Anticancer activities of pterostilbene-isothiocyanate conjugate in breast cancer cells: involvement of PPARγ.

Kumar Nikhil,Shruti Sharan,Ajanta Chakraborty,Partha Roy,Abhimanyu K Singh,Raju Reddy

doi:10.1371/journal.pone.0104592

Kumar Nikhil, Shruti Sharan + Show 4 more

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https://doi.org/10.1371/journal.pone.0104592

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Abstract

Trans-3,5-dimethoxy-4′-hydroxystilbene (PTER), a natural dimethylated analog of resveratrol, preferentially induces certain cancer cells to undergo apoptosis and could thus have a role in cancer chemoprevention. Peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, is a ligand-dependent transcription factor whose activation results in growth arrest and/or apoptosis in a variety of cancer cells. Here we investigated the potential of PTER-isothiocyanate (ITC) conjugate, a novel class of hybrid compound (PTER-ITC) synthesized by appending an ITC moiety to the PTER backbone, to induce apoptotic cell death in hormone-dependent (MCF-7) and -independent (MDA-MB-231) breast cancer cell lines and to elucidate PPARγ involvement in PTER-ITC action. Our results showed that when pre-treated with PPARγ antagonists or PPARγ siRNA, both breast cancer cell lines suppressed PTER-ITC-induced apoptosis, as determined by annexin V/propidium iodide staining and cleaved caspase-9 expression. Furthermore, PTER-ITC significantly increased PPARγ mRNA and protein levels in a dose-dependent manner and modulated expression of PPARγ-related genes in both breast cancer cell lines. This increase in PPARγ activity was prevented by a PPARγ-specific inhibitor, in support of our hypothesis that PTER-ITC can act as a PPARγ activator. PTER-ITC-mediated upregulation of PPARγ was counteracted by co-incubation with p38 MAPK or JNK inhibitors, suggesting involvement of these pathways in PTER-ITC action. Molecular docking analysis further suggested that PTER-ITC interacted with 5 polar and 8 non-polar residues within the PPARγ ligand-binding pocket, which are reported to be critical for its activity. Collectively, our observations suggest potential applications for PTER-ITC in breast cancer prevention and treatment through modulation of the PPARγ activation pathway.

Highlights

The incidence of cancer, in particular breast cancer, continues to be the focus of worldwide attention
MCF-7 and MDA-MB-231 cells were treated with increasing concentrations (1–60 mM) of PTER and PTER-investigated the potential of PTERisothiocyanate (ITC) for 24 h and cell survival was determined by MTT assay
Our data showed that treatment of these cells with PTER and PTER-ITC resulted in dose-dependent inhibition of cell proliferation, which was more pronounced after PTER-ITC treatment compared to vehicletreated control cells (Fig. 1B, C)

Summary

Introduction

The incidence of cancer, in particular breast cancer, continues to be the focus of worldwide attention. Since cancer cells exhibit deregulation of many cell signaling pathways, treatments using agents that target only one specific pathway usually fail in cancer therapy. Peroxisome proliferator-activated receptors (PPAR) are ligandbinding transcription factors of the nuclear receptor superfamily, which includes receptors for steroids, thyroids and retinoids [7,8]. Three types of PPAR have been identified (a, b, c), each encoded by distinct genes and expressed differently in many parts of the body [8]. They form heterodimers with the retinoid X receptor, and these complexes subsequently bind to a specific DNA sequence, the peroxisome proliferating response element (PPRE)

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