D,l-Sulforaphane Induces ROS-Dependent Apoptosis in Human Gliomablastoma Cells by Inactivating STAT3 Signaling Pathway.

Ziwei Miao,Yahao Ren,Jun Yang,Fei Yu

doi:10.3390/ijms18010072

Ziwei Miao, Yahao Ren + Show 2 more

Open Access

https://doi.org/10.3390/ijms18010072

Copy DOI

Abstract

d,l-Sulforaphane (SFN), a synthetic analogue of broccoli-derived isomer l-SFN, exerts cytotoxic effects on multiple tumor cell types through different mechanisms and is more potent than the l-isomer at inhibiting cancer growth. However, the means by which SFN impairs glioblastoma (GBM) cells remains poorly understood. In this study, we investigated the anti-cancer effect of SFN in GBM cells and determined the underlying molecular mechanisms. Cell viability assays, flow cytometry, immunofluorescence, and Western blot results revealed that SFN could induced apoptosis of GBM cells in a dose- and time-dependent manner, via up-regulation of caspase-3 and Bax, and down-regulation of Bcl-2. Mechanistically, SFN treatment led to increase the intracellular reactive oxygen species (ROS) level in GBM cells. Meanwhile, SFN also suppressed both constitutive and IL-6-induced phosphorylation of STAT3, and the activation of upstream JAK2 and Src tyrosine kinases, dose- and time-dependently. Moreover, blockage of ROS production by using the ROS inhibitor N-acetyl-l-cysteine totally reversed SFN-mediated down-regulation of JAK2/Src-STAT3 signaling activation and the subsequent effects on apoptosis by blocking the induction of apoptosis-related genes in GBM cells. Taken together, our data suggests that SFN induces apoptosis in GBM cells via ROS-dependent inactivation of STAT3 phosphorylation. These findings motivate further evaluation of SFN as a cancer chemopreventive agent in GBM treatment.

Highlights

Glioblastoma multiforme (GBM), known as glioblastoma and grade IV astrocytoma, is the most frequent and lethal form of primary malignant central nervous system and brain tumor in adults [1]
We demonstrated that SFN reduced the cell viability and promoted apoptosis in GBM cells and that this effect is mediated by elevated reactive oxygen species (ROS) levels, which suppress activation of the signal transducer and activator of transcription 3 (STAT3) signaling cascade
We evaluated the ability of SFN to induce apoptosis and to determine the molecular mechanism underlying this process in the GBM cells

Summary

Introduction

Glioblastoma multiforme (GBM), known as glioblastoma and grade IV astrocytoma, is the most frequent and lethal form of primary malignant central nervous system and brain tumor in adults [1]. Sulforaphane (1-isothiocyanato-4(methylsulfinyl)-butane) is a natural plant compound that is widely in the cruciferous vegetables and occurs naturally as an L-isomer [6]. It is a remarkable bio-active molecule that regulates cancer initiation and progression [7]. It can affect several critical genes expression, which are involved in key processes, such as apoptotic, cell cycle, and cell invasion pathways in various types of cancer [8]. Its synthetic analogue D,L-sulforaphane (SFN) has been mainly studied as a promising chemopreventive agent for cancer therapy. The effects of SFN on GBM have not been adequately investigated, and the precise molecular mechanisms by which SFN exerts anti-cancer effects on GBM remain to be thoroughly explored

Methods

Results

Conclusion