Document Type

Journal Article

Department/Unit

School of Chinese Medicine

Title

Astragalus saponins modulate mTOR and ERK signaling to promote apoptosis through the extrinsic pathway in HT-29 colon cancer cells

Language

English

Abstract

We have previously demonstrated that the total saponins of Astragalus membranaceus (AST) possess potential anti-tumorigenic effects in human colon cancer cells and tumor xenografts. In the present study, the proapoptotic effects of AST were investigated in native and cytokine-induced HT-29 cells to further unveil its mechanism of action. Growth-inhibitory action of AST (60 μg/ml) was demonstrated in native HT-29 cells, which was exaggerated in tumor necrosis factor (TNF) (5 ng/ml)-induced cells. These were accompanied by caspase 3 activation, cleavage of poly(ADP-ribose) polymerase and a subsequent increase in apoptotic cell numbers. Furthermore, activation of procaspase 8 indicates that the extrinsic apoptotic pathway was involved, while cleavage of Bid into t-Bid implicates cross-talk with the intrinsic apoptotic pathway. Alternatively, AST caused S and G2/M phase arrest, while in cytokine-induced cells S phase arrest was predominant. Further adding to our recent suggestion on its correlation with phosphatidylinositol 3-kinase (PI3K)-Akt signaling, we have now revealed that AST caused overexpression of PTEN and down-regulation of mammalian target of rapamycin (mTOR) expression. Nevertheless, these events were preceded by a decrease in nuclear factor-κB (NF-κB)/DNA binding activity with continuous ERK 1/2 activation. Some of these effects became more intense in cytokine-induced cells. Our findings in this study suggest that AST induces the extrinsic apoptotic cascade and causes cell cycle arrest in HT-29 cells by modulation of both mTOR and ERK signaling pathways, of which inhibition of NF-κB is important in the latter mechanism. Most of the above processes are more pronounced in cytokine-induced cells.

Keywords

Astragalus saponins, Extracellular signal-regulated protein kinase, HT-29 cells, Mammalian target of rapamycin, Nuclear factor-κB, Tumor necrosis factor-α

Publication Date

2010

Source Publication Title

International Journal of Molecular Medicine

Volume

26

Issue

3

Start Page

341

End Page

349

Publisher

Spandidos Publications

DOI

10.3892/ijmm_00000471

Link to Publisher's Edition

http://dx.doi.org/10.3892/ijmm_00000471

ISSN (print)

11073756

ISSN (electronic)

1791244X

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