Curcumin derivative 1,2-bis((3E,5E)-3,5-bis(4-chlorobenzylidene)-4-oxopiperidine-1- yl)ethane-1,2-dione hemihydrate, ST09, regulates miR-197-5p/GPX3 axis in breast cancer cells and abrogates tumor growth in mouse xenograft model

Abstract

Abstract Purpose: ST09, a potent curcumin derivative, exhibited apoptotic and anti-migratory activity in breast cancer cells in vitroand tumor reduction in vivo reported earlier. Here we aim to understand ST09 induced transcriptomic changes on regulation of the novel miR-197/GPX3 axis.We also aim to understand combinatory potential of ST09, anti-tumor efficacy in xenograft mice tumor model and its bioavailability studies. Methods: We performed mRNA-seq and miRNA-seq to capture the transcriptome of ST09 induced breast cancer cells. We used integrated approaches, to show regulation of miR-197/GPX3 axis via ST09. By performing luciferase assay and GPX activity assay, we confirm that GPX3 is one of the major targets of miR-197. We also showed anti-tumor effect ST09 on TNBC xenograft mice model. Phalloidin staining and wound healing assay were assayed to study migrastatic properties of ST09. The bioavailability studies of ST09 were also performed. Results:This study explored the global transcriptome profile of ST09 treated breast cancer cells (luminal and TNBC). The integrated approach revealed ST09 mediated regulation of a novel miRNA-mRNA axis, miR-197-5p/GPX3. Using GPX3 enzyme assay, we show the anti-proliferative role of GPX3 in breast cancer cells. We established GPX3 as a direct target of miR-197-5p. We show that ST09 potentiates the effect of cisplatin on breast cancer cells in vitro and reduces tumor burden in vivo with minimum toxicity. ST09 also showed a significant tumor reduction TNBC xenograft mice model. We show that the bioavailability of ST09 is 200X better than curcumin. Conclusion: ST09 is a potent curcumin derivative with a tumor-suppressive role. The integrated approach with the ST09 drug indicated the role of the miR-197-5p/GPX3 axis in breast cancer cells. ST09 upregulated GPX3 by repressing miR-197-5p and mediated the anti-proliferative effect in breast cancer cells. ST09 can be exploited either as a single chemotherapeutic agent or in combination treatment modalities, reducing the dosage of potent drugs.