YAP Inhibition by Nuciferine via AMPK-Mediated Downregulation of HMGCR Sensitizes Pancreatic Cancer Cells to Gemcitabine.

Ling Zhou,Qiaoyun Wang,Maolei Xu,Shuyang Xie,Youjie Li,Han Zhang

doi:10.3390/biom9100620

Abstract

Nuciferine, a major aporphine alkaloid constituent of lotus leaves, is a raw material for obesity treatment. Extensive studies have revealed that obesity is associated with pancreatic cancer (PC). However, it has not been clarified whether nuciferine could be used in PC treatment or prevention. Here, we show that nuciferine could enhance the sensitivity of PC cells to gemcitabine in both cultured cells and the xenograft mouse model. The mechanism study demonstrated that nuciferine induced YAP Ser127 phosphorylation [pYAP(Ser127)] through AMPK-mediated 3-hydroxy-3-methyl-glutaryl-coA reductase (HMGCR) downregulation. Remarkably, wild-type YAP overexpression or YAP Ser127 mutant could resist to nuciferine and no longer sensitize PC cells to gemcitabine. Knockdown of AMPK attenuated pYAP(Ser127) induced by nuciferine. Moreover, knockdown of AMPK reversed nuciferine-mediated HMGCR downregulation. Notably, HMGCR inhibiting could restrain YAP by phosphorylation Ser 127, and therefore enhance the efficiency of gemcitabine in PC cells. In line with this consistent, overexpression of HMGCR reduced growth inhibition caused by nuciferine and/or gemcitabine treatment in PC cells. In summary, these results provide an effective supplementary agent and suggest a therapeutic strategy to reduce gemcitabine resistance in PC.

Highlights

Pancreatic cancer (PC) is the seventh leading cause of cancer-related deaths worldwide
To determine whether nuciferine could enhance the susceptibility of PC cells to gemcitabine, combination treatments were carried out by varying gemcitabine in the presence of nuciferine for 72 h
305 nM (2.36 fold) in ASPC-1 cells. These experiments demonstrated that suboptimal dose of nuciferine could decrease the doses of gemcitabine required to reach the IC50 for these PC cell lines

Summary

Introduction

Pancreatic cancer (PC) is the seventh leading cause of cancer-related deaths worldwide. Since patients seldom exhibit symptoms until an advanced stage of the disease, PC remains one of the most lethal malignant neoplasms that caused 432,242 new deaths in 2018 worldwide (GLOBOCAN 2018 estimates). Worldwide incidence and mortality of PC correlate with increasing age and is slightly more common in men than in women [1]. Despite the great progress achieved in the last couple of decades, surgical intervention still remains the optimal treatment option. Due to the late diagnosis and early metastasis, patients with PC usually lose the opportunity to undergo radical surgery. Identifying new drugs or therapeutic treatments to address this troublesome disease is urgently needed

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