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Pharmacological Inhibition of DUSP6 Suppresses Gastric Cancer Growth and Metastasis and Overcomes Cisplatin Resistance

Pharmacological Inhibition of DUSP6 Suppresses Gastric Cancer Growth and Metastasis and Overcomes Cisplatin Resistance

Qi-Nian Wu, Yi-Fu Liao, Yun-Xin Lu, Yun Wang, Jia-Huan Lu, Zhao-Lei Zeng, Qi-Tao Huang, Hui Sheng, Jing-Ping Yun, Dan Xie, Huai-Qiang Ju, Rui-Hua Xu

Cancer Lett. 2018 Jan 1;412:243-255.

PMID: 29050982

Abstract:

Gastric cancer (GC) is the second cause of cancer-related death. Cisplatin (CDDP) is widely used as the standard GC treatment, but relapse and metastasis are common because of intrinsic or acquired drug resistance. The mitogen-activated protein kinase phosphatases (MAPK)-extracellular signal regulated kinases (ERK) pathway contributes to GC progression and drug resistance, but targeting the MAPK-ERK pathway is challenging in GC therapy. Here, we demonstrated that dual-specificity phosphatases 6 (DUSP6) was overexpressed in GC and predicted poor overall survival and progression-free survival. Knockdown DUSP6 inhibited GC proliferation, migration, invasion and induced apoptosis. (E/Z)-BCI hydrochloride (BCI), a DUSP6 small molecule inhibitor, increased the activity of ERK but interestingly decreased the expression of ERK response genes in BGC823, SGC7901 and CDDP-resistant SGC7901/DDP cells. BCI also caused cell death through the DNA damage response (DDR) pathway. Moreover, BCI inhibited cell proliferation, migration and invasion in a receptor-independent manner and enhanced CDDP cytotoxicity at pharmacological concentrations in the GC cells. In vivo experiments further showed that BCI enhances the antitumor effects of CDDP in cell-based xenografts and PDX models. In summary, our findings indicated that disruption of DUSP6 by BCI enhanced CDDP-induced cell death and apoptosis in GC may partly through ERK and DDR pathways. Thus, this study suggests that DUSP6 is a potential prognostic biomarker and a promising target for GC therapy.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP95130237	(E/Z)-BCI hydrochloride		95130-23-7	Price

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