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

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: Jan. 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.

Language: Английский

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The Multifaceted Roles of NRF2 in Cancer: Friend or Foe?

Antioxidants, Journal Year: 2024, Volume and Issue: 13(1), P. 70 - 70

Published: Jan. 2, 2024

Physiological concentrations of reactive oxygen species (ROS) play vital roles in various normal cellular processes, whereas excessive ROS generation is central to disease pathogenesis. The nuclear factor erythroid 2-related 2 (NRF2) a critical transcription that regulates the antioxidant systems response oxidative stress by governing expression genes encoding enzymes shield cells from diverse alterations. NRF2 and its negative regulator Kelch-like ECH-associated protein 1 (KEAP1) have been focus numerous investigations elucidating whether suppresses tumor promotion or conversely exerts pro-oncogenic effects. has found participate pathological including dysregulated cell proliferation, metabolic remodeling, resistance apoptosis. Herein, this review article will examine intriguing role phase separation activating transcriptional activity explore dual impacts on immunology, cancer stem cells, metastasis, long non-coding RNAs (LncRNAs). Taken together, aims discuss multifaceted both prevention while also addressing advantages, disadvantages, limitations associated with modulating therapeutically treatment.

Language: Английский

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Nrf2 Pathway and Oxidative Stress as a Common Target for Treatment of Diabetes and Its Comorbidities

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 821 - 821

Published: Jan. 9, 2024

Diabetes is a chronic disease that induces many comorbidities, including cardiovascular disease, nephropathy, and liver damage. Many mechanisms have been suggested as to how diabetes leads these of which increased oxidative stress in diabetic patients has strongly implicated. Limited knowledge antioxidative antidiabetic drugs substances can address comorbidities through the nuclear factor erythroid 2-related 2 (Nrf2) pathway calls for detailed investigation. This review will describe increases stress, general impact primarily contributes comorbidities. It also treatments diabetes, especially focusing on their effects Nrf2 pathway, shown similarly affect heart, kidney, systems. demonstrates common pathogenic component its associated potentially identifying this target guide future treatments.

Language: Английский

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5-Methylcytosine transferase NSUN2 drives NRF2-mediated ferroptosis resistance in non-small cell lung cancer

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(4), P. 106793 - 106793

Published: Feb. 24, 2024

RNA 5-methylcytosine (m5C) is an abundant chemical modification in mammalian RNAs and plays crucial roles regulating vital physiological pathological processes, especially cancer. However, the dysregulation of m5C its underlying mechanisms non-small cell lung cancer (NSCLC) remain unclear. Here we identified that NSUN2, a key methyltransferase, highly expressed NSCLC tumor tissue. We found elevated NSUN2 expression levels strongly correlate with grade size, predicting poor outcomes for patients. Furthermore, RNA-seq subsequent confirmation studies revealed antioxidant-promoting transcription factor NRF2 target depleting decreases increases sensitivity cells to ferroptosis activators both vitro vivo. Intriguingly, methylated-RIP-qPCR assay results indicated mRNA has higher level when overexpressed but shows no significant changes methyltransferase-deficient group. Mechanistically, confirmed upregulates by enhancing stability through within 5'UTR region recognized specific reader protein YBX1, rather than influencing translation. In rescue experiments, show knocking down diminished proliferation, migration, tolerance mediated overexpression. conclusion, our study unveils novel regulatory mechanism which sustains m5C-YBX1-axis, suggesting targeting regulated pathway might offer promising therapeutic strategies

Language: Английский

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Brusatol hinders the progression of bladder cancer by Chac1/Nrf2/SLC7A11 pathway

Experimental Cell Research, Journal Year: 2024, Volume and Issue: 438(2), P. 114053 - 114053

Published: April 24, 2024

Bladder cancer is a common tumor that impacts the urinary system and marked by significant fatality rate an unfavorable prognosis. Promising antineoplastic properties are exhibited brusatol, which obtained from dried ripe fruit of Brucea javanica. The present study aimed to evaluate influence brusatol on progression bladder uncover molecular mechanism involved. We used Cell Counting Kit-8, colony formation EdU assays detect cell numbers, viability proliferation. transwell migration assay ability. inhibition proliferation was studied flow cytometry western blotting. It revealed could reduce T24 5637 cells. able attenuate found treatment with increased levels reactive oxygen species, malondialdehyde Fe2+, thereby further promoting ferroptosis in In addition, RSL3 (an agonistor ferroptosis) ferrostatin-1 (a selective inhibitor enhanced or reversed brusatol-induced inhibition. vivo, significantly suppressed growth nude mice. Mechanistically, induced upregulating expression ChaC glutathione-specific gamma-glutamylcyclotransferase (Chac1) decreasing SLC7A11 Nrf2 To summarize, findings this research demonstrated hindered triggered via Chac1/Nrf2/SLC7A11 pathway.

Language: Английский

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Brusatol induces ferroptosis to inhibit hepatocellular carcinoma progression by targeting ATF3

Chemical Biology & Drug Design, Journal Year: 2024, Volume and Issue: 103(6)

Published: June 1, 2024

Ferroptosis is a novel form of programmed cell death that triggered by iron-dependent lipid peroxidation. Brusatol (BRU), natural nuclear factor erythroid 2-related 2 inhibitor, exhibits potent anticancer effects in various types cancer. However, the exact mechanism BRU treatment hepatocellular carcinoma (HCC) remains unknown. The HCC were detected using counting kit-8 and colony formation assays xenograft model. RNA sequencing (RNA-seq) bioinformatics analyses cells utilized to elucidate underlying HCC. levels reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), Fe

Language: Английский

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MicroRNA-204-5p Ameliorates Renal Injury via Regulating Keap1/Nrf2 Pathway in Diabetic Kidney Disease

Diabetes Metabolic Syndrome and Obesity, Journal Year: 2024, Volume and Issue: Volume 17, P. 75 - 92

Published: Jan. 1, 2024

Background: Diabetic kidney disease (DKD) is characterized by renal fibrosis, and the pathogenesis of fibrosis still not definitely confirmed. MiR-204-5p plays an important role in regulation autophagy oxidative stress. In this study, we aimed to investigate miR-204-5p on damage diabetic kidneys underlying mechanisms involved. Methods: vivo, AAV-Ksp-miR-204-5p mimics were injected into mice via tail vein. vitro, high glucose-induced HK-2 cells treated with inhibitor, mimics, ATG5 siRNA, tertiary butyl hydroquinone (TBHQ), ML385, or 3-Methyladenine (3-MA). FISH qRT-PCR used detect expression. The expressions protein mRNA detected Western blotting, immunofluorescence, immunohistochemistry qRT-PCR. concentration fibronectin culture medium was ELISA. Results: expression significantly inhibited than that control group. Delivering increased expression, improved function, stress, restored db/db mice. HG treatment cells. effectively reduced collagen I dysfunction, Nrf2 whereas these alterations abrogated inhibitor 3-methyladenine (3-MA, 5 mM) siRNA transfection HG-induced addition, aggravated decreased while abolished activator TBHQ. Furthermore, binding Keap1 confirmed luciferase reporter assay negatively regulated resulting activation pathway. Conclusion: MicroRNA-204-5p protects against progression restoring regulating Keap1/Nrf2 Keywords: disease, miR-204-5p, Keap1, Nrf2,

Language: Английский

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The Role of Nrf2 in the Regulation of Mitochondrial Function and Ferroptosis in Pancreatic Cancer

Antioxidants, Journal Year: 2024, Volume and Issue: 13(6), P. 696 - 696

Published: June 6, 2024

The transcription factor nuclear erythroid 2-related 2 (Nrf2) represents the master regulator of cellular antioxidant response and plays a critical role in tumorigenesis. This includes preventive effect Nrf2 on cell death through ferroptosis, which an essential mechanism therapy resistance malignant tumors, such as pancreatic ductal adenocarcinoma (PDAC) one most aggressive still incurable tumors. Addressing this issue, we provide overview mediated with particular emphasis its mitochondria organelle responsible for execution ferroptosis. We further outline how deregulated adds to progression PDAC, especially respect ferroptosis anti-cancer drug killing is impaired by resistance. Our review discusses recent approaches inhibition natural synthetic compounds overcome based enhanced Finally, outlook therapeutic strategies combined inducing drugs.

Language: Английский

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Identification of Penexanthone A as a Novel Chemosensitizer to Induce Ferroptosis by Targeting Nrf2 in Human Colorectal Cancer Cells

Marine Drugs, Journal Year: 2024, Volume and Issue: 22(8), P. 357 - 357

Published: Aug. 6, 2024

Ferroptosis has emerged as a potential mechanism for enhancing the efficacy of chemotherapy in cancer treatment. By suppressing nuclear factor erythroid 2-related 2 (Nrf2), cells may lose their ability to counteract oxidative stress induced by chemotherapy, thereby becoming more susceptible ferroptosis. In this study, we investigate penexanthone A (PXA), xanthone dimer component derived from endophytic fungus

Language: Английский

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In vitro and in silico hybrid approach to unveil triterpenoids from Helicteres hirsuta leaves as potential compounds for inhibiting Nrf2

RSC Advances, Journal Year: 2025, Volume and Issue: 15(3), P. 1915 - 1923

Published: Jan. 1, 2025

3β- O-trans -caffeoylbetulinic acid from Helicteres hirsuta inhibited Nrf2 in Huh7 with IC 50 of 74.5 μg mL −1 . Docking and dynamics simulations showed strong binding affinity this compound PI3Kα, an upstream modulator cancer cells.

Language: Английский

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