Comprehensive Computational Analysis of Honokiol Targets for Cell Cycle Inhibition and Immunotherapy in Metastatic Breast Cancer Stem Cells

Abstract

Breast cancer stem cells (BCSCs) play a critical role in chemoresistance, metastasis, and poor prognosis of breast cancer. BCSCs are mostly dormant, and therefore, activating them and modulating the cell cycle are important for successful therapy against BCSCs. The tumor microenvironment (TME) promotes BCSC survival and cancer progression, and targeting the TME can aid in successful immunotherapy. Honokiol (HNK), a bioactive polyphenol isolated from the bark and seed pods of Magnolia spp., is known to exert anticancer effects, such as inducing cell cycle arrest, inhibiting metastasis, and overcoming immunotherapy resistance in breast cancer cells. However, the molecular mechanisms of action of HNK in BCSCs, as well as its effects on the cell cycle, remain unclear. This study aimed to explore the potential targets and molecular mechanisms of HNK on metastatic BCSC (mBCSC)-cell cycle arrest and the impact of the TME. Using bioinformatics analyses, we predicted HNK protein targets from several databases and retrieved the genes differentially expressed in mBCSCs from the GEO database. The intersection between the differentially expressed genes (DEGs) and the HNK-targets was determined using a Venn diagram, and the results were analyzed using a protein-protein interaction network, hub gene selection, gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, genetic alteration analysis, survival rate, and immune cell infiltration levels. Finally, the interaction between HNK and two HNK-targets regulating the cell cycle was analyzed using molecular docking analysis. The identified potential therapeutic targets of HNK (PTTH) included CCND1, SIRT2, AURKB, VEGFA, HDAC1, CASP9, HSP90AA1, and HSP90AB1, which can potentially inhibit the cell cycle of mBCSCs. Moreover, our results showed that PTTH could modulate the PI3K/Akt/mTOR and HIF1/NFkB/pathways. Overall, these findings highlight the potential of HNK as an immunotherapeutic agent for mBCSCs by modulating the tumor immune environment.

Honokiol inhibits the growth of hormone-resistant breast cancer cells: its promising effect in combination with metformin

“…In a bioinformatic study, the potential targets and molecular mechanisms of honokiol in breast cancer stem cells were revealed ( 64 ). Honokiol inhibits the cell cycle via the PI3K/Akt/mTOR pathway by upregulating PTEN and P21 and suppressing p-Akt, cyclin D/CDK4, c-Myc, Rac1, and aurora kinase B. Honokiol can effectively block vascular endothelial growth factor receptor (VEGFR) 2 and suppress angiogenesis.…”

“…Honokiol inhibits the cell cycle via the PI3K/Akt/mTOR pathway by upregulating PTEN and P21 and suppressing p-Akt, cyclin D/CDK4, c-Myc, Rac1, and aurora kinase B. Honokiol can effectively block vascular endothelial growth factor receptor (VEGFR) 2 and suppress angiogenesis. It was also found that honokiol reduces hypoxia-inducible factor (HIF)-induced VEGFR/VEGF activation and inhibits MMP activity and cell migration ( 64 ). Also, honokiol can induce apoptosis by upregulating BAD (the BCL2-associated agonist of cell death), caspase-9, caspase-3, and caspase-8.…”

“…Also, honokiol can induce apoptosis by upregulating BAD (the BCL2-associated agonist of cell death), caspase-9, caspase-3, and caspase-8. Honokiol is also considered an immunotherapeutic agent for mBCSCs because of its ability to modulate the tumor's immune environment ( 64 ).…”

“…The idea of overcoming resistance to chemotherapy with honokiol has been addressed in several studies ( 64 68 69 ). It has been indicated that honokiol in combination with osimertinib exerted antiproliferative action towards osimertinib-resistant cell lines and induced apoptosis through enhanced myeloid cell leukemia-1 reduction.…”

Characterization of Potential Target Genes of Borneol in Increasing Trastuzumab Sensitivity in HER2+ Trastuzumab-Resistant Breast Cancer: Bioinformatics and In Vitro Studies

“…The docking results were analyzed based on the best pose and score. The 2D and 3D interactions were visualized in accordance with previous studies [42,43].…”