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Molecular Carcinogenesis Jun 2017Few kinases have been studied as extensively as protein kinase C (PKC), particularly in the context of cancer. As major cellular targets for the phorbol ester tumor... (Review)
Review
Few kinases have been studied as extensively as protein kinase C (PKC), particularly in the context of cancer. As major cellular targets for the phorbol ester tumor promoters and diacylglycerol (DAG), a second messenger generated by stimulation of membrane receptors, PKC isozymes play major roles in the control of signaling pathways associated with proliferation, migration, invasion, tumorigenesis, and metastasis. However, despite decades of research, fundamental questions remain to be answered or are the subject of intense controversy. Primary among these unresolved issues are the role of PKC isozymes as either tumor promoter or tumor suppressor kinases and the incomplete understanding on isozyme-specific substrates and effectors. The involvement of PKC isozymes in cancer progression needs to be reassessed in the context of specific oncogenic and tumor suppressing alterations. In addition, there are still major hurdles in addressing isozyme-specific function due to the limited specificity of most pharmacological PKC modulators and the lack of validated predictive biomarkers for response, which impacts the translation of these agents to the clinic. In this review we focus on key controversial issues and upcoming challenges, with the expectation that understanding the intricacies of PKC function will help fulfill the yet unsuccessful promise of targeting PKCs for cancer therapeutics.
Topics: Animals; Antineoplastic Agents; Diglycerides; Disease Progression; Humans; Isoenzymes; Molecular Targeted Therapy; Neoplasms; Phorbol Esters; Protein Kinase C; Substrate Specificity
PubMed: 28112438
DOI: 10.1002/mc.22617 -
IUBMB Life Jun 2019Protein kinase C (PKC) is activated by 1,2-diacylglycerol as a second messenger in the signaling mechanism coupled with the hydrolysis of membrane inositol... (Review)
Review
Protein kinase C (PKC) is activated by 1,2-diacylglycerol as a second messenger in the signaling mechanism coupled with the hydrolysis of membrane inositol phospholipids, although it was not found by screening for a 1,2-diacylglycerol-dependent enzyme. PKC is also a receptor for the tumor-promoting phorbol esters, but it was not identified by its property of binding phorbol esters, either. Instead, the discovery and characterization of PKC, now known to comprise a family with multiple isoforms, was through a circuitous voyage filled with unexpected twists and turns. This review summarizes the discovery and the initial experiments of PKC as a historical perspective of the enzyme family in the context of the progress in the studies on protein phosphorylation. © 2018 IUBMB Life, 71(6):697-705, 2019.
Topics: Diglycerides; Humans; Hydrolysis; Phorbol Esters; Phosphatidylinositols; Phosphorylation; Protein Binding; Protein Kinase C; Proteins
PubMed: 30393952
DOI: 10.1002/iub.1963 -
Polish Journal of Veterinary Sciences Dec 2021The aim of this study was to analyze the chemiluminescence (CL) of peripheral blood in clinically healthy horses of different sexes and ages. The tests were carried out...
The aim of this study was to analyze the chemiluminescence (CL) of peripheral blood in clinically healthy horses of different sexes and ages. The tests were carried out on 119 half- -breed horses, representing various forms of use (66 recreational horses and 53 sport horses). The test material was peripheral blood, which was collected under resting conditions, i.e. before physical activity related to the use of these animals. In the blood samples, spontaneous and stimulated CL with zymosan and phorbol myristate acetate were determined. It has been found that regular training effort increases the blood's pro-oxidative potential, which was demonstrated by significantly higher (p⟨0.05) CL values in sport horses compared to recreational animals. Analysis of the results did not show any statistically significant correlation between sex or age of the horses with chemiluminescence values in peripheral blood. The result of the research suggests the need to optimize the results of blood CL measurements, taking into account the number of neutrophils and the concentration of hemoglobin in the blood of tested animals. Analysis of non-optimized blood CL results may lead to premature conclusions.
Topics: Animals; Horses; Luminescence; Luminescent Measurements; Neutrophils; Tetradecanoylphorbol Acetate; Zymosan
PubMed: 35179840
DOI: 10.24425/pjvs.2021.139978 -
Journal of Cancer Research and Clinical... Aug 2017In 1988, we first reported the complete chemical structure of a new type of phorbol ester, abbreviated to DHPB, found in seed oil of Jatropha curcas L. (Saboodam in... (Review)
Review
PURPOSE
In 1988, we first reported the complete chemical structure of a new type of phorbol ester, abbreviated to DHPB, found in seed oil of Jatropha curcas L. (Saboodam in Thai) and its tumor-promoting activity on mouse skin. Although this seed oil contains toxic phorbol ester, it was planned to use it as a feasible renewable oil and the extracted seed cake as fertilizer. This utilization value opened a new science of Jatropha curcas.
METHODS
The main experimental results are cited from our publications, and the relevant literature screened from journals and PubMed.
RESULTS AND DISCUSSION
This paper begins with our original work on the structural elucidation of a new phorbol ester, 12-deoxy-16-hydroxyphorbol (DHPB): its tumor-promoting activity was compared with that of TPA. We think that it is timely to review the following research advances with Jatropha curcas, so numerous topics are classified as follows: (1) historical development of phorbol esters in seed oil; (2) toxicity of phorbol ester based on various bioassays; (3) degradation of phorbol ester; (4) a new pharmaceutical compound in seed; and (5) tumor promotion and progression with endogeneous tumor promoters in human carcinogenesis. The discovery of phorbol ester in seed oil raised awareness of the danger of public use of seed oil and seed cake in Thailand, and also indicated the necessity of discussing the concept of primary and tertiary cancer preventions.
CONCLUSION
It is worthwhile to study the future benefits and cancer risks of globally distributed Jatropha curcas L.
Topics: Carcinogenesis; Humans; Jatropha; Neoplasms; Phorbol Esters; Plant Oils; Seeds
PubMed: 28124725
DOI: 10.1007/s00432-017-2341-6 -
BioRxiv : the Preprint Server For... Aug 2023Activation of the Wnt pathway lies at the core of many human cancers. Wnt and macropinocytosis are often active in the same processes, and understanding how Wnt...
Activation of the Wnt pathway lies at the core of many human cancers. Wnt and macropinocytosis are often active in the same processes, and understanding how Wnt signaling and membrane trafficking cooperate should improve our understanding of embryonic development and cancer. Here we show that a macropinocytosis activator, the tumor promoter Phorbol 12-myristate 13-acetate (PMA), enhances Wnt signaling. Experiments using the embryo as an in vivo model showed marked cooperation between the PMA phorbol ester and Wnt signaling, which was blocked by inhibitors of macropinocytosis, Rac1 activity, and lysosome acidification. Human colorectal cancer tissue arrays and xenografts in mice showed a correlation of cancer progression with increased macropinocytosis/multivesicular body/lysosome markers and decreased GSK3 levels. The crosstalk between canonical Wnt, focal adhesions, lysosomes, and macropinocytosis suggests possible therapeutic targets for cancer progression in Wnt-driven cancers.
PubMed: 37333286
DOI: 10.1101/2023.06.02.543509 -
BMC Veterinary Research May 2022Sheep are an important livestock species worldwide and an essential large-animal model for animal husbandry and veterinary research. Understanding fundamental immune...
BACKGROUND
Sheep are an important livestock species worldwide and an essential large-animal model for animal husbandry and veterinary research. Understanding fundamental immune indicators, especially T-lymphocyte parameters, is necessary for research on sheep diseases and vaccines, to better understand the immune response to bacteria and viruses for reducing the use of antibiotics and improving the welfare of sheep. We randomly selected 36 sheep of similar ages to analyze cell-related immune indicators in peripheral blood mononuclear cells (PBMCs). The proportions of CD4 and CD8 T cells in PBMCs were detected by flow cytometry. We used Concanavalin A (Con A) and Phorbol-12-myristate-13-acetate (PMA)/Ionomycin to stimulate PBMCs, and measured the expression of IFN-γ, IL-4, and IL-17A using enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunospot assay (ELISpot). Simultaneously, PMA/Ionomycin/brefeldin A (BFA) was added to PBMCs, then the expression of IFN-γ, IL-4, and IL-17A was detected by flow cytometry after 4 h of culturing. In addition, we observed the proliferation of PBMCs stimulated with Con A for 3, 4, and 5 days.
RESULTS
The proportions of CD4 T lymphocytes (18.70 ± 4.21%) and CD8 T lymphocytes (8.70 ± 3.65%) were generally consistent among individuals, with a CD4/CD8 ratio of 2.40 ± 0.79. PBMCs produced high levels of IFN-γ, IL-4, and IL-17A after stimulation with PMA/Ionomycin and Con A. Furthermore, PMA/Ionomycin stimulation of PBMC yielded significantly higher cytokine levels than Con A stimulation. Flow cytometry showed that the level of IFN-γ (51.49 ± 11.54%) in CD8 T lymphocytes was significantly (p < 0.001) higher than that in CD4 T lymphocytes (14.29 ± 3.26%); IL-4 (16.13 ± 6.81%) in CD4 T lymphocytes was significantly (p < 0.001) higher than that in CD8 T lymphocytes (1.84 ± 1.33%), There was no difference in IL-17A between CD4 (2.83 ± 0.98%) and CD8 T lymphocytes (1.34 ± 0.67%). The proliferation of total lymphocytes, CD4 T lymphocytes, and CD8 T lymphocytes continued to increase between days 3 and 5; however, there were no significant differences in proliferation between the cell types during the stimulation period.
CONCLUSIONS
Evaluating primary sheep immune indicators, especially T lymphocytes, is significant for studying cellular immunity. This study provided valuable data and theoretical support for assessing the immune response of sheep to pathogens and improving sheep welfare.
Topics: Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cytokines; Flow Cytometry; Interleukin-17; Interleukin-4; Ionomycin; Leukocytes, Mononuclear; Lymphocyte Activation; Sheep; Tetradecanoylphorbol Acetate
PubMed: 35513847
DOI: 10.1186/s12917-022-03268-7 -
Journal of Medicinal Chemistry May 2021A small library of phorbol 12,13-diesters bearing low lipophilicity ester chains was prepared as potential neurogenic agents in the adult brain. They were also used in a...
A small library of phorbol 12,13-diesters bearing low lipophilicity ester chains was prepared as potential neurogenic agents in the adult brain. They were also used in a targeted UHPLC-HRMS screening of the latex of . Two new 12-deoxy-16-hydroxyphorbol 13,16-diesters were isolated, and their structures were deduced using two-dimensional NMR spectroscopy and NOE experiments. The ability of natural and synthetic compounds to stimulate transforming growth factor alpha (TFGα) release, to increase neural progenitor cell proliferation, and to stimulate neurogenesis was evaluated. All compounds that facilitated TGFα release promoted neural progenitor cell proliferation. The presence of two acyloxy moieties on the tigliane skeleton led to higher levels of activity, which decreased when a free hydroxyl group was at C-12. Remarkably, the compound bearing isobutyryloxy groups was the most potent on the TGFα assay and at inducing neural progenitor cell proliferation , also leading to enhanced neurogenesis when administered intranasally to mice.
Topics: Animals; Cell Proliferation; Mice; Neural Stem Cells; Neurogenesis; Phorbol Esters; Transforming Growth Factor alpha
PubMed: 33945688
DOI: 10.1021/acs.jmedchem.1c00156 -
Cell Death & Disease Jun 2019The transient receptor potential ion-channel superfamily consists of nonselective cation channels located mostly on the plasma membranes of numerous animal cell types,... (Review)
Review
The transient receptor potential ion-channel superfamily consists of nonselective cation channels located mostly on the plasma membranes of numerous animal cell types, which are closely related to sensory information transmission (e.g., vision, pain, and temperature perception), as well as regulation of intracellular Ca balance and physiological activities of growth and development. Transient receptor potential ion channel subfamily V (TRPV) is one of the largest and most diverse subfamilies, including TRPV1-TRPV6 involved in the regulation of a variety of cellular functions. TRPV4 can be activated by various physical and chemical stimuli, such as heat, mechanical force, and phorbol ester derivatives participating in the maintenance of normal cellular functions. In recent years, the roles of TRPV4 in cell proliferation, differentiation, apoptosis, and migration have been extensively studied. Its abnormal expression has also been closely related to the onset and progression of multiple tumors, so TRPV4 may be a target for cancer diagnosis and treatment. In this review, we focused on the latest studies concerning the role of TRPV4 in tumorigenesis and the therapeutic potential. As evidenced by the effects on cancerogenesis, TRPV4 is a potential target for anticancer therapy.
Topics: Animals; Apoptosis; Biomarkers; Cell Differentiation; Cell Membrane; Cell Movement; Cell Proliferation; Humans; Phorbol Esters; TRPV Cation Channels
PubMed: 31235786
DOI: 10.1038/s41419-019-1708-9 -
Seminars in Cancer Biology Feb 2018The AGC family of serine/threonine kinases (PKA, PKG, PKC) includes more than 60 members that are critical regulators of numerous cellular functions, including cell... (Review)
Review
The AGC family of serine/threonine kinases (PKA, PKG, PKC) includes more than 60 members that are critical regulators of numerous cellular functions, including cell cycle and differentiation, morphogenesis, and cell survival and death. Mutation and/or dysregulation of AGC kinases can lead to malignant cell transformation and contribute to the pathogenesis of many human diseases. Members of one subgroup of AGC kinases, the protein kinase C (PKC), have been singled out as critical players in carcinogenesis, following their identification as the intracellular receptors of phorbol esters, which exhibit tumor-promoting activities. This observation attracted the attention of researchers worldwide and led to intense investigations on the role of PKC in cell transformation and the potential use of PKC as therapeutic drug targets in cancer diseases. Studies demonstrated that many cancers had altered expression and/or mutation of specific PKC genes. However, the causal relationships between the changes in PKC gene expression and/or mutation and the direct cause of cancer remain elusive. Independent studies in normal cells demonstrated that activation of PKC is essential for the induction of cell activation and proliferation, differentiation, motility, and survival. Based on these observations and the general assumption that PKC isoforms play a positive role in cell transformation and/or cancer progression, many PKC inhibitors have entered clinical trials but the numerous attempts to target PKC in cancer has so far yielded only very limited success. More recent studies demonstrated that PKC function as tumor suppressors, and suggested that future clinical efforts should focus on restoring, rather than inhibiting, PKC activity. The present manuscript provides some historical perspectives on the tumor promoting function of PKC, reviewing some of the observations linking PKC to cancer progression, and discusses the role of PKC in the pathogenesis of cancer diseases and its potential usage as a therapeutic target.
Topics: Adenosine Triphosphate; Animals; Binding, Competitive; Genes, Tumor Suppressor; Humans; Molecular Targeted Therapy; Neoplasms; Oligonucleotides, Antisense; Phorbol Esters; Protein Isoforms; Protein Kinase C; Protein Kinase C beta; Protein Kinase C-delta; Protein Kinase Inhibitors
PubMed: 28571764
DOI: 10.1016/j.semcancer.2017.04.012 -
The Protein Journal Dec 2018Protein kinase C (PKC) is a family of signal transducing enzymes that have been implicated in anesthetic preconditioning signaling cascade. Evidences are emerging that... (Comparative Study)
Comparative Study
Protein kinase C (PKC) is a family of signal transducing enzymes that have been implicated in anesthetic preconditioning signaling cascade. Evidences are emerging that certain exogenous neuromodulators such as n-alkanols and general anesthetics can stimulate PKC activity by binding to regulatory C1A domain of the enzyme. However, the accurate binding sites in C1A domain as well as the molecular mechanism underlying binding-stimulated PKC activation still remain unelucidated. Here, we report a systematic investigation of the intermolecular interaction of human PKCδ C1A domain with its natural activator phorbol ester (PE) and co-activator dioleoylglycerol (DOG) as well as exogenous stimulators butanol, octanol and sevoflurane. The domain is computationally identified to potentially have three spatially vicinal ligand-binding pockets 1, 2 and 3, in which the pockets 1 and 2 have previously been determined as the binding sites of PE and DOG, respectively. Systematic cross-binding analysis reveals that long-chain octanol and DOG are well compatible with the flat, nonpolar pocket 2, where the nonspecific hydrophobic contacts and van der Waals packing are primarily responsible for the binding, while the general anesthetic sevoflurane prefer to interact with the rugged, polar pocket 3 through specific hydrogen bonds and electrostatic forces. Short-chain butanol appears to bind effectively none of the three pockets. In addition, the pocket 1 consists of two angled arms 1 and 2 that are also involved in pockets 2 and 3, respectively. Dynamics characterization imparts that binding of long-chain octanol and DOG to pocket 2 or binding of sevoflurane to pocket 3 can induce a conformational displacement in arm 1 or 2, thus further opening the included angle and enlarging pocket 1, which can improve the pocket 1-PE affinity via an allosteric mechanism, consequently stimulating the PE-induced PKCδ activation.
Topics: Butanols; Diglycerides; Humans; Molecular Dynamics Simulation; Octanols; Phorbol Esters; Protein Domains; Protein Kinase C-delta; Sevoflurane
PubMed: 30251087
DOI: 10.1007/s10930-018-9793-7