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

Cancers

Mouad Edderkaoui¹  Stephen J. Pandol¹  Jun Li²  Xiangsheng Fu²  Richard Hu³  Yuan-Ping Han⁴  Tianci Zhang⁴  Wei Liu⁴  Guangfu Zhao⁴ 

[1] Cedars-Sinai Medical Center, Los Angeles, CA 90001, USA;Department of Gastroenterology, Clinical Medical College and the First Affiliated Hospital of Chengdu Medical College, Chengdu 610083, China;Olive View-UCLA Medical Center, Los Angeles, CA 90001, USA;The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu 610017, China;

关键词: pancreatic cancer;    yes-associated protein;    bile acid;    endotoxin;    autophagy;    lysosome;   

DOI  :  10.3390/cancers14061407

来源: DOAJ

【 摘 要 】

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-Kras^G12D/+ 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.

【 授权许可】

Unknown