Human Cytochrome P450 Cancer-Related Metabolic Activities and Gene Polymorphisms: A Review.

Background: Cytochromes P450 (CYPs) are heme-containing oxidoreductase enzymes with mono-oxygenase activity. Human CYPs catalyze the oxidation of a great variety of chemicals, including xenobiotics, steroid hormones, vitamins, bile acids, procarcinogens, and drugs.

Findings: In our review article, we discuss recent data evidencing that the same CYP isoform can be involved in both bioactivation and detoxification reactions and convert the same substrate to different products.

Cytochrome P450 monooxygenase systems: Diversity and plasticity for adaptive stress response.

Superfamily of cytochromes P450 (CYPs) is composed of heme-thiolate-containing monooxygenase enzymes, which play crucial roles in the biosynthesis, bioactivation, and detoxification of a variety of organic compounds, both endogenic and exogenic. Majority of CYP monooxygenase systems are multi-component and contain various redox partners, cofactors and auxiliary proteins, which contribute to their diversity in both prokaryotes and eukaryotes. Recent progress in bioinformatics and computational biology approaches make it possible to undertake whole-genome and phylogenetic analyses of CYPomes of a variety of organisms.

Lipid peroxidation: Reactive carbonyl species, protein/DNA adducts, and signaling switches in oxidative stress and cancer.

Under the exposure of lipids to reactive oxygen species (ROS), lipid peroxidation proceeds non-enzymatically and generates an extremely heterogeneous mixture of reactive carbonyl species (RCS). Among them, HNE, HHE, MDA, methylglyoxal, glyoxal, and acrolein are the most studied and/or abundant ones. Over the last decades, significant progress has been achieved in understanding mechanisms of RCS generation, protein/DNA adduct formation, and their identification and quantification in biological samples.

Differentially expressed non-coding RNAs and their regulatory networks in liver cancer.

The vast majority of human transcriptome is represented by various types of small RNAs with little or no protein-coding capability referred to as non-coding RNAs (ncRNAs). Functional ncRNAs include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), which are expressed at very low, but stable and reproducible levels in a variety of cell types. ncRNAs regulate gene expression due to miRNA capability of complementary base pairing with mRNAs, whereas lncRNAs and circRNAs can sponge miRNAs off their target mRNAs to act as competitive endogenous RNAs (ceRNAs).

Evolutionary Conserved Short Linear Motifs Provide Insights into the Cellular Response to Stress.

Short linear motifs (SLiMs) are evolutionarily conserved functional modules of proteins composed of 3 to 10 residues and involved in multiple cellular functions. Here, we performed a search for SLiMs that exert sequence similarity to two segments of alpha-fetoprotein (AFP), a major mammalian embryonic and cancer-associated protein. Biological activities of the peptides, LDSYQCT (AFP) and EMTPVNPGV (GIP-9), have been previously confirmed under in vitro and in vivo conditions.

Short Linear Motifs Orchestrate Functioning of Human Proteins during Embryonic Development, Redox Regulation, and Cancer.

Short linear motifs (SLiMs) are evolutionarily conserved functional modules of proteins that represent amino acid stretches composed of 3 to 10 residues. The biological activities of two short peptide segments of human alpha-fetoprotein (AFP), a major embryo-specific and cancer-related protein, have been confirmed experimentally. This is a heptapeptide segment LDSYQCT in domain I designated as AFP and a nonapeptide segment EMTPVNPGV in domain III designated as GIP-9.

Oxidative distress in aging and age-related diseases: Spatiotemporal dysregulation of protein oxidation and degradation.

The concept of oxidative distress had arisen from the assessment of cellular response to high concentrations of reactive species that result from an imbalance between oxidants and antioxidants and cause biomolecular damage. The intracellular distribution and flux of reactive species dramatically change in time and space contributing to the remodeling of the redox landscape and sensitivity of protein residues to oxidants. Here, we hypothesize that compromised spatiotemporal control of generation, conversions, and removal of reactive species underlies protein damage and dysfunction of protein degradation machineries.

Predictive biomarkers for systemic therapy of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third cancer-related cause of death worldwide. In recent years, several systemic therapy drugs including sorafenib, lenvatinib, regorafenib, cabozantinib, ramucicurab, nivilumab, and pembrolizumab have been approved by FDA for advanced HCC. However, their insufficient efficacy, toxicity, and drug resistance require clinically applicable and validated predictive biomarkers.

Genomic Landscape of Liquid Biopsy for Hepatocellular Carcinoma Personalized Medicine.

Hepatocellular carcinoma (HCC) is the sixth most frequently diagnosed cancer and the third leading cause of cancer-related deaths worldwide. Advanced-stage HCC patients have poor survival rates and this requires the discovery of novel clear biomarkers for HCC early diagnosis and prognosis, identifying risk factors, distinguishing HCC from non-HCC liver diseases, and assessment of treatment response. Liquid biopsy has emerged as a novel minimally invasive approach to enable monitoring tumor progression, metastasis, and recurrence.

Proteomic Profiling and Artificial Intelligence for Hepatocellular Carcinoma Translational Medicine.

Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver with high morbidity and mortality rates worldwide. Since 1963, when alpha-fetoprotein (AFP) was discovered as a first HCC serum biomarker, several other protein biomarkers have been identified and introduced into clinical practice. However, insufficient specificity and sensitivity of these biomarkers dictate the necessity of novel biomarker discovery.

Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK.

It has been long recognized that cancer cells reprogram their metabolism under hypoxia conditions due to a shift from oxidative phosphorylation (OXPHOS) to glycolysis in order to meet elevated requirements in energy and nutrients for proliferation, migration, and survival. However, data accumulated over recent years has increasingly provided evidence that cancer cells can revert from glycolysis to OXPHOS and maintain both reprogrammed and oxidative metabolism, even in the same tumor. This phenomenon, denoted as cancer cell metabolic plasticity or hybrid metabolism, depends on a tumor micro-environment that is highly heterogeneous and influenced by an intensity of vasculature and blood flow, oxygen concentration, and nutrient and energy supply, and requires regulatory interplay between multiple oncogenes, transcription factors, growth factors, and reactive oxygen species (ROS), among others.

Dual Character of Reactive Oxygen, Nitrogen, and Halogen Species: Endogenous Sources, Interconversions and Neutralization.

Oxidative stress resulting from accumulation of reactive oxygen, nitrogen, and halogen species (ROS, RNS, and RHS, respectively) causes the damage of cells and biomolecules. However, over the long evolutionary time, living organisms have developed the mechanisms for adaptation to oxidative stress conditions including the activity of the antioxidant system (AOS), which maintains low intracellular levels of RONS (ROS and RNS) and RHS. Moreover, living organisms have adapted to use low concentrations of these electrophiles for the regulation of cell functions through the reversible post-translational chemical modifications of redox-sensitive amino acid residues in intracellular effectors of signal transduction pathways (protein kinases and protein phosphatases), transcription factors, etc.

Elucidating Binding Sites and Affinities of ERα Agonists and Antagonists to Human Alpha-Fetoprotein by In Silico Modeling and Point Mutagenesis.

Alpha-fetoprotein (AFP) is a major embryo- and tumor-associated protein capable of binding and transporting a variety of hydrophobic ligands, including estrogens. AFP has been shown to inhibit estrogen receptor (ER)-positive tumor growth, which can be attributed to its estrogen-binding ability. Despite AFP having long been investigated, its three-dimensional (3D) structure has not been experimentally resolved and molecular mechanisms underlying AFP-ligand interaction remains obscure.

Oxidative Stress and Advanced Lipoxidation and Glycation End Products (ALEs and AGEs) in Aging and Age-Related Diseases.

Oxidative stress is a consequence of the use of oxygen in aerobic respiration by living organisms and is denoted as a persistent condition of an imbalance between the generation of reactive oxygen species (ROS) and the ability of the endogenous antioxidant system (AOS) to detoxify them. The oxidative stress theory has been confirmed in many animal studies, which demonstrated that the maintenance of cellular homeostasis and biomolecular stability and integrity is crucial for cellular longevity and successful aging. Mitochondrial dysfunction, impaired protein homeostasis (proteostasis) network, alteration in the activities of transcription factors such as Nrf2 and NF-B, and disturbances in the protein quality control machinery that includes molecular chaperones, ubiquitin-proteasome system (UPS), and autophagy/lysosome pathway have been observed during aging and age-related chronic diseases.

Reactive Oxygen and Nitrogen Species-Induced Protein Modifications: Implication in Carcinogenesis and Anticancer Therapy.

Cancer is a complex disorder extremely dependent on its microenvironment and highly regulated by multiple intracellular and extracellular stimuli. Studies show that reactive oxygen and nitrogen species (RONS) play key roles in cancer initiation and progression. Accumulation of RONS caused by imbalance between RONS generation and activity of antioxidant system (AOS) has been observed in many cancer types.

ROS and RNS signalling: adaptive redox switches through oxidative/nitrosative protein modifications.

Over the last decade, a dual character of cell response to oxidative stress, eustress versus distress, has become increasingly recognized. A growing body of evidence indicates that under physiological conditions, low concentrations of reactive oxygen and nitrogen species (RONS) maintained by the activity of endogenous antioxidant system (AOS) allow reversible oxidative/nitrosative modifications of key redox-sensitive residues in regulatory proteins. The reversibility of redox modifications such as Cys S-sulphenylation/S-glutathionylation/S-nitrosylation/S-persulphidation and disulphide bond formation, or Tyr nitration, which occur through electrophilic attack of RONS to nucleophilic groups in amino acid residues provides redox switches in the activities of signalling proteins.

Human EGF-derived direct and reverse short linear motifs: conformational dynamics insight into the receptor-binding residues.

Short linear motifs (SLiMs) have been recognized to perform diverse functions in a variety of regulatory proteins through the involvement in protein-protein interactions, signal transduction, cell cycle regulation, protein secretion, etc. However, detailed molecular mechanisms underlying their functions including roles of definite amino acid residues remain obscure. In our previous studies, we demonstrated that conformational dynamics of amino acid residues in oligopeptides derived from regulatory proteins such as alpha-fetoprotein (AFP), carcino-embryonic antigen (CEA), and pregnancy specific β1-glycoproteins (PSGs) contributes greatly to their biological activities.

Pregnancy-Specific β1-Glycoproteins: Combined Biomarker Roles, Structure/Function Relationships and Implications for Drug Design.

Background: Pregnancy specific β1-glycoproteins (PSGs) have long been recognized as trophoblast quality and embryo viability markers. However, biological roles of PSGs remain obscure, and structure/function relationships to other feto-placental proteins as well as implications for drug design have not been reviewed. This review summarizes and discusses advances in 45-year studies of PSGs with focus on the latest achievements and the challenges for future investigations.

Alpha-fetoprotein: a renaissance.

Alpha-fetoprotein (AFP) is a major mammalian embryo-specific and tumor-associated protein that is also present in small quantities in adults at normal conditions. Discovery of the phenomenon of AFP biosynthesis in carcinogenesis by G. Abelev and Yu.

Correlation between biological activity and conformational dynamics properties of tetra- and pentapeptides derived from fetoplacental proteins.

In this work, using molecular dynamics simulation, we study conformational and dynamic properties of biologically active penta- and tetrapeptides derived from fetoplacental proteins such as alpha-fetoprotein, pregnancy specific β1-glycoprotein, and carcinoembryonic antigen. Existence of correlation between flexibility of peptide backbone and biological activity of the investigated peptides was shown. It was also demonstrated that flexibility of peptide backbone depends not only on its length, but also on the presence of reactive functional groups in amino acid side chains that participate in intramolecular interactions.

Modeling of three dimensional structure of human alpha-fetoprotein complexed with diethylstilbestrol: docking and molecular dynamics simulation study.

It has been long experimentally demonstrated that human alpha-fetoprotein (HAFP) has an ability to bind immobilized estrogens with the most efficiency for synthetic estrogen analog - diethylstilbestrol (DES). However, the question remains why the human AFP (HAFP), unlike rodent AFP, cannot bind free estrogens. Moreover, despite the fact that AFP was first discovered more than 50 years ago and is presently recognized as a "golden standard" among onco-biomarkers, its three-dimensional (3D) structure has not been experimentally solved yet.

Influence of intramolecular interactions on conformational and dynamic properties of analogs of heptapeptide AFP(14-20).

Conformational and dynamic properties of proteins and peptides play an important role in their functioning. However, mechanisms that underlie this influence have not been fully elucidated. In the present work we computationally constructed analogs of heptapeptide AFP(14-20) (LDSYQCT) - one of the biologically active sites of human α-fetoprotein (AFP) - to study their conformational and dynamic properties using molecular dynamics simulation.

Dynamic proteomics in modeling of the living cell. Protein-protein interactions.

This review is devoted to describing, summarizing, and analyzing of dynamic proteomics data obtained over the last few years and concerning the role of protein-protein interactions in modeling of the living cell. Principles of modern high-throughput experimental methods for investigation of protein-protein interactions are described. Systems biology approaches based on integrative view on cellular processes are used to analyze organization of protein interaction networks.

Cell adhesion proteins and alpha-fetoprotein. Similar structural motifs as prerequisites for common functions.

This review summarizes and analyzes data on structural and functional relationships between cell adhesion proteins and alpha-fetoprotein (AFP), which play an important role in embryo- and carcinogenesis and act in synergism with growth factors. These two groups of proteins are mosaic, multimodular, and polyfunctional, and each of their modules can function independently through binding with its specific membrane receptor. Most cell adhesion proteins contain modules similar to epidermal growth factor (EGF) and also their repeats, which determine the involvement of these proteins in regulation of cell proliferation, differentiation, and apoptosis.

[A molecular dynamics simulation study of human alpha-fetoprotein-derived peptide and its analogues. Influence of dielectric constant].

A comparative study of the conformation dynamics of a series of heptapeptides: the human alpha-fetoprotein fragment LDSYQCT and its seven analogues has been conducted. The effect of the dielectric constant of medium on the dynamics of heptapeptide conformation is considered. It is shown that electrostatic interactions have a marked effect on several accessible conformations and the dynamics of the behavior of amino acid residues.