Therapeutic targeting of
            SPIB
            /
            SPI1
            ‐facilitated interplay of cancer cells and neutrophils inhibits aerobic glycolysis and cancer progression

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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Effect of Monoclonal Antibodies Conjugation With Gallium-Containing Solamargine: Warburg Effect- Based Cancer Therapeutic Strategy. Article Review

Global Journal of Medical Research ◽

10.34257/gjmrbvol21is3pg47 ◽

2021 ◽

pp. 47-59

Author(s):

Waleed O. Atta

Keyword(s):

Monoclonal Antibody ◽

Monoclonal Antibodies ◽

Cancer Cells ◽

Cancer Progression ◽

Warburg Effect ◽

Therapeutic Strategy ◽

Aerobic Glycolysis ◽

Malignant Cells ◽

Long Time ◽

High Degree

Therapy by Monoclonal antibodies is considered extremely hoping method for cancer therapy. But cancer cells have variable methods for resistance by multiple genetic mutations. The aim of that article to illustrate tagging monoclonal antibodies by gallium containing solamargine glycoside within the antibody by glycosylation the asparagine of its Fc portion. Malignant cells need to a big extent high carbohydrate content for aerobic glycolysis for cancer progression. Solamargine as a specific glycoside can be diffused easily and effectively into malignant cells with a high degree of specificity. Complexion gallium to solamargine then conjugation into monoclonal antibodies will increase Monoclonal antibody potency and affinity by Warburg effect based mechanism and gallium particles. Gallium can be retained for a long time inside malignant cells. By that method, the monoclonal antibody will be targeted to cancer cells by solamargine, retained gallium particles besides its functioning specific Fab region.

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Dihydropyrimidinase Like 2 Promotes Bladder Cancer Progression via Pyruvate Kinase M2-Induced Aerobic Glycolysis and Epithelial–Mesenchymal Transition

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.641432 ◽

2021 ◽

Vol 9 ◽

Author(s):

Jun Zou ◽

Ruiyan Huang ◽

Yanfei Chen ◽

Xiaoping Huang ◽

Huajun Li ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Pyruvate Kinase ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Aerobic Glycolysis ◽

Mesenchymal Transition ◽

Bladder Cancer Cells ◽

Malignant Behavior

BackgroundAerobic glycolysis and epidermal–mesenchymal transition (EMT) play key roles in the development of bladder cancer. This study aimed to investigate the function and the underlying mechanism of dihydropyrimidinase like 2 (DPYSL2) in bladder cancer progression.MethodsThe expression pattern of DPYSL2 in bladder cancer and the correlation of DPYSL2 expression with clinicopathological characteristics of bladder cancer patients were analyzed using the data from different databases and tissue microarray. Gain- and loss-of-function assays were performed to explore the role of DPYSL2 in bladder cancer progression in vitro and in mice. Proteomic analysis was performed to identify the interacting partner of DPYSL2 in bladder cancer cells.FindingsThe results showed that DPYSL2 expression was upregulated in bladder cancer tissue compared with adjacent normal bladder tissue and in more aggressive cancer stages compared with lower stages. DPYSL2 promoted malignant behavior of bladder cancer cells in vitro, as well as tumor growth and distant metastasis in mice. Mechanistically, DPYSL2 interacted with pyruvate kinase M2 (PKM2) and promoted the conversion of PKM2 tetramers to PKM2 dimers. Knockdown of PKM2 completely blocked DPYSL2-induced enhancement of the malignant behavior, glucose uptake, lactic acid production, and epithelial–mesenchymal transition in bladder cancer cells.InterpretationIn conclusion, the results suggest that DPYSL2 promotes aerobic glycolysis and EMT in bladder cancer via PKM2, serving as a potential therapeutic target for bladder cancer treatment.

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Pieces of the complex puzzle of cancer cell energy metabolism: an overview of energy metabolism and alternatives for targeted cancer therapy

Current Medicinal Chemistry ◽

10.2174/0929867327999200819123357 ◽

2020 ◽

Vol 27 ◽

Author(s):

Zeinab Ghasemishahrestani ◽

Larissa Maura Melo Mattos ◽

Tatiana Martins Tilli ◽

André Souza dos Santos ◽

Marcos Dias Pereira

Keyword(s):

Energy Metabolism ◽

Cancer Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Warburg Effect ◽

Cell Biology ◽

Aerobic Glycolysis ◽

Target Therapy ◽

Cell Metabolism ◽

Cancer Cell Metabolism

Over the past decades, several advances in cancer cell biology have led to relevant details about a phenomenon called "Warburg effect". Currently, it has been accepted that Warburg effect is not anymore compatible with all cancer cells, and thus the process of aerobic glycolysis is now challenged by the knowledge of a large number of cells presenting mitochondrial function. The energy metabolism of cancer cells is focused in the bioenergetic and biosynthetic pathways to meet the requirements of rapid proliferation. Changes in the metabolism of carbohydrate, amino acids and lipids have already been reported in cancer cells and might play relevant roles for cancer progression. To the best of our knowledge, mostly of these changes are established, mainly due to genetic reprogramming that leads to the transformation of a healthy into a cancerous cell. Indeed, several enzymes of high relevance for the energy are targets of oncogenes (ex. PI3K, HIF1 and Myc) and tumor suppressor proteins (ex. p53). As a consequence of the extensive study on cancer cell metabolism, some new therapeutic strategies have appeared that aim to interrupt the aberrant metabolism, as well as the influence of genetic reprogramming in cancer cells. In this perspective, we briefly review the cancer cell metabolism (carbohydrate, amino acid and lipid), and also describe oncogenes and tumor suppressors that affect cancer cell metabolism. We also discuss some potential candidates for target therapy to disrupt the main driven-force for cancer cell metabolism and proliferation.

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Gamma-enolase: a well-known tumour marker, with a less-known role in cancer

Radiology and Oncology ◽

10.1515/raon-2015-0035 ◽

2015 ◽

Vol 49 (3) ◽

pp. 217-226 ◽

Cited By ~ 24

Author(s):

Tjasa Vizin ◽

Janko Kos

Keyword(s):

Cancer Cells ◽

Cancer Progression ◽

Tumour Cell ◽

Aerobic Glycolysis ◽

Neuron Specific Enolase ◽

Tumour Marker ◽

Glycolytic Pathway ◽

Migration And Invasion ◽

Additional Function ◽

Gamma Enolase

Abstract Background. Gamma-enolase, known also as neuron-specific enolase (NSE), is an enzyme of the glycolytic pathway, which is expressed predominantly in neurons and cells of the neuroendocrine system. As a tumour marker it is used in diagnosis and prognosis of cancer; however, the mechanisms enrolling it in malignant progression remain elusive. As a cytoplasmic enzyme gamma-enolase is involved in increased aerobic glycolysis, the main source of energy in cancer cells, supporting cell proliferation. However, different cellular localisation at pathophysiological conditions, proposes other cellular engagements. Conclusions. The C-terminal part of the molecule, which is not related to glycolytic pathway, was shown to promote survival of neuronal cells by regulating neuronal growth factor receptor dependent signalling pathways, resulting also in extensive actin cytoskeleton remodelling. This additional function could be important also in cancer cells either to protect cells from stressful conditions and therapeutic agents or to promote tumour cell migration and invasion. Gamma-enolase might therefore have a multifunctional role in cancer progression: it supports increased tumour cell metabolic demands, protects tumour cells from stressful conditions and promotes their invasion and migration.

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Therapeutic Targeting of Osteopontin in Breast Cancer Cells

Breast Cancer - Current and Alternative Therapeutic Modalities ◽

10.5772/21115 ◽

2011 ◽

Author(s):

Gopal C. ◽

Supriya Saraswati ◽

Megha Sanyal ◽

Anuradha Bulbule ◽

Anuja Ramdasi ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Therapeutic Targeting

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PDIA6 contributes to aerobic glycolysis and cancer progression in oral squamous cell carcinoma

World Journal of Surgical Oncology ◽

10.1186/s12957-021-02190-w ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Ling Mao ◽

Xiaoweng Wu ◽

Zhengpeng Gong ◽

Ming Yu ◽

Zhi Huang

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Growth ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Expression Pattern ◽

Cancer Progression ◽

Squamous Cell ◽

Aerobic Glycolysis ◽

Lactate Production ◽

Control Group

Abstract Background/objective Accumulated evidence has demonstrated that aerobic glycolysis serves as a regulator of tumor cell growth, invasion, and angiogenesis. Herein, we explored the role of protein disulfide isomerase family 6 (PDIA6) in the aerobic glycolysis and the progression of oral squamous cell carcinoma (OSCC). Methods The expression pattern of PDIA6 in OSCC tissues was determined by qPCR and western blotting. Lentivirus and small interfering RNAs (siRNAs) were introduced into cells to upregulate and downregulate PDIA6 expression. CCK-8, flow cytometry, transwell, and xenotransplantation models were applied to detect cell proliferation, apoptosis, migration, invasion, and tumorigenesis, respectively. Results A high expression pattern of PDIA6 was observed in OSCC tissues, which was closely associated with lower overall survival and malignant clinical features in OSCC. Compared with the control group, overexpression of PDIA6 induced significant enhancements in cell growth, migration, invasiveness, and tumorigenesis and decreased cell apoptosis, while knockdown of PDIA6 caused opposite results. In addition, overexpression of PDIA6 increased glucose consumption, lactate production, and ATP level in OSCC cells. Conclusion This study demonstrated that PDIA6 expression was elevated in OSCC tissues, and overexpression of it promoted aerobic glycolysis and OSCC progression.

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Hemistepsin A suppresses colorectal cancer growth through inhibiting pyruvate dehydrogenase kinase activity

Scientific Reports ◽

10.1038/s41598-020-79019-1 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Ling Jin ◽

Eun-Yeong Kim ◽

Tae-Wook Chung ◽

Chang Woo Han ◽

So Young Park ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Pyruvate Dehydrogenase ◽

Cancer Metabolism ◽

Aerobic Glycolysis ◽

Lactate Production ◽

Pyruvate Dehydrogenase Kinase ◽

Cancer Drug ◽

Potential Candidate ◽

Mitochondrial Ros

AbstractMost cancer cells primarily produce their energy through a high rate of glycolysis followed by lactic acid fermentation even in the presence of abundant oxygen. Pyruvate dehydrogenase kinase (PDK) 1, an enzyme responsible for aerobic glycolysis via phosphorylating and inactivating pyruvate dehydrogenase (PDH) complex, is commonly overexpressed in tumors and recognized as a therapeutic target in colorectal cancer. Hemistepsin A (HsA) is a sesquiterpene lactone isolated from Hemistepta lyrata Bunge (Compositae). Here, we report that HsA is a PDK1 inhibitor can reduce the growth of colorectal cancer and consequent activation of mitochondrial ROS-dependent apoptotic pathway both in vivo and in vitro. Computational simulation and biochemical assays showed that HsA directly binds to the lipoamide-binding site of PDK1, and subsequently inhibits the interaction of PDK1 with the E2 subunit of PDH complex. As a result of PDK1 inhibition, lactate production was decreased, but oxygen consumption was increased. Mitochondrial ROS levels and mitochondrial damage were also increased. Consistent with these observations, the apoptosis of colorectal cancer cells was promoted by HsA with enhanced activation of caspase-3 and -9. These results suggested that HsA might be a potential candidate for developing a novel anti-cancer drug through suppressing cancer metabolism.

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Matrix Stiffness Modulates Metabolic Interaction between Human Stromal and Breast Cancer Cells to Stimulate Epithelial Motility

Metabolites ◽

10.3390/metabo11070432 ◽

2021 ◽

Vol 11 (7) ◽

pp. 432

Author(s):

Iván Ponce ◽

Nelson Garrido ◽

Nicolás Tobar ◽

Francisco Melo ◽

Patricio C. Smith ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Stromal Cells ◽

Glucose Transporter ◽

Lactate Production ◽

Resonance Energy ◽

Metabolic Reprogramming ◽

Dependent Manner ◽

Functional Link

Breast tumors belong to the type of desmoplastic lesion in which a stiffer tissue structure is a determinant of breast cancer progression and constitutes a risk factor for breast cancer development. It has been proposed that cancer-associated stromal cells (responsible for this fibrotic phenomenon) are able to metabolize glucose via lactate production, which supports the catabolic metabolism of cancer cells. The aim of this work was to investigate the possible functional link between these two processes. To measure the effect of matrix rigidity on metabolic determinations, we used compliant elastic polyacrylamide gels as a substrate material, to which matrix molecules were covalently linked. We evaluated metabolite transport in stromal cells using two different FRET (Fluorescence Resonance Energy Transfer) nanosensors specific for glucose and lactate. Cell migration/invasion was evaluated using Transwell devices. We show that increased stiffness stimulates lactate production and glucose uptake by mammary fibroblasts. This response was correlated with the expression of stromal glucose transporter Glut1 and monocarboxylate transporters MCT4. Moreover, mammary stromal cells cultured on stiff matrices generated soluble factors that stimulated epithelial breast migration in a stiffness-dependent manner. Using a normal breast stromal cell line, we found that a stiffer extracellular matrix favors the acquisition mechanistical properties that promote metabolic reprograming and also constitute a stimulus for epithelial motility. This new knowledge will help us to better understand the complex relationship between fibrosis, metabolic reprogramming, and cancer malignancy.

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Sympathetic activity in breast cancer and metastasis: partners in crime

Bone Research ◽

10.1038/s41413-021-00137-1 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Francisco Conceição ◽

Daniela M. Sousa ◽

Joana Paredes ◽

Meriem Lamghari

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Bone Remodeling ◽

Cancer Progression ◽

Breast Cancer Cells ◽

Sympathetic Innervation ◽

Breast Cancer Progression ◽

Vicious Cycle ◽

Native Bone ◽

Cancer Management

AbstractThe vast majority of patients with advanced breast cancer present skeletal complications that severely compromise their quality of life. Breast cancer cells are characterized by a strong tropism to the bone niche. After engraftment and colonization of bone, breast cancer cells interact with native bone cells to hinder the normal bone remodeling process and establish an osteolytic “metastatic vicious cycle”. The sympathetic nervous system has emerged in recent years as an important modulator of breast cancer progression and metastasis, potentiating and accelerating the onset of the vicious cycle and leading to extensive bone degradation. Furthermore, sympathetic neurotransmitters and their cognate receptors have been shown to promote several hallmarks of breast cancer, such as proliferation, angiogenesis, immune escape, and invasion of the extracellular matrix. In this review, we assembled the current knowledge concerning the complex interactions that take place in the tumor microenvironment, with a special emphasis on sympathetic modulation of breast cancer cells and stromal cells. Notably, the differential action of epinephrine and norepinephrine, through either α- or β-adrenergic receptors, on breast cancer progression prompts careful consideration when designing new therapeutic options. In addition, the contribution of sympathetic innervation to the formation of bone metastatic foci is highlighted. In particular, we address the remarkable ability of adrenergic signaling to condition the native bone remodeling process and modulate the bone vasculature, driving breast cancer cell engraftment in the bone niche. Finally, clinical perspectives and developments on the use of β-adrenergic receptor inhibitors for breast cancer management and treatment are discussed.

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