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Current Pharmacology Reports Oct 2023Castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer (PCa) due to the development of resistance to androgen deprivation therapy and...
PURPOSE OF REVIEW
Castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer (PCa) due to the development of resistance to androgen deprivation therapy and anti-androgens. Here, we review the emerging role of Wnt signaling in therapeutic resistance of CRPC.
RECENT FINDINGS
Convincing evidence have accumulated that Wnt signaling is aberrantly activated through genomic alterations and autocrine and paracrine augmentations. Wnt signaling plays a critical role in a subset of CRPC and in resistance to anti-androgen therapies. Wnt signaling navigates CRPC through PCa heterogeneity, neuroendocrine differentiation, DNA repair, PCa stem cell maintenance, epithelial-mesenchymal-transition and metastasis, and immune evasion.
SUMMARY
Components of Wnt signaling can be harnessed for inhibiting PCa growth and metastasis and for developing novel therapeutic strategies to manage metastatic CRPC. There are many Wnt pathway-based potential drugs in different stages of pre-clinical development and clinical trials but so far, no Wnt signaling-specific drug has been approved by FDA for clinical use in CRPC.
PubMed: 37994344
DOI: 10.1007/s40495-023-00333-z -
Progress in Lipid Research Jan 2024Lipoprotein metabolism is critical to inflammation. While the periphery and central nervous system (CNS) have separate yet connected lipoprotein systems, impaired... (Review)
Review
Lipoprotein metabolism is critical to inflammation. While the periphery and central nervous system (CNS) have separate yet connected lipoprotein systems, impaired lipoprotein metabolism is implicated in both cardiometabolic and neurological disorders. Despite the substantial investigation into the composition, structure and function of lipoproteins, the lipoprotein oxylipin profiles, their influence on lipoprotein functions, and their potential biological implications are unclear. Lipoproteins carry most of the circulating oxylipins. Importantly, lipoprotein-mediated oxylipin transport allows for endocrine signaling by these lipid mediators, long considered to have only autocrine and paracrine functions. Alterations in plasma lipoprotein oxylipin composition can directly impact inflammatory responses of lipoprotein metabolizing cells. Similar investigations of CNS lipoprotein oxylipins are non-existent to date. However, as APOE4 is associated with Alzheimer's disease-related microglia dysfunction and oxylipin dysregulation, ApoE4-dependent lipoprotein oxylipin modulation in neurological pathologies is suggested. Such investigations are crucial to bridge knowledge gaps linking oxylipin- and lipoprotein-related disorders in both periphery and CNS. Here, after providing a summary of existent literatures on lipoprotein oxylipin analysis methods, we emphasize the importance of lipoproteins in oxylipin transport and argue that understanding the compartmentalization and distribution of lipoprotein oxylipins may fundamentally alter our consideration of the roles of lipoprotein in cardiometabolic and neurological disorders.
Topics: Humans; Oxylipins; Apolipoprotein E4; Lipoproteins; Nervous System Diseases; Cardiovascular Diseases
PubMed: 37979798
DOI: 10.1016/j.plipres.2023.101265 -
Contralateral Astrocyte Response to Acute Optic Nerve Damage Is Mitigated by PANX1 Channel Activity.International Journal of Molecular... Oct 2023Glial reactivity is considered a hallmark of damage-induced innate immune responses in the central nervous system. In the visual system, unilateral optic nerve damage...
Glial reactivity is considered a hallmark of damage-induced innate immune responses in the central nervous system. In the visual system, unilateral optic nerve damage elicits dramatic glial reactivity in the retina directly affected by the lesion and a similar, albeit more modest, effect in the contralateral eye. Evaluation of astrocyte changes in a mouse model of optic nerve crush indicates that astrocyte reactivity, as a function of retinal coverage and cellular hypertrophy, occurs within both the experimental and contralateral retinas, although the hypertrophic response of the astrocytes in the contralateral eyes is delayed for at least 24 h. Evaluation of astrocytic reactivity as a function of expression indicates a similar, muted but significant, response in contralateral eyes. This constrained glial response is completely negated by conditional knock out of in both astrocytes and Müller cells. Further studies are required to identify if this is an autocrine or a paracrine suppression of astroglial reactivity.
Topics: Mice; Animals; Astrocytes; Neuroglia; Retina; Optic Nerve Injuries; Optic Nerve; Glial Fibrillary Acidic Protein; Nerve Tissue Proteins; Connexins
PubMed: 37958624
DOI: 10.3390/ijms242115641 -
EGastroenterology Jun 2023The understanding of the mechanisms of liver fibrosis has been dominated by models in which chronic hepatocellular injury is the initiating step as is seen with viral...
The understanding of the mechanisms of liver fibrosis has been dominated by models in which chronic hepatocellular injury is the initiating step as is seen with viral infections. The increased prevalence of the metabolic syndrome, and the increases in liver fibrosis due to metabolic syndrome driven non-alcoholic steatohepatitis (NASH), has made it a priority to understand how this type of liver fibrosis is similar to, and different from, pure hepatocellular injury driven liver fibrosis. Both types of liver fibrosis have the transformation of the hepatic stellate cell (HSC) into a myofibroblast as a key step. In metabolic syndrome, there is little evidence that metabolite changes such as high levels of glucose and free fatty acids are directly inducing HSC transdifferentiation, however, metabolite changes may lead to reductions in immunomodulatory and hepatoprotective molecules such as lipoxins, resolvins and Interleukin (IL)-22. Cells of the innate immune system are known to be important intermediaries between hepatocellular damage and HSC transdifferentiation, primarily by producing cytokines such as transforming growth factor-β (TGF-β) and platelet derived growth factor (PDGF). Resident and infiltrating macrophages are the dominant innate immune cells, but others (dendritic cells, neutrophils, natural killer T cells and mucosal-associated invariant T cells) also have important roles in inducing and resolving liver fibrosis. CD8+ and CD4+ T cells of the adaptive immune system have been identified to have greater profibrotic roles than previously realised by inducing hepatocyte death (auto-aggressive CD8+T) cells and cytokines producing (TH17 producing CD4+T) cells. Finally, the cellular networks present in NASH fibrosis are being identified and suggest that once fibrosis has developed cell-to-cell communication is dominated by myofibroblasts autocrine signalling followed by communication with cholangiocytes and endothelial cells, with myofibroblast-hepatocyte, and myofibroblast-macrophage signalling having minor roles. Such information is essential to the development of antifibrotic strategies for different stages of fibrosis.
PubMed: 37946713
DOI: 10.1136/egastro-2023-100015 -
Neuron Nov 2023Efforts are ongoing to map synaptic wiring diagrams, or connectomes, to understand the neural basis of brain function. However, chemical synapses represent only one type...
Efforts are ongoing to map synaptic wiring diagrams, or connectomes, to understand the neural basis of brain function. However, chemical synapses represent only one type of functionally important neuronal connection; in particular, extrasynaptic, "wireless" signaling by neuropeptides is widespread and plays essential roles in all nervous systems. By integrating single-cell anatomical and gene-expression datasets with biochemical analysis of receptor-ligand interactions, we have generated a draft connectome of neuropeptide signaling in the C. elegans nervous system. This network is characterized by high connection density, extended signaling cascades, autocrine foci, and a decentralized topology, with a large, highly interconnected core containing three constituent communities sharing similar patterns of input connectivity. Intriguingly, several key network hubs are little-studied neurons that appear specialized for peptidergic neuromodulation. We anticipate that the C. elegans neuropeptidergic connectome will serve as a prototype to understand how networks of neuromodulatory signaling are organized.
Topics: Animals; Connectome; Caenorhabditis elegans; Neurons; Gene Expression; Synapses
PubMed: 37935195
DOI: 10.1016/j.neuron.2023.09.043 -
Scientific Reports Nov 2023Glutamate, the major excitatory neurotransmitter in the central nervous system, has also been found to play a role in embryonic stem (ES) cells. However, the exact...
Glutamate, the major excitatory neurotransmitter in the central nervous system, has also been found to play a role in embryonic stem (ES) cells. However, the exact mechanism and function of glutamatergic signaling in ES cells remain poorly understood. In this study, we identified a glutamatergic transmission circuit in ES cells that operates through an autocrine mechanism and regulates cell proliferation. We performed biological analyses to identify the key components involved in glutamate biosynthesis, packaging for secretion, reaction, and reuptake in ES cells, including glutaminase, vesicular glutamate transporter, glutamate N-methyl-D-aspartate (NMDA) receptor, and cell membrane excitatory amino-acid transporter (EAAT). We directly quantified the released glutamate signal using microdialysis-high performance liquid chromatography-tandem mass spectrometry (MD-HPLC-MS-MS). Pharmacological inhibition of endogenous glutamate release and the resulting tonic activation of NMDA receptors significantly affected ES cell proliferation, suggesting that ES cells establish a glutamatergic autocrine niche via releasing and responding to the transmitter for their own regulation.
Topics: Glutamic Acid; Embryonic Stem Cells; Receptors, N-Methyl-D-Aspartate; Excitatory Amino Acids; Cell Proliferation
PubMed: 37925518
DOI: 10.1038/s41598-023-46477-2 -
Journal of Clinical Medicine Oct 2023In recent years, numerous approaches have been developed to comprehend the molecular alterations underlying thyroid cancer (TC) oncogenesis and explore novel therapeutic...
In recent years, numerous approaches have been developed to comprehend the molecular alterations underlying thyroid cancer (TC) oncogenesis and explore novel therapeutic strategies for TC. It is now well established that the neurokinin-1 receptor (NK-1R) is overexpressed in cancer cells and that NK-1R is essential for the viability of cancer cells. The binding of substance P (SP) to NK-1R in neoplastic cells plays a pivotal role in cancer progression by promoting neoplastic cell growth, protecting tumor cells from apoptosis, triggering invasion and metastasis through the enhanced migration of cancer cells, and stimulating endothelial cell proliferation for tumor angiogenesis. Remarkably, all types of human TC (papillary, follicular, medullary, anaplastic), as well as metastatic lesions, exhibit the overexpression of SP and NK-1R compared to the normal thyroid gland. TC cells synthesize and release SP, which exerts its multiple functions through autocrine, paracrine, intracrine, and neuroendocrine processes, including the regulation of tumor burden. Consequently, the secretion of SP from TC results in increased SP levels in plasma, which are significantly higher in TC patients compared to controls. Additionally, NK-1R antagonists have demonstrated a dose-dependent antitumor action. They impair cancer cell proliferation on one side and induce apoptosis of tumor cells on the other side. Furthermore, it has been demonstrated that NK-1R antagonists inhibit neoplastic cell migration, thereby impairing both invasiveness and metastatic abilities, as well as angiogenesis. Given the consistent overexpression of NK-1R in all types of TC, targeting this receptor represents a promising therapeutic approach for TC. Therefore, NK-1R antagonists, such as the drug aprepitant, may represent novel drugs for TC treatment.
PubMed: 37835053
DOI: 10.3390/jcm12196409 -
BMC Cancer Oct 2023Cancer cells express immunosuppressive molecules, such as programmed death ligands (PD-L)1 and PD-L2, enabling evasion from the host's immune system. Cancer cells...
BACKGROUND
Cancer cells express immunosuppressive molecules, such as programmed death ligands (PD-L)1 and PD-L2, enabling evasion from the host's immune system. Cancer cells synthesize and secrete acetylcholine (ACh), acting as an autocrine or paracrine hormone to promote their proliferation, differentiation, and migration.
METHODS
We correlated the expression of PD-L1, PD-L2, cholinergic muscarinic receptor 3 (M3R), alpha 7 nicotinic receptor (α7nAChR), and choline acetyltransferase (ChAT) in colorectal cancer (CRC) tissues with the stage of disease, gender, age, risk, and patient survival. The effects of a muscarinic receptor blocker, atropine, and a selective M3R blocker, 4-DAMP, on the expression of immunosuppressive and cholinergic markers were evaluated in human CRC (LIM-2405, HT-29) cells.
RESULTS
Increased expression of PD-L1, M3R, and ChAT at stages III-IV was associated with a high risk of CRC and poor survival outcomes independent of patients' gender and age. α7nAChR and PD-L2 were not changed at any CRC stages. Atropine and 4-DAMP suppressed the proliferation and migration of human CRC cells, induced apoptosis, and decreased PD-L1, PD-L2, and M3R expression in CRC cells via inhibition of EGFR and phosphorylation of ERK.
CONCLUSIONS
The expression of immunosuppressive and cholinergic markers may increase the risk of recurrence of CRC. These markers might be used in determining prognosis and treatment regimens for CRC patients. Blocking cholinergic signaling may be a potential therapeutic for CRC through anti-proliferation and anti-migration via inhibition of EGFR and phosphorylation of ERK. These effects allow the immune system to recognize and eliminate cancer cells.
Topics: Humans; alpha7 Nicotinic Acetylcholine Receptor; Atropine; B7-H1 Antigen; Cholinergic Agents; Colorectal Neoplasms; ErbB Receptors; HT29 Cells; Immune Checkpoint Inhibitors; Receptors, Muscarinic; Programmed Cell Death 1 Ligand 2 Protein
PubMed: 37828429
DOI: 10.1186/s12885-023-11410-3 -
Frontiers in Oncology 2023Recently published work provide the first known evidence of a malignancy-associated regulatory mechanism, functionally connecting a phospho-regulated degron domain...
Recently published work provide the first known evidence of a malignancy-associated regulatory mechanism, functionally connecting a phospho-regulated degron domain embedded in a receptor tyrosine kinase (RTK), with its ectopic expression in cancer, conditional to a specific autocrine growth factor signal. Mechanistically, the growth factor-triggered phosphorylation inhibits the degron domain present in the regulated RTK, blocking access to a specific degradation complex. This ultimately rescues the RTK from rapid ubiquitin-proteasome-system-mediated degradation and, most importantly, causes its cellular overexpression. This mechanism, which has been here assigned the new functional name "" (), provides an additional layer and potentially preferential tool for the control of RTKs expression in cancer, in addition to other mechanisms acting at the transcriptional and messenger transcript stabilization levels. We propose this newly defined phosphorylation/ubiquitination switch-dependent signal to bear wider unexploited relevance in cell biology and human pathophysiology. The recently identified mechanism underlying an -regulated RTK is discussed herein in the context of physiological endocrine circuits and cancer.
PubMed: 37823054
DOI: 10.3389/fonc.2023.1278402 -
Cell Oct 2023Pollen-pistil interactions establish interspecific/intergeneric pre-zygotic hybridization barriers in plants. The rejection of undesired pollen at the stigma is crucial...
Pollen-pistil interactions establish interspecific/intergeneric pre-zygotic hybridization barriers in plants. The rejection of undesired pollen at the stigma is crucial to avoid outcrossing but can be overcome with the support of mentor pollen. The mechanisms underlying this hybridization barrier are largely unknown. Here, in Arabidopsis, we demonstrate that receptor-like kinases FERONIA/CURVY1/ANJEA/HERCULES RECEPTOR KINASE 1 and cell wall proteins LRX3/4/5 interact on papilla cell surfaces with autocrine stigmatic RALF1/22/23/33 peptide ligands (sRALFs) to establish a lock that blocks the penetration of undesired pollen tubes. Compatible pollen-derived RALF10/11/12/13/25/26/30 peptides (pRALFs) act as a key, outcompeting sRALFs and enabling pollen tube penetration. By treating Arabidopsis stigmas with synthetic pRALFs, we unlock the barrier, facilitating pollen tube penetration from distantly related Brassicaceae species and resulting in interspecific/intergeneric hybrid embryo formation. Therefore, we uncover a "lock-and-key" system governing the hybridization breadth of interspecific/intergeneric crosses in Brassicaceae. Manipulating this system holds promise for facilitating broad hybridization in crops.
Topics: Arabidopsis; Arabidopsis Proteins; Brassicaceae; Peptide Hormones; Peptides; Pollen; Pollen Tube; Reproductive Isolation
PubMed: 37806310
DOI: 10.1016/j.cell.2023.09.003