Hedyotis diffusa Willd. extract suppresses proliferation and induces apoptosis via IL-6-inducible STAT3 pathway inactivation in human colorectal cancer cells.

Jiumao Lin,Zijun Lai,Jun Peng,Qiongyu Li,Hongwei Chen,Hui Lin

doi:10.3892/ol.2015.2956

Abstract

Recent studies have indicated that the inflammatory microenvironment plays a significant role in colorectal cancer (CRC). The interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling pathway mediates the proliferative and anti-apoptotic activities required for oncogenesis under inflammatory conditions; thus, suppressing tumor growth by targeting the IL-6/STAT3 pathway is a promising therapeutic strategy for CRC. Our previous study reported that the ethanol extract obtained from Hedyotis diffusa Willd. (EEHDW) can induce apoptosis, and inhibit the proliferation of colon cancer cells and tumor angiogenesis by modulating various signaling pathways; however, less is known regarding the activity of EEHDW in a cancer-promoting inflammatory environment. Therefore, the present study investigated whether EEHDW inhibits the growth of the CRC HT-29 cell line via the IL-6/STAT3 signaling pathway. Pretreatment of HT-29 cells with IL-6 led to an increase in cell viability, colony formation and phosphorylated STAT3 (p-STAT3) expression. Treatment of these cells with EEHDW prior to IL-6 stimulation resulted in a significant reduction in the IL-6-induced phosphorylation of STAT3. In addition, EEHDW treatment significantly reduced the mRNA expression levels of cyclin D1, cyclin-dependent kinase 4 and B-cell lymphoma-2 (Bcl-2), and upregulated the expression levels of Bcl-2-associated X protein (P<0.05), which are important target genes of the IL-6/STAT3 pathway. These findings strongly indicated that EEHDW suppresses tumor cell growth and induces the apoptosis of human CRC cells via inactivation of the IL-6/STAT3 signaling pathway.

Highlights

A recent study estimated that >65,000 male and female individuals would likely be diagnosed with colorectal cancer (CRC) in the USA in 2014 [1]
To determine whether the potency of extract obtained from Hedyotis diffusa Willd. (EEHDW) was maintained under inflammatory conditions, the effect of EEHDW on HT‐29 cell viability was measured in the presence of IL‐6 by performing an MTT assay (Fig. 1A)
Dysregulation of the IL‐6‐mediated Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is closely associated with the development of a diverse range of solid tumors in humans, including CRC [27,28]

Summary

Introduction

A recent study estimated that >65,000 male and female individuals would likely be diagnosed with colorectal cancer (CRC) in the USA in 2014 [1]. Various cellular factors have recently emerged as important elements in maintaining the survival and proliferation of CRC tumor cells, including signal transducer and activator of transcription 3 (STAT3) [2]. The binding of IL‐6 to the IL‐6 receptor (IL‐6R) initiates an intracellular signaling cascade that activates STAT3 and enhances the localized inflammatory environment, contributing toward c ancer progression [5,6]. This association was highlighted by a study that measured the cytokine levels in the sera of CRC patients and identified a direct correlation between IL‐6 expression levels and CRC progression [7]. The IL‐6/STAT3 pathway is an emerging therapeutic target for CRC

Methods

Results

Conclusion