Abstract
(E)-3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (DPP23) is a synthetic polyphenol derivative that selectively induces apoptosis in cancer cells through the unfolded protein response pathway. In the present study, we evaluated the effect of DPP23 on tumour invasion and metastasis. Here, we show that DPP23 inhibited tumour necrosis factor alpha (TNFα)-induced motility, F-actin formation, and the invasive capability of MDA-MB-231 cells. DPP23 inhibited NF-κB-dependent MMP-9 expression at the transcriptional level. Akt is involved in the activation of IKK, an upstream regulator of NF-κB. DPP23 inhibited IKK and Akt, and knockdown of Akt2 significantly inhibited TNFα-induced IKK phosphorylation. We found that DPP23 bound to the catalytic domain of Akt2, as revealed by an in silico molecular docking analysis. These results suggest that DPP23 prevents TNFα-induced invasion of highly metastatic MDA-MB-231 breast cancer cells by inhibiting Akt–IKK–NF-κB axis-mediated MMP-9 gene expression. In addition, DPP23 attenuated experimental liver metastasis in a syngenic intrasplenic transplantation model using 4T1 mouse mammary carcinoma cells. Collectively, these results suggest that DPP23 could be used as a potential platform for the prevention of invasion and metastasis of early-stage breast cancer or as an adjuvant for chemo/radiotherapy.
Highlights
Metastasis is a hallmark of malignant cancer[1], which is characterized by the spread of primary tumour cells to distant parts of the body
We investigated the effects of DPP23 on anti-metastatic activity using the highly metastatic MDA-MB-231 human breast cancer cells and a syngenic experimental liver metastasis model in vivo
We found that DPP23 inhibits the TNFα-induced invasion of MDA-MB-231 cells by targeting the Akt-IKK-NF-κBaxis to inhibit expression of the Matrix metalloproteinases (MMPs)-9 gene
Summary
DPP23 reduces TNFα-induced migration of MDA-MB-231 breast cancer cells. Motility is an essential feature of metastatic cancer cells[21]. Silencing of endogenous Akt[2] significantly attenuated the ability of TNFαto induce IKKα/βphosphorylation (all P < 0.05 by one-way ANOVA followed by Sidak’s multiple comparisons test, n = 3) These findings suggest that DPP23 inhibits IKK activity by targeting Akt, resulting in the suppression of TNFα-induced NF-κB phosphorylation. Real-time PCR analysis demonstrated a 17.07 ± 1.96-fold increase in the level of the MMP-9 mRNA in the MB231/shCT cells, whereas a 6.30 ± 0.56-fold increase was observed in MB231/shAkt[2] cells following TNFαstimulation compared with the basal levels (Fig. 6d) These data suggest that Akt plays an important role in the TNFα-induced regulation of MMP-9 transcription in MDA-MB-231 cells. This study shows that DPP23 inhibits the TNFα-induced invasion of highly metastatic MDA-MB-231 breast cancer cells by targeting the Akt–IKK–NF-κB axis to inhibit the expression of the MMP-9 gene. This finding suggests that DPP23 could be used to prevent the invasion and metastasis of early-stage breast cancer or as an adjuvant for chemo/radiotherapy
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