Silver nanoparticles of different sizes induce a mixed type of programmed cell death in human pancreatic ductal adenocarcinoma.

Ewelina Zielinska,Agata Zauszkiewicz-Pawlak,Michal Wojcik,Iwona Inkielewicz-Stepniak

doi:10.18632/oncotarget.22563

Ewelina Zielinska, Agata Zauszkiewicz-Pawlak + Show 2 more

Open Access

https://doi.org/10.18632/oncotarget.22563

Copy DOI

Journal: Oncotarget	Publication Date: Nov 20, 2017
Citations: 101	License type: cc-by

Affiliation: Gdańsk Medical University

Abstract

Pancreatic ductal adenocarcinoma, with the high resistance to chemotherapeutic agents, remains the fourth leading cause of cancer-death in the world. Due to the wide range of biological activity and unique properties, silver nanoparticles (AgNPs) are indicated as agents with potential to overcome barriers involved in chemotherapy failure. Therefore, in our study we decided to assess the ability of AgNPs to kill pancreatic cancer cells, and then to identify the molecular mechanism underlying this effect. Moreover, we evaluated the cytotoxicity of AgNPs against non-tumor cell of the same tissue (hTERT-HPNE cells) for comparison. Our results indicated that AgNPs with size of 2.6 and 18 nm decreased viability, proliferation and caused death of pancreatic cancer cells in a size- and concentration-dependent manner. Ultrastructural analysis identified that cellular uptake of AgNPs resulted in apoptosis, autophagy, necroptosis and mitotic catastrophe. These alterations were associated with increased pro-apoptotic protein Bax and decreased level of anti-apoptotic protein Bcl-2. Moreover, AgNPs significantly elevated the level of tumor suppressor p53 protein as well as necroptosis- and autophagy-related proteins: RIP-1, RIP-3, MLKL and LC3-II, respectively.In addition, we found that PANC-1 cells were more vulnerable to AgNPs-induced cytotoxicity compared to pancreatic non-tumor cells.In conclusion, AgNPs by inducing mixed type of programmed cell death in PANC-1 cells, could provide a new therapeutic strategy to overcome chemoresistance in one of the deadliest human cancer.

Highlights

Despite the huge progress that has been made in recent decades in the diagnosis, treatment and prevention of cancer, the survival rate for pancreatic cancer is still very low
We observed higher cytotoxic effect of 2.6 and 18 nm AgNPs on human pancreas ductal www.impactjournals.com/oncotarget adenocarcinoma cells compared with non-tumor cells of the same tissue
Our finding documented that treatment with AgNPs resulted in a significant, concentration-dependent inhibition of pancreatic cancer cell proliferation as well as induction of apoptosis and necroptosis

Summary

Introduction

Despite the huge progress that has been made in recent decades in the diagnosis, treatment and prevention of cancer, the survival rate for pancreatic cancer is still very low. Today we know that necrosis can be induced in a controlled manner by specific genes and regulated by kinases RIP-1 and RIP-3 and MLKL protein [5] This process has been designated as programmed necrosis (III type) or necroptosis, or regulated necrosis and represents a therapeutic alternative to apoptosis-resistant forms of cancer [5, 6]. Mitotic catastrophe in response to treatment with anticancer drug was found in pancreatic tumor cell [17] It is distinct from apoptosis, autophagy, necroptosis and necrosis, oncosuppressive mechanism, which restrains tumorigenesis and cancer progression [18]. The knowledge of molecular mechanism regarding cancer cell death is crucial for the development and progress in pancreatic anticancer therapy [20]

Methods

Results

Discussion

Conclusion