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Dexmedetomidine Affects Triple-Negative Breast Cancer by Targeting IDO1 and CHRM3
Vol 38, Issue 3, 2024
Abstract
Background: Triple-negative BrCa (TNBC) has been recognized as the most invasive type of breast cancer (BrCa), posing the worst outcomes with a minimal overall survival rate. The use of dexmedetomidine potentially affected BrCa surgery and dexmedetomidine was reported to have direct effects on TNBC cells. Therefore, this study aimed to explore the mechanisms underlying the effect of dexmedetomidine on TNBC. Methods: Through bioinformatic analysis, dexmedetomidine targets were predicted using The Cancer Genome Atlas data and SwissTargetPrediction database. These targets were validated in TBNC using both clinical samples and cell lines (MDA-MB-231, MCF7, and MCF10A). The cancer cell lines, and normal breast cell lines were divided into cancer and normal groups. Both groups were exposed to dexmedetomidine treatment. Furthermore, silencing and overexpression experimental models were used to determine the effect of dexmedetomidine treatment. Expression levels of target genes and their proteins were evaluated using qRT-PCR, western blot analysis, and immunohistochemistry. Cell Counting Kit-8 was used to determine the effect of dexmedetomidine on cells with target silencing. The binding model of the candidate targets was docked, and critical amino acids were mutated to validate the binding model. Results: Dexmedetomidine selectively inhibited cancer cells. Catalytic subunit of the DNA-dependent protein kinase (PRKDC), indoleamine 2,3-dioxygenase 1 (IDO1), opioid receptor kappa 1 (OPRK1), glutaminyl-peptide acyltransferase (QPCT), macrophage migration inhibitory factor (MIF), potassium voltage-gated channel subfamily H (Eag-related) member 2 (KCNH2), cholinergic receptor muscarinic 3 (CHRM3), and potassium intermediate/small conductance calcium-activated channel subfamily N member 4 (KCNN4) were identified as dexmedetomidine targets in TNBC. The expression levels of PRKDC, IDO1, MIF, KCNH2, CHRM3, and KCNN4 were found to be upregulated in TNBC tissues compared to the non-TNBC tissues (p < 0.05). Silencing of these genes reduced the sensitivity of TNBC cells to dexmedetomidine (p < 0.05). However, this effect was counteracted when the silenced genes were overexpressed, increasing the sensitivity of cells to dexmedetomidine (p < 0.05). Furthermore, a direct interaction of dexmedetomidine with IDO1 and CHRM3 was observed, impacting the sensitivity of cells to dexmedetomidine (p < 0.05). Conclusion: IDO1 and CHRM3 are direct targets of dexmedetomidine in TNBC.
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Copyright (c) 2024 Jie Luo, Hong Cao
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Medical Genetics, University of Torino Medical School, Italy

Department of Biomedical, Surgical and Dental Sciences, University of Milan, Italy