cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment

Journal of Hematology & Oncology, Год журнала: 2024, Номер 17(1)

Опубликована: Янв. 17, 2024

Cancer is a complex disease resulting from abnormal cell growth that induced by number of genetic and environmental factors. The tumor microenvironment (TME), which involves extracellular matrix, cancer-associated fibroblasts (CAF), tumor-infiltrating immune cells angiogenesis, plays critical role in progression. Cyclic adenosine monophosphate (cAMP) second messenger has pleiotropic effects on the TME. downstream effectors cAMP include cAMP-dependent protein kinase (PKA), exchange activated (EPAC) ion channels. While can activate PKA or EPAC promote cancer growth, it also inhibit proliferation survival context- type-dependent manner. Tumor-associated stromal cells, such as CAF release cytokines factors either stimulate production within Recent studies have shown targeting signaling TME therapeutic benefits cancer. Small-molecule agents adenylate cyclase been to growth. In addition, cAMP-elevating agents, forskolin, not only induce death, but directly some types. this review, we summarize current understanding biology immunology discuss basis for its context-dependent dual oncogenesis. Understanding precise mechanisms interact will be development effective therapies. Future aimed at investigating cAMP-cancer axis regulation may provide new insights into underlying tumorigenesis lead novel strategies.

Язык: Английский

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Rapid hippocampal synaptic potentiation induced by ketamine metabolite (2R,6R)-hydroxynorketamine persistently primes synaptic plasticity

Neuropsychopharmacology, Год журнала: 2025, Номер unknown

Опубликована: Март 17, 2025

Язык: Английский

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cAMP-Dependent Signaling and Ovarian Cancer

Cells, Год журнала: 2022, Номер 11(23), С. 3835 - 3835

Опубликована: Ноя. 29, 2022

cAMP-dependent pathway is one of the most significant signaling cascades in healthy and neoplastic ovarian cells. Working through its major effector proteins—PKA EPAC—it regulates gene expression many cellular functions. PKA promotes phosphorylation cAMP response element-binding protein (CREB) which mediates transcription, cell migration, mitochondrial homeostasis, proliferation, death. EPAC, on other hand, involved adhesion, binding, differentiation, interaction between junctions. Ovarian cancer growth metabolism largely depend changes signal processing cAMP-PKA-CREB axis, often associated with transformation, metastasis, inhibition apoptosis. In addition, intracellular level also determines course pathways including AKT, ERK, MAPK, mTOR, that are hypo- or hyperactivated among patients neoplasm. With this review, we summarize current findings ovary association carcinogenesis, multiplication, survival Additionally, indicate targeting particular stages processes might provide promising therapeutic opportunities for effective management cancer.

Язык: Английский

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Fine-tuning GPCR-mediated neuromodulation by biasing signaling through different G protein subunits

Molecular Cell, Год журнала: 2023, Номер 83(14), С. 2540 - 2558.e12

Опубликована: Июнь 29, 2023

Язык: Английский

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Regulatory sites of CaM-sensitive adenylyl cyclase AC8 revealed by cryo-EM and structural proteomics

EMBO Reports, Год журнала: 2024, Номер 25(3), С. 1513 - 1540

Опубликована: Фев. 13, 2024

Abstract Membrane adenylyl cyclase AC8 is regulated by G proteins and calmodulin (CaM), mediating the crosstalk between cAMP pathway Ca 2+ signalling. Despite importance of in physiology, structural basis its regulation CaM not well defined. Here, we report 3.5 Å resolution cryo-EM structure bovine bound to stimulatory Gαs protein presence /CaM. The reveals architecture ordered domains small molecule activator forskolin. extracellular surface features a negatively charged pocket, potential site for unknown interactors. well-resolved forskolin density, captured state does favour tight nucleotide binding. proteomics approaches, limited proteolysis crosslinking mass spectrometry (LiP-MS XL-MS), allowed us identify contact sites regulators, CaM, Gαs, Gβγ, as infer conformational changes induced these interactions. Our results provide framework understanding role flexible regions mechanism AC regulation.

Язык: Английский

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Emerging modes of regulation of neuromodulatory G protein-coupled receptors

Trends in Neurosciences, Год журнала: 2024, Номер 47(8), С. 635 - 650

Опубликована: Июнь 12, 2024

Язык: Английский

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Forskolin affects proliferation, migration and Paclitaxel-mediated cytotoxicity in non-small-cell lung cancer cell lines via adenylyl cyclase/cAMP axis

European Journal of Cell Biology, Год журнала: 2023, Номер 102(2), С. 151292 - 151292

Опубликована: Янв. 28, 2023

Non-Small-Cell Lung Cancer (NSCLC) is considered one of the most frequently diagnosed cancers and leading cause cancer-related deaths worldwide. Despite undoubted therapeutic advances that have occurred in clinical practice over time, due to its high degree both heterogeneity resistance, NSCLC remains largely incurable. As a natural cAMP elevating agent, Forskolin has shown anti-cancer properties different tumor types, thus supposing possible usage treating malignancies. In this study, we investigated outcome H1299 A549 cell lines, either alone or combination with Paclitaxel. We proved impairs growth migration ability these cells, concurrently. Albeit extent between A549, changes cell-cycle progression epithelial-mesenchymal markers were observed response administration. Interestingly, comparable impairment was also obtained phosphodiesterase inhibitor IBMX, while employment adenylyl cyclase SQ22536 counteracted, at least part, Forskolin-mediated anticancer effects. Besides as single demonstrated strongly enhances Paclitaxel-induced cytotoxicity, affecting death mainly via apoptosis induction. Notably, H89-mediated protein kinase A (PKA) inhibition further deteriorated outcome. Altogether, our data designate molecule NSCLC, recognize cyclase/cAMP axis pathways involved in. Although achieved preclinical stage, findings encourage design future studies aimed exploring treatment.

Язык: Английский

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Glucocorticoids and Their Receptor Isoforms: Roles in Female Reproduction, Pregnancy, and Foetal Development

Biology, Год журнала: 2023, Номер 12(8), С. 1104 - 1104

Опубликована: Авг. 9, 2023

Alterations in the hypothalamic–pituitary–adrenal (HPA) axis and associated changes circulating levels of glucocorticoids are integral to an organism’s response stressful stimuli. Glucocorticoids acting via glucocorticoid receptors (GRs) play a role fertility, reproduction, placental function, foetal development. GRs ubiquitously expressed throughout female reproductive system regulate normal function. Stress-induced have been shown inhibit reproduction affect gonadal function by suppressing hypothalamic–pituitary–gonadal (HPG) at each level. Furthermore, during pregnancy, mother’s exposure prenatal stress or external can result long-lasting alterations HPA neuroendocrine Several GR isoforms generated alternative splicing translation initiation from gene identified mammalian ovary uterus. The include splice variants, GRα GRβ, GRγ GR-P. exert both stimulatory inhibitory effects pro- anti-inflammatory functions ovary, vitro. In placenta, thirteen humans, guinea pigs, sheep, rats, mice, indicating they conserved across species may be important mediating differential stress. Distinctive responses glucocorticoids, birth outcomes pregnancy complications, sex-based variations could all potentially dependent on particular expression pattern. This comprehensive review provides overview structure relation fertility discusses signalling pregnancy. To generate this overview, extensive non-systematic literature search was conducted multiple databases, including PubMed, Web Science, Google Scholar, with focus original research articles, meta-analyses, previous papers addressing subject. integrates current understanding variants their roles signalling, growth.

Язык: Английский

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Modeling of enzyme-catalyzed P–O bond cleavage in the adenosine triphosphate molecule

Mendeleev Communications, Год журнала: 2024, Номер 34(1), С. 1 - 7

Опубликована: Янв. 1, 2024

Язык: Английский

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Enhanced kinase translocation reporters for simultaneous real-time measurement of PKA, ERK, and calcium

Journal of Biological Chemistry, Год журнала: 2025, Номер unknown, С. 108183 - 108183

Опубликована: Янв. 1, 2025

Kinase translocation reporters (KTRs) are powerful tools for single-cell measurement of time-integrated kinase activity but suffer from restricted dynamic range and limited sensitivity, particularly in neurons. To address these limitations, we developed enhanced KTRs (eKTRs) protein A (PKA) extracellular signal-regulated (ERK) by (i) increasing KTR size, which reduces the confounding effect diffusion through nuclear pore, (ii) modulating strength bipartite localization signal (bNLS) their sensor domains, to ensures that relative distribution between nucleus cytoplasmic is determined active import, export, cognate kinase. The resultant sets ePKA-KTRs eERK-KTRs display high broad range, cell type-specific tuning. Moreover, co-expression optically separable allowed us simultaneously monitor activation inhibition PKA ERK live cells, verified eKTRs respond as expected direct agonists inhibitors, crosstalk pathways highly unbalanced, with suppressing activity, while induces activity. Taken together, our findings highlight importance size bNLS sensitivity show different types require eKTRs, identify ePKA-KTR1.4 eERK-KTR1.2 well-suited monitoring primary sensory

Язык: Английский

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