus novel and more efficient therapeutic options for the benefit of each patient.

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