Exploration of targets and molecular mechanisms of cinnamaldehyde in overcoming fulvestrant-resistant breast cancer: a bioinformatics study

Hermawan A., Putri H., Utomo R.Y.

Laboratory of Macromolecular Engineering, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta, 55281, Indonesia; Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta, 55281, Indonesia; Laboratory of Medicinal Chemistry, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta, 55281, Indonesia


Abstract

The efficacy of fulvestrant therapy for estrogen receptor positive (ER+) or luminal breast cancer therapy may decrease on account of chemoresistance, which contributes to tumor relapse and metastasis. Cinnamaldehyde has previously been shown to trigger apoptosis in MCF-7 cells, which are ER+ breast cancer cells. This study aimed to identify the targets and molecular mechanisms of cinnamaldehyde in overcoming fulvestrant-resistant breast cancer using a bioinformatics approach. The microarray data of fulvestrant-resistant and cinnamaldehyde-treated MCF-7 cells were obtained from GSE74391 and GSE85871, respectively, and a total of 310 differentially expressed genes (DEGs) were recovered from these databases. Gene Ontology analysis revealed several DEGs that participated in metabolic processes, responded to a stimulus, were located in the membrane and nucleus, and regulated the molecular functions of the protein and ion binding. Drug association analysis revealed the associations between these DEGs and protein kinase inhibitors. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that the DEGs regulated pathways for cancer, erbB, and MAPK signaling. Genetic alterations for each target gene ranged from 3 to 14% (CDK2, 3%; MDM2, 6%; KRAS, 7%; PIK3R1, 7%; CDH1, 8%; ESR1, 14%). Further investigation was conducted to examine the impact of genetic alterations on the signaling, resulting in BRCA-2012-RTK-RAS-PI(3)K-pathway. This study identified six possible targets of cinnamaldehyde in overcoming fulvestrant-resistant breast cancer, including CDK2, MDM2, KRAS, PIK3R1, CDH1, and ESR1. PI3K/Akt signaling is a possible target of cinnamaldehyde in overcoming fulvestrant-resistant breast cancer. Molecular docking study results showed that cinnamaldehyde could bind to several protein targets with specific properties and could also be considered to inhibit the activity of target proteins because of its protein-binding distance. Further investigations to verify the findings of this study are necessary. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.

Bioinformatics; Breast cancer; Cinnamaldehyde; Fulvestrant resistance; PI3K/Akt signaling


Journal

Network Modeling Analysis in Health Informatics and Bioinformatics

Publisher: Springer

Volume 10, Issue 1, Art No 30, Page – , Page Count


Journal Link: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85104586637&doi=10.1007%2fs13721-021-00303-9&partnerID=40&md5=74946ff0efad9c300b94a37efd090036

doi: 10.1007/s13721-021-00303-9

Issn: 21926662

Type:


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