Repression of YAP by NCTD disrupts NSCLC progression.

Jiwei Guo,Lijuan Yang,Sichuan Xi,Kaikai Gong,Yan Wu,Weiwei Chen,Juanjuan Dai,Xuelin Li,Jing Du

doi:10.18632/oncotarget.13668

Abstract

The efficacy of available lung cancer therapeutic interference is significantly limited by various resistance mechanisms to those drugs. Activation of the oncogene YAP underlying the initiation, progression, and metastasis of lung cancer associates with poor prognosis and confers drug resistance against targeted therapy. In this study, we evaluated the specificity of norcantharidin (NCTD) in repressing YAP to inhibit non-small cell lung carcinoma (NSCLC) progression. Our study revealed that YAP signal pathways were aberrantly activated in lung cancer tissues and cells which rendered more proliferative and invasive phenotypes to human lung cancer cells. We confirmed that NCTD specifically repressed YAP signaling pathway to interfere the YAP-mediated non-small cell lung carcinoma progression and metastasis via arresting cell cycle, enhancing apoptosis and inducing senescence. We also found NCTD-mediated repression of YAP decreased epithelial-to-mesenchymal transition (EMT) and reduced the motile and invasive cellular phenotype in vitro via enhancing E-cadherin and decreasing fibronectin/vimentin. Mechanistic investigations revealed that NCTD transcriptionally downregulated YAP and post-translationally modulated the subcellular redistribution of YAP between nucleus and cytoplasm. Collectively, our results indicated that NCTD is a novel therapeutic drug candidate for NSCLC which specifically and sensitively target YAP signal pathway.

Highlights

As the number one cancer killer worldwide [1,2,3,4,5,6] and with enormous efforts in surveillance, surgery, radiotherapy and platinum-based chemotherapy, lung cancer still remains the most aggressive malignant tumor with one of the lowest survival rates [7, 8, 9]
We evaluated the specificity of norcantharidin (NCTD) in repressing YAP to inhibit non-small cell lung carcinoma (NSCLC) progression
This study examined the specificity of NCTD in repressing YAP to inhibit non-small cell lung carcinoma progression and revealed that NCTD inhibits cell growth and metastasis, enhances s cell apoptosis and senescence, and arrest cell cycle in lung cancer cells via downregulating aberrantly activated YAP signaling

Summary

Introduction

As the number one cancer killer worldwide [1,2,3,4,5,6] and with enormous efforts in surveillance, surgery, radiotherapy and platinum-based chemotherapy, lung cancer still remains the most aggressive malignant tumor with one of the lowest survival rates [7, 8, 9]. The oncoprotein Yap negatively regulated by the tumor suppressor Mst in this kinase cascade transcriptionally activates its downstream target genes involved in cell growth and survival [17,18,19,20,21]. Sav (WW-45) is another core component of the Mst tumor suppressor pathway, offering assistance of the activated Mst kinase phosphorylates and activates Lats, which itself phosphorylates Yap with the involvement of the Mob. Phosphorylated Yap is retained in the cytoplasm by interacting with 14-3-3 protein, so cannot combine with its target transcription factors to interact with promoters, and is thereby inactivated [19,20,21,22,23,24,25]. In the case of the loss of function of the Mst cell signals, the unphosphorylated Yap gets into the nucleus and physically binds to the transcription factors TEAD family proteins, which itself regulates the target genes of the Mst/Yap pathway such as connective www.impactjournals.com/oncotarget tissue growth factor (CTGF), Cyr, Cyclin D1, Survivin, and so on [25,26,27,28,29,30,31]

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Results

Conclusion