Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, and its incidence is increasing annually. It is critical to reveal and delineate the molecular mechanism promoting PDAC development and progression. Mammalian STE20-like kinase 1 (MST1) is a proapoptotic cytoplasmic kinase and also one of the core components of the Hippo pathway. Here, we showed that MST1 expression was decreased in PDAC, and restored expression of MST1 promoted PDAC cell death and suppressed the proliferation, migration, invasion, and cell spheroid formation of PDAC via caspase-1-induced pyroptosis. Further studies demonstrated that pyroptosis induced by MST1 was independent of the Hippo pathway, but mediated by reactive oxygen species (ROS). And ROS scavenger N-acetyl-cysteine attenuated the activation of caspase-1 induced by MST1 and the effect of MST1 in PDAC cell death, proliferation, migration, and invasion. Collectively, our study demonstrated that MST1 suppressed the progression of PDAC cells at least partly through ROS-induced pyroptosis. IMPLICATIONS: In this study, we identified a new mechanism of MST1 in inhibiting PDAC development and progression and revealed that MST1 would be a potential prognostic and therapeutic target for PDAC.

Highlights

  • Pancreatic ductal adenocarcinoma (PDAC) accounts for 95% of all pancreatic malignancy and is often called pancreatic cancer

  • We found that the protein levels of Mammalian STE20-like kinase 1 (MST1) were markedly decreased in most PDAC cell lines as compared with normal HEK293 cells (Fig. 1A)

  • MST1 was first reported as a proapoptotic cytoplasmic kinase; we investigated the effect of MST1 in PDAC cell death

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Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) accounts for 95% of all pancreatic malignancy and is often called pancreatic cancer. Its 5-year survival rate remains about 8% and has been called the king of cancer [1]. PDAC is projected to be the second leading cause of death related to cancer by the year 2030 [2]. It has been demonstrated that many genes and signaling pathways played essential roles in PDAC development and progression, including KRAS, TP53, CDKN2A, and SMAD4 genes, and the Wnt, Notch, and Hippo pathways [3]. The mechanism of PDAC initiation and progression is far to be fully demonstrated, and it is still highly important to reveal and delineate the molecular mechanism and pathways and identify new targets for the treatment of PDAC. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/)

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