scholarly journals The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma

2020 ◽  
Vol 11 ◽  
Author(s):  
Song Peng ◽  
Jun Zhang ◽  
Xintao Tan ◽  
Yiqiang Huang ◽  
Jing Xu ◽  
...  
Keyword(s):  
Chromaffin Cells ◽  
Metabolic Diseases ◽  
Cell Metabolism ◽  
Germline Mutations ◽  
Genetic Alterations ◽  
The Road ◽  
Cancer Cell Metabolism ◽  
Underlying Mechanisms ◽  
Lines Of Evidence

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells in the adrenal medulla (PCCs) or extra-adrenal sympathetic or parasympathetic paraganglia (PGLs). About 40% of PPGLs result from germline mutations and therefore they are highly inheritable. Although dysfunction of any one of a panel of more than 20 genes can lead to PPGLs, mutations in genes involved in the VHL/HIF axis including PHD, VHL, HIF-2A (EPAS1), and SDHx are more frequently found in PPGLs. Multiple lines of evidence indicate that pseudohypoxia plays a crucial role in the tumorigenesis of PPGLs, and therefore PPGLs are also known as metabolic diseases. However, the interplay between VHL/HIF-mediated pseudohypoxia and metabolic disorder in PPGLs cells is not well-defined. In this review, we will first discuss the VHL/HIF axis and genetic alterations in this axis. Then, we will dissect the underlying mechanisms in VHL/HIF axis-driven PPGL pathogenesis, with special attention paid to the interplay between the VHL/HIF axis and cancer cell metabolism. Finally, we will summarize the currently available compounds/drugs targeting this axis which could be potentially used as PPGLs treatment, as well as their underlying pharmacological mechanisms. The overall goal of this review is to better understand the role of VHL/HIF axis in PPGLs development, to establish more accurate tools in PPGLs diagnosis, and to pave the road toward efficacious therapeutics against metastatic PPGLs.

scholarly journals Pyruvate Dehydrogenase Contributes to Drug Resistance of Lung Cancer Cells Through Epithelial Mesenchymal Transition

2022 ◽  
Vol 9 ◽  
Author(s):  
Buse Cevatemre ◽  
Engin Ulukaya ◽  
Egemen Dere ◽  
Sukru Dilege ◽  
Ayhan Ceyda Acilan
Keyword(s):  
Drug Resistance ◽  
Pyruvate Dehydrogenase ◽  
Epithelial Mesenchymal Transition ◽  
Morphological Changes ◽  
Cell Metabolism ◽  
Careful Consideration ◽  
Mesenchymal Transition ◽  
Cancer Cell Metabolism ◽  
Underlying Mechanisms

Recently, there has been a growing interest on the role of mitochondria in metastatic cascade. Several reports have shown the preferential utilization of glycolytic pathway instead of mitochondrial respiration for energy production and the pyruvate dehydrogenase (PDH) has been considered to be a contributor to this switch in some cancers. Since epithelial mesenchymal transition (EMT) is proposed to be one of the significant mediators of metastasis, the molecular connections between cancer cell metabolism and EMT may reveal underlying mechanisms and improve our understanding on metastasis. In order to explore a potential role for PDH inhibition on EMT and associated drug resistance, we took both pharmacological and genetic approaches, and selectively inhibited or knocked down PDHA1 by using Cpi613 and shPDHA1, respectively. We found that both approaches triggered morphological changes and characteristics of EMT (increase in mesenchymal markers). This change was accompanied by enhanced wound healing and an increase in migration. Interestingly, cells were more resistant to many of the clinically used chemotherapeutics following PDH inhibition or PDHA1 knockdown. Furthermore, the TGFβRI (known as a major inducer of the EMT) inhibitor (SB-431542) together with the PDHi, was effective in reversing EMT. In conclusion, interfering with PDH induced EMT, and more importantly resulted in chemoresistance. Therefore, our study demonstrates the need for careful consideration of PDH-targeting approaches in cancer treatment.

scholarly journals Chloroplast Hsp70 Isoform Is Required for Age-Dependent Tissue Preference of Bamboo mosaic virus in Mature Nicotiana benthamiana Leaves

2017 ◽  
Vol 30 (8) ◽  
pp. 631-645 ◽  
Author(s):  
Ying Wen Huang ◽  
Chung Chi Hu ◽  
Ching Hsiu Tsai ◽  
Na Sheng Lin ◽  
Yau Heiu Hsu
Keyword(s):  
Mosaic Virus ◽  
Nicotiana Benthamiana ◽  
Transit Peptide ◽  
Plant Viruses ◽  
Age Dependent ◽  
Efficient Replication ◽  
Underlying Mechanisms ◽  
Lines Of Evidence ◽  
Suitable Environment

Plant viruses may exhibit age-dependent tissue preference in their hosts but the underlying mechanisms are not well understood. In this study, we provide several lines of evidence to reveal the determining role of a protein of the Nicotiana benthamiana chloroplast Hsp70 (NbcpHsp70) family, NbcpHsp70-2, involved in the preference of Bamboo mosaic virus (BaMV) to infect older tissues. NbcpHsp70 family proteins were identified in complexes pulled down with BaMV replicase as the bait. Among the isoforms of NbcpHsp70, only the specific silencing of NbcpHsp70-2 resulted in the significant decrease of BaMV RNA in N. benthamiana protopalsts, indicating that NbcpHsp70-2 is involved in the efficient replication of BaMV RNA. We further identified the age-dependent import regulation signal contained in the transit peptide of NbcpHsp70-2. Deletion, overexpression, and substitution experiments revealed that the signal in the transit peptide of NbcpHsp70-2 is crucial for both the import of NbcpHsp70-2 into older chloroplasts and the preference of BaMV for infecting older leaves of N. benthamiana. Together, these data demonstrated that BaMV may exploit a cellular age-dependent transportation mechanism to target a suitable environment for viral replication.

scholarly journals MECHANISMS IN ENDOCRINOLOGY: Gut microbiota in patients with type 2 diabetes mellitus

2015 ◽  
Vol 172 (4) ◽  
pp. R167-R177 ◽  
Author(s):  
Kristine H Allin ◽  
Trine Nielsen ◽  
Oluf Pedersen
Keyword(s):  
Type 2 Diabetes ◽  
Gut Microbiota ◽  
Metabolic Diseases ◽  
Short Chain Fatty Acids ◽  
Intestinal Content ◽  
Low Grade ◽  
Bacterial Fermentation ◽  
Underlying Mechanisms

Perturbations of the composition and function of the gut microbiota have been associated with metabolic disorders including obesity, insulin resistance and type 2 diabetes. Studies on mice have demonstrated several underlying mechanisms including host signalling through bacterial lipopolysaccharides derived from the outer membranes of Gram-negative bacteria, bacterial fermentation of dietary fibres to short-chain fatty acids and bacterial modulation of bile acids. On top of this, an increased permeability of the intestinal epithelium may lead to increased absorption of macromolecules from the intestinal content resulting in systemic immune responses, low-grade inflammation and altered signalling pathways influencing lipid and glucose metabolism. While mechanistic studies on mice collectively support a causal role of the gut microbiota in metabolic diseases, the majority of studies in humans are correlative of nature and thus hinder causal inferences. Importantly, several factors known to influence the risk of type 2 diabetes, e.g. diet and age, have also been linked to alterations in the gut microbiota complicating the interpretation of correlative studies. However, based upon the available evidence, it is hypothesised that the gut microbiota may mediate or modulate the influence of lifestyle factors triggering development of type 2 diabetes. Thus, the aim of this review is to critically discuss the potential role of the gut microbiota in the pathophysiology and pathogenesis of type 2 diabetes.

Retinol binding protein 4 and its membrane receptors: a metabolic perspective

2015 ◽  
Vol 22 (1) ◽  
Author(s):  
Ronja Fedders ◽  
Matthias Muenzner ◽  
Michael Schupp
Keyword(s):  
Metabolic Diseases ◽  
Binding Protein ◽  
Current Data ◽  
Membrane Receptors ◽  
Retinol Binding Protein ◽  
Metabolic Effects ◽  
Retinol Binding Protein 4 ◽  
Underlying Mechanisms

AbstractNearly a decade of intense research has passed since the first report linking circulating retinol binding protein 4 (RBP4) to the development of insulin resistance. By now, a variety of underlying mechanisms have been identified; some of them are adherent to the canonical role of this circulating protein, which is to transport and deliver retinol to target tissues, and others that seem rather independent of retinol transport. Despite all these efforts, a consensus in the basic principles of RBP4’s metabolic effects has not been reached and some controversy remains. Using this as an opportunity, we here review and discuss current data on RBP4’s action on insulin sensitivity and its dependency on retinol homeostasis. We pay special attention to the involvement of RBP4 membrane receptors that were identified during these years, such as ‘stimulated by retinoic acid 6’ (STRA6), and whose identification added another layer of complexity to RBP4’s diverse actions. A better understanding of RBP4’s functions might allow its therapeutic exploitations, urgently needed in our period that is defined by an epidemic increase in metabolic diseases such as obesity and type 2 diabetes.

scholarly journals TIGAR's promiscuity

2014 ◽  
Vol 458 (3) ◽  
pp. e5-e7 ◽  
Author(s):  
Juan P. Bolaños
Keyword(s):  
Cell Metabolism ◽  
Glucose Consumption ◽  
Pentose Phosphate ◽  
Regulator Protein ◽  
Biochemical Journal ◽  
Cellular Context ◽  
Health And Disease ◽  
Rigorous Study ◽  
Cancer Cell Metabolism

TIGAR [TP53 (tumour protein 53)-induced glycolysis and apoptosis regulator] protein is known for its ability to inhibit glycolysis, shifting glucose consumption towards the pentose phosphate pathway to promote antioxidant protection of cancer cells. According to sequence homology and activity analyses, TIGAR was initially considered to be a fructose-2,6-bisphosphatase; it has thus received much attention in cancer cell metabolism, given its dependence on p53 and the key role of F26BP (fructose 2,6-bisphosphate) at modulating glycolysis and gluconeogenesis. However, in a rigorous study published in this issue of the Biochemical Journal, Gerin and colleagues report that recombinant TIGAR is a 23BPG (2,3-bisphosphoglycerate) phosphatase, although it also dephosphorylates other carboxylic acid-phosphate esters and, weakly, F26BP. As such, inhibition of endogenous TIGAR leads to a dramatic increase in cellular 23BPG, influencing F26BP to a lower extent that depends on the cellular context. These results challenge the currently held notion that TIGAR modulates glycolysis through decreasing F26BP, and opens a yet unrecognized function(s) for TIGAR-mediated 23BPG control of cellular metabolism in health and disease.

scholarly journals Glutamine-Derived Aspartate Biosynthesis in Cancer Cells: Role of Mitochondrial Transporters and New Therapeutic Perspectives

Cancers ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 245
Author(s):  
Ruggiero Gorgoglione ◽  
Valeria Impedovo ◽  
Christopher L. Riley ◽  
Deborah Fratantonio ◽  
Stefano Tiziani ◽  
...  
Keyword(s):  
Uncoupling Protein ◽  
Cell Metabolism ◽  
Redox Homeostasis ◽  
Nucleotide Biosynthesis ◽  
Specific Tumor ◽  
Mitochondrial Carrier Family ◽  
Cancer Types ◽  
Cancer Cell Metabolism ◽  
Tumor Types

Aspartate has a central role in cancer cell metabolism. Aspartate cytosolic availability is crucial for protein and nucleotide biosynthesis as well as for redox homeostasis. Since tumor cells display poor aspartate uptake from the external environment, most of the cellular pool of aspartate derives from mitochondrial catabolism of glutamine. At least four transporters are involved in this metabolic pathway: the glutamine (SLC1A5_var), the aspartate/glutamate (AGC), the aspartate/phosphate (uncoupling protein 2, UCP2), and the glutamate (GC) carriers, the last three belonging to the mitochondrial carrier family (MCF). The loss of one of these transporters causes a paucity of cytosolic aspartate and an arrest of cell proliferation in many different cancer types. The aim of this review is to clarify why different cancers have varying dependencies on metabolite transporters to support cytosolic glutamine-derived aspartate availability. Dissecting the precise metabolic routes that glutamine undergoes in specific tumor types is of upmost importance as it promises to unveil the best metabolic target for therapeutic intervention.

Cancer Cell Metabolism Featuring Nrf2

2020 ◽  
Vol 17 (3) ◽  
pp. 263-271 ◽  
Author(s):  
Payal Chatterjee ◽  
Mukesh Yadav ◽  
Namrata Chauhan ◽  
Ying Huang ◽  
Yun Luo
Keyword(s):  
Cancer Cells ◽  
Cell Metabolism ◽  
Cellular Metabolism ◽  
Energy Requirements ◽  
Genetic Mutations ◽  
Cellular Protection ◽  
Key Factor ◽  
Cancer Cell Metabolism ◽  
Cancerous Cells

Although the major role of Nrf2 has long been established as a transcription factor for providing cellular protection against oxidative stress, multiple pieces of research and reviews now claim exactly the opposite. The dilemma - “to activate or inhibit” the protein requires an immediate answer, which evidently links cellular metabolism to the causes and purpose of cancer. Profusely growing cancerous cells have prolific energy requirements, which can only be fulfilled by modulating cellular metabolism. This review highlights the cause and effect of Nrf2 modulation in cancer that in turn channelize cellular metabolism, thereby fulfilling the energy requirements of cancer cells. The present work also highlights the purpose of genetic mutations in Nrf2, in relation to cellular metabolism in cancer cells, thus pointing out a newer approach where parallel mutations may be the key factor to decide whether to activate or inhibit Nrf2.

scholarly journals Hypoxia Pathway Mutations in Pheochromocytomas and Paragangliomas

2016 ◽  
Vol 150 (3-4) ◽  
pp. 227-241 ◽  
Author(s):  
Diana Amorim-Pires ◽  
Joana Peixoto ◽  
Jorge Lima
Keyword(s):  
Chromaffin Cells ◽  
Neck Region ◽  
Germline Mutations ◽  
Genetic Alterations ◽  
Hypoxia Inducible Factors ◽  
Head And Neck Region ◽  
Hereditary Syndromes ◽  
Key Players ◽  
Sporadic Tumors ◽  
Associated Tumors

Pheochromocytomas (PCC) and sympathetic paragangliomas (PGL) are rare neuroendocrine tumors, which derive from chromaffin cells occurring in the adrenal medulla and extra-adrenal sympathetic paraganglia. PCC and PGL are often benign, catecholamine-producing tumors, responsible for a myriad of symptoms that may be potentially hazardous to the patient. In contrast, nonsecreting parasympathetic PGL, derived from chief cells, develop mainly in the head and neck region. Although PCC/PGL are more commonly sporadic tumors, germline mutations are present in up to 40% of the patients, ranking these tumors among those with the highest degree of heritability. PCC/PGL are associated with a variety of hereditary syndromes, comprising genetic alterations in RET, NF1, VHL, and SDHx genes, the last 2 being involved in regulating the hypoxia pathway. Additional hypoxia pathway-related genes have been recently associated with PCC/PGL development, namely EGLN1 and EPAS1. Thus, dysregulation of the hypoxia pathway seems to play a major role in PCC/PGL development, in particular through the stabilization of hypoxia-inducible factors and the appearance of a pseudohypoxia signature. This article is focused on reviewing the tumorigenic mechanisms resultant from VHL, SDHx, EGLN1, and EPAS1 mutations, as well as the associated tumors, namely PCC/PGL, and extra manifestations such as polycythemia. In the light of the recent discoveries, hypoxia pathway molecules appear as key players in PCC/PGL development.

scholarly journals Cereblon: A Protein Crucial to the Multiple Functions of Immunomodulatory Drugs as well as Cell Metabolism and Disease Generation

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Qinglin Shi ◽  
Lijuan Chen
Keyword(s):  
Cell Proliferation ◽  
Autosomal Recessive ◽  
Metabolic Diseases ◽  
Cell Metabolism ◽  
Regulatory Mechanisms ◽  
Immunomodulatory Drugs ◽  
Multiple Functions ◽  
Intrinsic Mechanism ◽  
Intermediary Role ◽  
Underlying Mechanisms

It is well known that cereblon is a key protein in autosomal recessive nonsyndromic mental retardation. Studies have reported that it has an intermediary role in helping immunomodulatory drugs perform their immunomodulatory and tumoricidal effects. In addition, cereblon also regulates the expression, assembly, and activities of other special proteins related to cell proliferation and metabolism, resulting in the occurrence and development of metabolic diseases. This review details the multiple functions of cereblon and the underlying mechanisms. We also put forward some unsolved problems, including the intrinsic mechanism of cereblon function and the possible regulatory mechanisms of its expression.

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