Diallyl disulfide suppresses epithelial-mesenchymal transition, invasion and proliferation by downregulation of LIMK1 in gastric cancer.

Bo Su,Zhi-Gang Zhou,You-Hua Wu,Yan-Hua Ma,Qi Su,Shuo Zhang,Xi Zeng,Xiao-Hong Ai,Jian Su,Hui Ling,Bang-Min Yang,Fang Liu,Hong Xia,Hao Jiang,Ying Zeng

doi:10.18632/oncotarget.7252

Bo Su, Zhi-Gang Zhou + Show 13 more

Open Access

https://doi.org/10.18632/oncotarget.7252

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Abstract

Diallyl disulfide (DADS) has been shown to have multi-targeted antitumor activities. We have previously discovered that it has a repressive effect on LIM kinase-1 (LIMK1) expression in gastric cancer MGC803 cells. This suggests that DADS may inhibit epithelial-mesenchymal transition (EMT) by downregulating LIMK1, resulting in the inhibition of invasion and growth in gastric cancer. In this study, we reveal that LIMK1 expression is correlated with tumor differentiation, invasion depth, clinical stage, lymph node metastasis, and poor prognosis. DADS downregulated the Rac1-Pak1/Rock1-LIMK1 pathway in MGC803 cells, as shown by decreased p-LIMK1 and p-cofilin1 levels, and suppressed cell migration and invasion. Knockdown and overexpression experiments performed in vitro demonstrated that downregulating LIMK1 with DADS resulted in restrained EMT that was coupled with decreased matrix metalloproteinase-9 (MMP-9) and increased tissue inhibitor of metalloproteinase-3 (TIMP-3) expression. In in vitro and in vivo experiments, the DADS-induced suppression of cell proliferation was enhanced and antagonized by the knockdown and overexpression of LIMK1, respectively. Similar results were observed for DADS-induced changes in the expression of vimentin, CD34, Ki-67, and E-cadherin in xenografted tumors. These results indicate that downregulation of LIMK1 by DADS could explain the inhibition of EMT, invasion and proliferation in gastric cancer cells.

Highlights

Diallyl disulfide (DADS), a major oil-soluble compound derived from garlic, has multi-targeted antitumor activities in diverse cancers that result in the induction of cellular processes, including cell cycle arrest, growth inhibition, differentiation, and apoptosis, by interfering in a variety of cell signaling pathways [1,2].We previously have reported that DADS induces gastric cancer cell differentiation by downregulating the ERK signaling pathway [3]
We first confirmed that LIM kinase-1 (LIMK1) is upregulated in primary gastric cancer and that a higher level of LIMK1 expression is correlated with tumor differentiation, tumor size, advanced clinical stage, lymph node metastasis, and poor prognosis, suggesting that LIMK1 may contribute to carcinogenesis and the clinical progression of gastric cancer
We explored the effects of DADS on the Rac1-Pak1/Rock1-LIMK1 signaling pathway, focusing on whether the downregulation of LIMK1 is associated with DADS-induced inhibition of epithelial-mesenchymal transition (EMT), invasion and proliferation

Summary

Introduction

Diallyl disulfide (DADS), a major oil-soluble compound derived from garlic, has multi-targeted antitumor activities in diverse cancers that result in the induction of cellular processes, including cell cycle arrest, growth inhibition, differentiation, and apoptosis, by interfering in a variety of cell signaling pathways [1,2]. We previously have reported that DADS induces gastric cancer cell differentiation by downregulating the ERK signaling pathway [3]. It induces G2/M phase cell cycle arrest by activating p38 [4], increasing histone H3 and H4 acetylation and p21WAF1 expression [5], and suppressing the ATR/Chk1/Cdc25C/cyclinB1 signaling pathway by activating Chk1 [6,7]. A recent study has revealed that DADS induces the reversal of the epithelial-mesenchymal transition (EMT) and inhibits growth by inactivating the β-catenin signaling pathway in breast cancer cells [12]

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