Sequestration of Intestinal Acidic Toxins by Cationic Resin Attenuates Pancreatic Cancer Progression through Promoting Autophagic Flux for YAP Degradation.

Guangfu Zhao,Stephen J Pandol,Tianci Zhang,Jun Li,Xiangsheng Fu,Richard Hu,Yuan-Ping Han,Wei Liu,Mouad Edderkaoui

doi:10.3390/cancers14061407

Abstract

Simple SummaryAnnually, more than 450,000 people are diagnosed with pancreatic cancer worldwide with over 430,000 mortalities. Pancreatic ductal carcinoma (PDAC) accounts for around 80% of pancreatic cancer cases with an extremely high mortality rate. Emerging research has demonstrated that gut dysbiosis is closely associated with pancreatic cancer, while the underlying mechanisms remain elusive. In this study, we found that elevated levels of endotoxin (LPS) and bile acids were associated with malignant progression in Kras-driven pancreatic cancer mice. Importantly, oral administration of cationic resins to sequestrate intestinal endotoxins and bile acids efficiently attenuated tumor progression. Thus, sequestration of intestinal acidic toxins by oral administration of cationic resins may have potential as an intervention strategy for pancreatic malignancy.Pancreatic cancer is driven by risk factors such as diabetes and chronic pancreatic injury, which are further associated with gut dysbiosis. Intestinal toxins such as bile acids and bacterial endotoxin (LPS), in excess and persistence, can provoke chronic inflammation and tumorigenesis. Of interest is that many intestinal toxins are negatively charged acidic components in essence, which prompted us to test whether oral administration of cationic resin can deplete intestinal toxins and ameliorate pancreatic cancer. Here, we found that increased plasma levels of endotoxin and bile acids in Pdx1-Cre: LSL-KrasG12D/+ mice were associated with the transformation of the pancreatic ductal carcinoma (PDAC) state. Common bile-duct-ligation or LPS injection impeded autolysosomal flux, leading to Yap accumulation and malignant transformation. Conversely, oral administration of cholestyramine to sequestrate intestinal endotoxin and bile acids resumed autolysosomal flux for Yap degradation and attenuated metastatic incidence. Conversely, chloroquine treatment impaired autolysosomal flux and exacerbated malignance, showing jeopardization of p62/ Sqxtm1 turnover, leading to Yap accumulation, which is also consistent with overexpression of cystatin A (CSTA) in situ with pancreatic cancer cells and metastatic tumor. At cellular levels, chenodeoxycholic acid or LPS treatment activated the ligand–receptor-mediated AKT-mTOR pathway, resulting in autophagy-lysosomal stress for YAP accumulation and cellular dissemination. Thus, this work indicates a potential new strategy for intervention of pancreatic metastasis through sequestration of intestinal acidic toxins by oral administration of cationic resins.

Highlights

Pancreatic cancer, known as pancreatic ductal adenocarcinoma (PDAC), has a dismal prognosis [1,2]
We found that elevated levels of plasma endotoxin and serum levels of bile acids are associated with impaired autolysosomal flux leading to Yap accumulation in metastatic malignancies
Serum levels of bile acids and plasma levels of endotoxin were measured, and both had an approximately two-fold increment (Figure 1B), which is in agreement with clinically observed hyperbileacidemia and hyperendotoxemia in association with chronic pancreatitis and PDAC

Summary

Introduction

Pancreatic cancer, known as pancreatic ductal adenocarcinoma (PDAC), has a dismal prognosis [1,2]. Gut bacterial metabolites and toxins can enter portal and systemic circulation through paracellular diffusion or cotransport with chylomicrons [15–17]. Increased endotoxin levels were often found in the pancreatic tissue of PDAC patients, which was further related to the poor prognosis of PDAC under chemotherapy [18]. Another study found that plasma levels of endotoxin and IL-6 together with C-reactive protein (CRP) were increased in blood samples in line with duodenal bacterial up-localization in PDAC patients [19]. High-level expression of FXR was found in the pancreatic tissues of PDAC with poor prognosis [22]. Bacterial endotoxin from the gut could enter portal and systolic circulation with diet facilitated by chylomicrons; and plasma endotoxin and cytokines were increased with obesity [16].

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