Role of A-kinase anchoring proteins in cyclic-AMP-mediated Schwann cell proliferation

Asirvatham, Angela L.; Schworer, Charles M.; Stahl, Richard C.; Heitzman, Deborah A.; Carey, David J.

doi:10.1016/j.cellsig.2021.109977

Cited by 4 publications

(11 citation statements)

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“…The cAMP pathway is a universal signaling pathway involved in various biological processes, including cell proliferation, differentiation, and apoptosis [ 9 ]. A recent study demonstrated cAMP’s ability to promote Schwann cell proliferation through the upregulation of A-kinase anchoring protein 95 (AKAP95) and cyclin D3 [ 9 ]. AKAP95 is a scaffolding protein that coordinates downstream signaling events in the nucleus, and cyclin D3 is a cell cycle regulatory protein [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…A recent study demonstrated cAMP’s ability to promote Schwann cell proliferation through the upregulation of A-kinase anchoring protein 95 (AKAP95) and cyclin D3 [ 9 ]. AKAP95 is a scaffolding protein that coordinates downstream signaling events in the nucleus, and cyclin D3 is a cell cycle regulatory protein [ 9 ]. The cAMP pathway is also known to be anti-inflammatory in addition to its proliferative effects.…”

Section: Introductionmentioning

confidence: 99%

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Forskolin-mediated cAMP activation upregulates TNF-α expression despite NF-κB downregulation in LPS-treated Schwann cells

Henry,

Wilcox,

Asirvatham

2024

PLoS ONE

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Although Schwann cells have been found to play a key role in inflammation and repair following nerve injury, the exact pathway is still unknown. To explore the mechanism by which Schwann cells exert their effects in the neuron microenvironment, we investigated two main inflammatory pathways: the NF-κB and cAMP pathways, and their downstream signaling molecules. In this study, lipopolysaccharide (LPS), a bacterial endotoxin, was used to activate the NF-κB pathway, and forskolin, a plant extract, was used to activate the cAMP pathway. The rat RT4-D6P2T Schwann cell line was treated with 0.1, 1, or 10 μg/mL of LPS, with or without 2 μM of forskolin, for 1, 3, 12, and 24 hours to determine the effects of elevated cAMP levels on LPS-treated cell viability. To investigate the effects of elevated cAMP levels on the expression of downstream signaling effector proteins, specifically NF-κB, TNF-α, AKAP95, and cyclin D3, as well as TNF-α secretion, RT4-D6P2T cells were incubated in the various treatment combinations for a 3-hour time period. Overall, results from the CellTiter-Glo viability assay revealed that forskolin increased viability in cells treated with smaller doses of LPS for 1 and 24 hours. For all time points, 10 μg/mL of LPS noticeably reduced viability regardless of forskolin treatment. Results from the Western blot analysis revealed that, at 10 μg/mL of LPS, forskolin upregulated the expression of TNF-α despite a downregulation of NF-κB, which was also accompanied by a decrease in TNF-α secretion. These results provide evidence that cAMP might regulate TNF-α expression through alternate pathways. Furthermore, although cAMP activation altered AKAP95 and cyclin D3 expression at different doses of LPS, there does not appear to be an association between the expression of AKAP95 or cyclin D3 and the expression of TNF-α. Exploring the possible interactions between cAMP, NF-κB, and other key inflammatory signaling pathways might reveal a potential therapeutic target for the treatment of nerve injury and inflammation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Forskolin-mediated cAMP activation upregulates TNF-α expression despite NF-κB downregulation in LPS-treated Schwann cells

Henry,

Wilcox,

Asirvatham

2024

PLoS ONE

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“…Cyclic adenosine monophosphate signaling has also been shown to enhance the survival of Schwann cells, suggesting that it plays a crucial role in the development and maintenance of the peripheral nerves. 16 Based on available evidence, it could be hypothesized that PDE inhibitors might prevent paclitaxel-induced peripheral neuropathy. Koyanagi et al 17 investigated cilostazol as a preventive agent for paclitaxel-induced dedifferentiation of Schwann cell.…”

Section: Introductionmentioning

confidence: 99%

“…Activation of these factors leads to increased expression of myelin‐specific genes, which is necessary for proper nerve function. Cyclic adenosine monophosphate signaling has also been shown to enhance the survival of Schwann cells, suggesting that it plays a crucial role in the development and maintenance of the peripheral nerves 16 . Based on available evidence, it could be hypothesized that PDE inhibitors might prevent paclitaxel‐induced peripheral neuropathy.…”

Section: Introductionmentioning

confidence: 99%

Effect of cilostazol on preventing paclitaxel‐induced neuropathy in patients with breast cancer: A randomized controlled trial

et al. 2023

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Study ObjectivePaclitaxel‐induced peripheral neuropathy is a significant clinical problem can markedly deteriorate patient's quality of life (QoL). Preclinical evidence exists about the preventive capacity of cilostazol against peripheral neuropathy. However, this hypothesis has not yet been clinically investigated. This proof‐of‐concept study evaluated the effect of cilostazol on the incidence of paclitaxel‐induced peripheral neuropathy in patients with non‐metastatic breast cancer.DesignThis is a parallel randomized placebo‐controlled trial.SettingThe Oncology Center at Mansoura University, Egypt.PatientsPatients with breast cancer scheduled to receive paclitaxel 175 mg/m2 biweekly.InterventionsPatients were randomized to either cilostazol group who received cilostazol tablets 100 mg BID, or to control group who received placebo instead.MeasurementsThe primary endpoint was the incidence of paclitaxel‐induced neuropathy evaluated through common terminology criteria for adverse event (NCI‐CTCAE) version 4. Secondary endpoints included assessment of the patient's QoL by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group‐Neurotoxicity (FACT‐GOG‐NTx) subscale. Exploratory outcome measures included changes in serum levels of biomarkers namely nerve growth factor (NGF), and neurofilament light chain (NfL).Main ResultsThe incidence of grade 2 and 3 peripheral neuropathies were significantly lower in the cilostazol group (40%) compared to the control group (86.7%) (p < 0.001). The incidence of clinically significant worsening in neuropathy‐related QoL was higher in control group compared to the cilostazol group (p = 0.001). A higher percent increase from baseline in serum NGF was observed in the cilostazol group (p = 0.043). The circulating levels of NfL deemed comparable between the two arms at the end of the study (p = 0.593).ConclusionAdjunctive use of cilostazol is as a novel option that might reduce the incidence of paclitaxel‐induced peripheral neuropathy and improve the patients' QoL. Future larger clinical trials are warranted to confirm these findings.

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“…AKAP is a structurally distinct but equally functional scaffolding protein that contains an amphipathic helix domain that binds to the N-terminal end of the PKA-RII dimer and a directed structural part that determines the intracellular subcellular location of the PKA/AKAP complex, which together act to bind to cAMP-dependent protein kinase A (PKA) and anchor its regulatory subunit in the vicinity of the substrate [3]. A substantial amount of recent research has revealed that scaffold protein-organized macromolecular transduction complexes regulate the coordination of signaling events that result in the development and progression of cancer [4].…”

Section: Introductionmentioning

confidence: 99%

AKAP8L as a Novel Prognostic Biomarker Correlated with Immune Infiltrates in Gastric Cancer

Zhang,

Liu,

Yang

et al. 2023

Preprint

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Background Stomach adenocarcinoma (STAD), the most common histologic type of gastric cancer (GC), has unclear molecular mechanisms. A-kinase anchoring protein 8 (AKAP8L) is significantly linked to various tumor processes, including immune invasion and metabolism. However, the role of AKAP8L in STAD development remains enigmatic. This study illuminates AKAP8L’s molecular mechanism, metabolic implications in STAD progression, and potential as a prognostic biomarker. Methods Employing diverse databases (TCGA, TIMER, GEPIA, Human Protein Atlas, GSEA), we examined the AKAP8L-STAD correlation. Comparative AKAP8L mRNA/protein analysis was conducted in STAD vs. normal tissues. Immunohistochemistry assays validated the findings in stomach samples from STAD patients. The connection of AKAP8L to clinical attributes is revealed. The prognostic potential was assessed via Kaplan‒Meier analysis and Cox regression. AKAP8L’s link to STAD immune cell infiltration was explored through TIMER. STRING was used to construct the AKAP8L-binding protein network. The R package clusterProfiler enriches AKAP8L’s functions. Immune infiltration’s relationship with AKAP8L in STAD was analyzed via the single-sample GSEA (ssGSEA) method from the R package GSVA and the TIMER database. The diagnostic potential of AKAP8L was assessed using the receiver operating characteristic (ROC) curve, quantified by the area under the curve (AUC) score. Results Pancancer analysis revealed upregulated AKAP8L expression in STAD tissues compared to normal tissues, with elevated expression correlated with poor prognosis. The ROC curve indicated that the possible diagnostic biomarker AKAP8L (AUC = 0.821) might exist. Low survival, tumor stage, sample type, subgroup, tumor grade, and lymph node metastasis are all related to higher AKAP8L expression. AKAP8L was connected with tumor-infiltrating lymphocytes (TILs), including immune supporting cells and immunosuppressive cells, and was substantially linked with several immunological marker sets in STAD. Further enrichment analysis showed that the carcinogenicity of AKAP8L may be related to "phosphoinositide metabolism", which provides a novel idea for treating STAD. Conclusion In STAD development, upregulated AKAP8L emerges as a key factor associated with immune cell infiltration levels and cellular metabolism. AKAP8L may hold promise as a biomarker, prognostically signifying a more unfavorable outcome for individuals afflicted by STAD.

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Role of A-kinase anchoring proteins in cyclic-AMP-mediated Schwann cell proliferation

Cited by 4 publications

References 45 publications

Forskolin-mediated cAMP activation upregulates TNF-α expression despite NF-κB downregulation in LPS-treated Schwann cells

Forskolin-mediated cAMP activation upregulates TNF-α expression despite NF-κB downregulation in LPS-treated Schwann cells

Effect of cilostazol on preventing paclitaxel‐induced neuropathy in patients with breast cancer: A randomized controlled trial

AKAP8L as a Novel Prognostic Biomarker Correlated with Immune Infiltrates in Gastric Cancer

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