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In silico prediction of the action of bromelain on PI3K/Akt signalling pathway to arrest nasopharyngeal cancer oncogenesis by targeting phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha protein

Shamsuri AS, Sim EU

BMC Res Notes, 2024 Nov 26;17(1):346.
PMID: 39593139 DOI: 10.1186/s13104-024-06995-2

OBJECTIVE: This research investigates the potential anti-tumour effects of bromelain, an aqueous extract from pineapple stems and fruits, on nasopharyngeal cancer (NPC). While bromelain is known for its medicinal properties in various cancers, its impact on NPC remains unexplored.
RESULTS: Using in silico methods, we studied the predicted interactions between bromelain and key proteins involved in NPC oncogenesis, specifically β-catenin, PIK3CA, mTOR, EGFR, and BCL2. Molecular docking strategies were performed using a myriad of computational tools. A 3D model of bromelain was constructed using SWISS-MODEL, followed by molecular docking simulations performed with ClusPro. The binding affinities of the docked complexes were evaluated using HawkDock, and the interactions were analysed with LigPlot+. The docking scores indicated potential spontaneous interactions, with binding affinities based on being - 103.89 kcal/mol (PIK3CA), -73.16 kcal/mol (EGFR), -71.18 kcal/mol (mTOR), -65.22 kcal/mol (β-catenin), and - 57.48 kcal/mol (BCL2). LigPlot + analysis revealed the presence of hydrogen bonds, hydrophobic interactions, and salt bridges, indicating stable predicted interactions.
CONCLUSION: Our findings suggest that bromelain can target key proteins involved in NPC oncogenesis, with the strongest affinity towards PIK3CA. This suggests a hypothetical insight into bromelain's anticancer effects on NPC through the modulation of the PI3K/Akt signaling pathway.

Matched MeSH terms: Class I Phosphatidylinositol 3-Kinases/metabolism
Phosphoinositide 3-kinase δ inactivation prevents vitreous-induced activation of AKT/MDM2/p53 and migration of retinal pigment epithelial cells

Han H, Chen N, Huang X, Liu B, Tian J, Lei H

J Biol Chem, 2019 10 18;294(42):15408-15417.
PMID: 31467081 DOI: 10.1074/jbc.RA119.010130

Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that play a critical role in transmitting signals from cell-surface molecules to intracellular protein effectors. Key PI3Ks include PI3Kα, PI3Kβ, and PI3Kδ, which are regulated by receptors. The signaling pathway comprising the PI3Ks, along with a Ser/Thr kinase (AKT), a proto-oncogene product (mouse double minute (MDM)2), and a tumor suppressor protein (p53), plays an essential role in experimental proliferative vitreoretinopathy (PVR), which is a fibrotic blinding eye disorder. However, which PI3K isoforms are involved in PVR is unknown. A major characteristic of PVR is the formation of epi (or sub)-retinal membranes that consist of extracellular matrix and cells, including retinal pigment epithelium (RPE) cells, glial cells, and macrophages. RPE cells are considered key players in PVR pathogenesis. Using immunoblotting and immunofluorescence analyses, we herein provide the evidence that PI3Kδ is highly expressed in human RPEs when it is primarily expressed in leukocytes. We also found that PI3Kδ inactivation through two approaches, CRISPR/Cas9-mediated depletion and a PI3Kδ-specific inhibitor (idelalisib), not only blocks vitreous-induced activation of AKT and MDM2 but also abrogates a vitreous-stimulated decrease in p53. Furthermore, we demonstrate that PI3Kδ inactivation prevents vitreous-induced proliferation, migration, and contraction of human RPEs. These results suggest that PI3Kδ may represent a potential therapeutic target for RPE-related eye diseases, including PVR.

Matched MeSH terms: Class I Phosphatidylinositol 3-Kinases/metabolism*

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