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Cells Aug 2022Mitochondria are not only the main energy supplier but are also the cell metabolic center regulating multiple key metaborates that play pivotal roles in epigenetics... (Review)
Review
Mitochondria are not only the main energy supplier but are also the cell metabolic center regulating multiple key metaborates that play pivotal roles in epigenetics regulation. These metabolites include acetyl-CoA, α-ketoglutarate (α-KG), S-adenosyl methionine (SAM), NAD, and O-linked beta-N-acetylglucosamine (O-GlcNAc), which are the main substrates for DNA methylation and histone post-translation modifications, essential for gene transcriptional regulation and cell fate determination. Tumorigenesis is attributed to many factors, including gene mutations and tumor microenvironment. Mitochondria and epigenetics play essential roles in tumor initiation, evolution, metastasis, and recurrence. Targeting mitochondrial metabolism and epigenetics are promising therapeutic strategies for tumor treatment. In this review, we summarize the roles of mitochondria in key metabolites required for epigenetics modification and in cell fate regulation and discuss the current strategy in cancer therapies via targeting epigenetic modifiers and related enzymes in metabolic regulation. This review is an important contribution to the understanding of the current metabolic-epigenetic-tumorigenesis concept.
Topics: Carcinogenesis; Epigenesis, Genetic; Histones; Humans; Mitochondria; Neoplasms; Tumor Microenvironment
PubMed: 36010594
DOI: 10.3390/cells11162518 -
Trends in Cancer Aug 2019Circadian clocks constitute the evolutionary molecular machinery that dictates the temporal regulation of physiology to maintain homeostasis. Disruption of the circadian... (Review)
Review
Circadian clocks constitute the evolutionary molecular machinery that dictates the temporal regulation of physiology to maintain homeostasis. Disruption of the circadian rhythm plays a key role in tumorigenesis and facilitates the establishment of cancer hallmarks. Conversely, oncogenic processes directly weaken circadian rhythms. Pharmacological modulation of core clock genes is a new approach in cancer therapy. The integration of circadian biology into cancer research offers new options for making cancer treatment more effective, encompassing the prevention, diagnosis, and treatment of this devastating disease. This review highlights the role of the circadian clock in tumorigenesis and cancer hallmarks, and discusses how pharmacological modulation of circadian clock genes can lead to new therapeutic options.
Topics: Antineoplastic Agents; Carcinogenesis; Circadian Clocks; Circadian Rhythm; Gene Expression Regulation, Neoplastic; Homeostasis; Humans; Neoplasms
PubMed: 31421905
DOI: 10.1016/j.trecan.2019.07.002 -
International Journal of Molecular... Sep 2021HSP90 is a vital chaperone protein conserved across all organisms. As a chaperone protein, it correctly folds client proteins. Structurally, this protein is a dimer with... (Review)
Review
HSP90 is a vital chaperone protein conserved across all organisms. As a chaperone protein, it correctly folds client proteins. Structurally, this protein is a dimer with monomer subunits that consist of three main conserved domains known as the N-terminal domain, middle domain, and the C-terminal domain. Multiple isoforms of HSP90 exist, and these isoforms share high homology. These isoforms are present both within the cell and outside the cell. Isoforms HSP90 and HSP90 are present in the cytoplasm; TRAP1 is present in the mitochondria; and GRP94 is present in the endoplasmic reticulum and is likely secreted due to post-translational modifications (PTM). HSP90 is also secreted into an extracellular environment via an exosome pathway that differs from the classic secretion pathway. Various co-chaperones are necessary for HSP90 to function. Elevated levels of HSP90 have been observed in patients with cancer. Despite this observation, the possible role of HSP90 in cancer was overlooked because the chaperone was also present in extreme amounts in normal cells and was vital to normal cell function, as observed when the drastic adverse effects resulting from gene knockout inhibited the production of this protein. Differences between normal HSP90 and HSP90 of the tumor phenotype have been better understood and have aided in making the chaperone protein a target for cancer drugs. One difference is in the conformation: HSP90 of the tumor phenotype is more susceptible to inhibitors. Since overexpression of HSP90 is a factor in tumorigenesis, HSP90 inhibitors have been studied to combat the adverse effects of HSP90 overexpression. Monotherapies using HSP90 inhibitors have shown some success; however, combination therapies have shown better results and are thus being studied for a more effective cancer treatment.
Topics: Animals; Carcinogenesis; HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Neoplasms; Protein Isoforms
PubMed: 34638658
DOI: 10.3390/ijms221910317 -
Frontiers of Medicine Aug 2018The cell-biological program termed the epithelial-to-mesenchymal transition (EMT) plays an important role in both development and cancer progression. Depending on the... (Review)
Review
The cell-biological program termed the epithelial-to-mesenchymal transition (EMT) plays an important role in both development and cancer progression. Depending on the contextual signals and intracellular gene circuits of a particular cell, this program can drive fully epithelial cells to enter into a series of phenotypic states arrayed along the epithelial-mesenchymal phenotypic axis. These cell states display distinctive cellular characteristics, including stemness, invasiveness, drug-resistance and the ability to form metastases at distant organs, and thereby contribute to cancer metastasis and relapse. Currently we still lack a coherent overview of the molecular and biochemical mechanisms inducing cells to enter various states along the epithelial-mesenchymal phenotypic spectrum. An improved understanding of the dynamic and plastic nature of the EMT program has the potential to yield novel therapies targeting this cellular program that may aid in the management of high-grade malignancies.
Topics: Carcinogenesis; Disease Progression; Epithelial-Mesenchymal Transition; Humans; Neoplasm Metastasis
PubMed: 30043221
DOI: 10.1007/s11684-018-0656-6 -
International Journal of Molecular... Oct 2018The immense diversity of extracellular matrix (ECM) proteins confers distinct biochemical and biophysical properties that influence cell phenotype. The ECM is highly... (Review)
Review
The immense diversity of extracellular matrix (ECM) proteins confers distinct biochemical and biophysical properties that influence cell phenotype. The ECM is highly dynamic as it is constantly deposited, remodelled, and degraded during development until maturity to maintain tissue homeostasis. The ECM's composition and organization are spatiotemporally regulated to control cell behaviour and differentiation, but dysregulation of ECM dynamics leads to the development of diseases such as cancer. The chemical cues presented by the ECM have been appreciated as key drivers for both development and cancer progression. However, the mechanical forces present due to the ECM have been largely ignored but recently recognized to play critical roles in disease progression and malignant cell behaviour. Here, we review the ways in which biophysical forces of the microenvironment influence biochemical regulation and cell phenotype during key stages of human development and cancer progression.
Topics: Animals; Carcinogenesis; Epithelial-Mesenchymal Transition; Extracellular Matrix; Humans; Tumor Microenvironment
PubMed: 30287763
DOI: 10.3390/ijms19103028 -
Cells Nov 2021G-protein-coupled receptors (GPCRs) are the largest family of cell surface signaling receptors known to play a crucial role in various physiological functions, including... (Review)
Review
G-protein-coupled receptors (GPCRs) are the largest family of cell surface signaling receptors known to play a crucial role in various physiological functions, including tumor growth and metastasis. Various molecules such as hormones, lipids, peptides, and neurotransmitters activate GPCRs that enable the coupling of these receptors to highly specialized transducer proteins, called G-proteins, and initiate multiple signaling pathways. Integration of these intricate networks of signaling cascades leads to numerous biochemical responses involved in diverse pathophysiological activities, including cancer development. While several studies indicate the role of GPCRs in controlling various aspects of cancer progression such as tumor growth, invasion, migration, survival, and metastasis through its aberrant overexpression, mutations, or increased release of agonists, the explicit mechanisms of the involvement of GPCRs in cancer progression is still puzzling. This review provides an insight into the various responses mediated by GPCRs in the development of cancers, the molecular mechanisms involved and the novel pharmacological approaches currently preferred for the treatment of cancer. Thus, these findings extend the knowledge of GPCRs in cancer cells and help in the identification of therapeutics for cancer patients.
Topics: Animals; Carcinogenesis; GTP-Binding Proteins; Humans; Models, Biological; Neoplasms; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 34943797
DOI: 10.3390/cells10123288 -
Current Cancer Drug Targets Nov 2013Epithelial-mesenchymal transition (EMT) is a highly conserved process in which polarized, immobile epithelial cells lose tight junctions, associated adherence, and... (Review)
Review
Epithelial-mesenchymal transition (EMT) is a highly conserved process in which polarized, immobile epithelial cells lose tight junctions, associated adherence, and become migratory mesenchymal cells. Several transcription factors, including the Snail/Slug family, Twist, δEF1/ZEB1, SIP1/ZEB2 and E12/E47 respond to microenvironmental stimuli and function as molecular switches for the EMT program. Snail is a zinc-finger transcriptional repressor controlling EMT during embryogenesis and tumor progression. Through its N-terminal SNAG domain, Snail interacts with several corepressors and epigenetic remodeling complexes to repress specific target genes, such as the E-cadherin gene (CDH1). An integrated and complex signaling network, including the RTKs, TGF-β, Notch, Wnt, TNF-α, and BMPs pathways, activates Snail, thereby inducing EMT. Snail expression correlates with the tumor grade, nodal metastasis of many types of tumor and predicts a poor outcome in patients with metastatic cancer. Emerging evidences indicate that Snail causes a metabolic reprogramming, bestows tumor cells with cancer stem cell-like traits, and additionally, promotes drug resistance, tumor recurrence and metastasis. Despite many new and exciting developments, several challenges remain to be addressed in order to understand more thoroughly the role of Snail in metastasis. Additional investigations are required to disclose the contribution of microenvironmental factors on tumor progression. This information will lead to a comprehensive understanding of Snail in cancer and will provide us with novel approaches for preventing and treating metastatic cancers.
Topics: Carcinogenesis; Epithelial-Mesenchymal Transition; Humans; Neoplasm Metastasis; Signal Transduction; Snail Family Transcription Factors; Transcription Factors; Tumor Microenvironment
PubMed: 24168186
DOI: 10.2174/15680096113136660102 -
International Journal of Molecular... Sep 2020is a class one carcinogen which causes chronic atrophic gastritis, gastric intestinal metaplasia, dysplasia and adenocarcinoma. The mechanisms by which interacts with... (Review)
Review
is a class one carcinogen which causes chronic atrophic gastritis, gastric intestinal metaplasia, dysplasia and adenocarcinoma. The mechanisms by which interacts with other risk and protective factors, particularly vitamin C in gastric carcinogenesis are complex. Gastric carcinogenesis includes metabolic, environmental, epigenetic, genomic, infective, inflammatory and oncogenic pathways. The molecular classification of gastric cancer subtypes has revolutionized the understanding of gastric carcinogenesis. This includes the tumour microenvironment, germline mutations, and the role of bacteria, virus and epigenetics in somatic mutations. There is evidence that ascorbic acid, phytochemicals and endogenous antioxidant systems can modify the risk of gastric cancer. Gastric juice ascorbate levels depend on dietary intake of ascorbic acid but can also be decreased by infection, CagA secretion, tobacco smoking, achlorhydria and chronic atrophic gastritis. Ascorbic acid may be protective against gastric cancer by its antioxidant effect in gastric cytoprotection, regenerating active vitamin E and glutathione, inhibiting endogenous N-nitrosation, reducing toxic effects of ingested nitrosodimethylamines and heterocyclic amines, and preventing infection. The effectiveness of such cytoprotection is related to strain virulence, particularly CagA expression. The role of vitamin C in epigenetic reprogramming in gastric cancer is still evolving. Other factors in conjunction with vitamin C also play a role in gastric carcinogenesis. Eradication of may lead to recovery of vitamin C secretion by gastric epithelium and enable regression of premalignant gastric lesions, thereby interrupting the Correa cascade of gastric carcinogenesis.
Topics: Animals; Antioxidants; Ascorbic Acid; Carcinogenesis; Gastric Juice; Helicobacter Infections; Helicobacter pylori; Humans; Phytochemicals; Stomach Neoplasms
PubMed: 32899442
DOI: 10.3390/ijms21176451 -
EMBO Reports Nov 2014In response to a variety of stresses, mammalian cells undergo a persistent proliferative arrest known as cellular senescence. Many senescence-inducing stressors are... (Review)
Review
In response to a variety of stresses, mammalian cells undergo a persistent proliferative arrest known as cellular senescence. Many senescence-inducing stressors are potentially oncogenic, strengthening the notion that senescence evolved alongside apoptosis to suppress tumorigenesis. In contrast to apoptosis, senescent cells are stably viable and have the potential to influence neighboring cells through secreted soluble factors, which are collectively known as the senescence-associated secretory phenotype (SASP). However, the SASP has been associated with structural and functional tissue and organ deterioration and may even have tumor-promoting effects, raising the interesting evolutionary question of why apoptosis failed to outcompete senescence as a superior cell fate option. Here, we discuss the advantages that the senescence program may have over apoptosis as a tumor protective mechanism, as well as non-neoplastic functions that may have contributed to its evolution. We also review emerging evidence for the idea that senescent cells are present transiently early in life and are largely beneficial for development, regeneration and homeostasis, and only in advanced age do senescent cells accumulate to an organism's detriment.
Topics: Aging; Animals; Apoptosis; Carcinogenesis; Cellular Senescence; Humans; Signal Transduction; Stress, Physiological
PubMed: 25312810
DOI: 10.15252/embr.201439245 -
Carcinogenesis Sep 2020Many metals are essential for living organisms, but at higher doses they may be toxic and carcinogenic. Metal exposure occurs mainly in occupational settings and... (Review)
Review
Many metals are essential for living organisms, but at higher doses they may be toxic and carcinogenic. Metal exposure occurs mainly in occupational settings and environmental contaminations in drinking water, air pollution and foods, which can result in serious health problems such as cancer. Arsenic (As), beryllium (Be), cadmium (Cd), chromium (Cr) and nickel (Ni) are classified as Group 1 carcinogens by the International Agency for Research on Cancer. This review provides a comprehensive summary of current concepts of the molecular mechanisms of metal-induced carcinogenesis and focusing on a variety of pathways, including genotoxicity, mutagenesis, oxidative stress, epigenetic modifications such as DNA methylation, histone post-translational modification and alteration in microRNA regulation, competition with essential metal ions and cancer-related signaling pathways. This review takes a broader perspective and aims to assist in guiding future research with respect to the prevention and therapy of metal exposure in human diseases including cancer.
Topics: Animals; Carcinogenesis; Carcinogens; Environmental Exposure; Humans; Metals; Neoplasms
PubMed: 32674145
DOI: 10.1093/carcin/bgaa076