Bioinformatics Studies Provide Insight into Possible Target and Mechanisms of Action of Nobiletin against Cancer Stem Cells.

Adam Hermawan,Herwandhani Putri

doi:10.31557/apjcp.2020.21.3.611

Abstract

Objective:Nobiletin treatment on MDA-MB 231 cells reduces the expression of CXC chemokine receptor type 4 (CXCR4), which is highly expressed in cancer stem cell populations in tumor patients. However, the mechanisms of nobiletin in cancer stem cells (CSCs) remain elusive. This study was aimed to explore the potential target and mechanisms of nobiletin in cancer stem cells using bioinformatics approaches. Methods:Gene expression profiles by public COMPARE predicting the sensitivity of tumor cells to nobiletin. Functional annotations on gene lists are carried out with The Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.8, and WEB-based GEne SeT Analysis Toolkit (WebGestalt). The protein-protein interaction (PPI) network was analyzed by STRING-DB and visualized by Cytoscape. Results:Microarray analyses reveal many genes involved in protein binding, transcriptional and translational activity. Pathway enrichment analysis revealed breast cancer regulation of estrogen signaling and Wnt/ß-catenin by nobiletin. Moreover, three hub genes, i.e. ESR1, NCOA3, and RPS6KB1 and one significant module were filtered out and selected from the PPI network. Conclusion:Nobiletin might serve as a lead compound for the development of CSCs-targeted drugs by targeting estrogen and Wnt/ß-catenin signaling. Further studies are needed to explore the full therapeutic potential of nobiletin in cancer stem cells.

Highlights

Recent studies have shown that the ability of tumors to develop and propagate depends on a small population of cells called cancer stem cells (CSCs) (Pan et al, 2018; Zhu and Fan, 2018)
This study explored the molecular mechanism of nobiletin in CSCs
Analysis of cytotoxicity with a public database of COMPARE showed that nobiletin exhibits cytotoxicity at the same level in the National Cancer Institute (NCI)-60 cells panel showing by similar IC50 value (Figure 1B)

Summary

Introduction

Recent studies have shown that the ability of tumors to develop and propagate depends on a small population of cells called cancer stem cells (CSCs) (Pan et al, 2018; Zhu and Fan, 2018). Flavonoid compounds have been shown to overcome chemoresistance (Meiyanto et al, 2012) and to inhibit CSCs (Hermawan and Putri, 2018). Nobiletin increased doxorubicin cytotoxicity in MCF-7 breast cancer cells but not T47D cells (Meiyanto et al, 2011). Nobiletin showed the effect of inhibiting metastasis by downregulating CXC chemokine receptor type 4 (CXCR4) and matrix metallopeptidase-9 on MDA-MB 231 breast cancer cells (Baek et al, 2012). It has been proven that nobiletin is able to overcome chemoresistance and inhibit CXCR4 which is one of the regulators of CSCs, but its molecular mechanism on CSCs need to be clarified further

Methods

Results

Conclusion