Transforming Growth Factor TGFβ Increases Levels of Microtubule-Associated Protein MAP1S and Autophagy Flux in Pancreatic Ductal Adenocarcinomas.

Kun Song,Leyuan Liu,Weijia Sun,Qi Chen,Jing Zou,Qizhi Yao,Fei Yue,Wenjiao Li,Wei Hu,Chunhong Yan

doi:10.1371/journal.pone.0143150

Abstract

Background and AimAutophagy is a cellular process to regulate the turnover of misfolded/aggregated proteins or dysfunctional organelles such as damaged mitochondria. Microtubule-associated protein MAP1S (originally named C19ORF5) is a widely-distributed homologue of neuronal-specific MAP1A and MAP1B with which autophagy marker light chain 3 (LC3) was originally co-purified. MAP1S bridges autophagic components with microtubules and mitochondria through LC3 and positively regulates autophagy flux from autophagosomal biogenesis to degradation. The MAP1S-mediated autophagy suppresses tumorigenesis as suggested in a mouse liver cancer model and in prostate cancer patients. The TGFβ signaling pathway plays a central role in pancreatic tumorigenesis, and high levels of TGFβ suggest a tumor suppressive function and predict a better survival for some patients with resectable pancreatic ductal adenocarcinoma. In this study, we try to understand the relationship between TGFβ and MAP1S-mediated autophagy in pancreatic ductal adenocarcinoma.MethodsWe collected the tumor and its adjacent normal tissues from 33 randomly selected patients of pancreatic ductal adenocarcinomas to test the association between TGFβ and autophagy markers MAP1S and LC3. Then we tested the cause and effect relation between TGFβ and autophagy markers in cultured pancreatic cancer cell lines.ResultsHere we show that levels of TGFβ and autophagy markers MAP1S and LC3 are dramatically elevated in tumor tissues from patients with pancreatic ductal adenocarcinomas. TGFβ increases levels of MAP1S protein and enhances autophagy flux.ConclusionTGFβ may suppress the development of pancreatic ductal adenocarcinomas by enhancing MAP1S-mediated autophagy.

Highlights

Autophagy-lysosome system is the major pathway to degrade damaged organelles, misfolded/ aggregated proteins and other macromolecules in mammalian cells [1, 2]
We show that levels of TGFβ and autophagy markers MAP1S and light chain 3 (LC3) are dramatically elevated in tumor tissues from patients with pancreatic ductal adenocarcinomas
TGFβ may suppress the development of pancreatic ductal adenocarcinomas by enhancing MAP1S-mediated autophagy

Summary

Introduction

Autophagy-lysosome system is the major pathway to degrade damaged organelles, misfolded/ aggregated proteins and other macromolecules in mammalian cells [1, 2]. In a mouse model of chemical carcinogen-induced hepatocellular carcinomas, we found that the autophagy-defective MAP1S-deficient mice exhibit higher levels of genome instability and develop more tumor foci and higher malignance of hepatocellular carcinomas than the wild-type mice [20]. The protein levels of MAP1S and LRPPRC are closely associated with survival of patients with prostate adenocarcinomas [19, 21, 22]. A link between MAP1S-enhanced autophagy and suppression of genomic instability and tumorigenesis has been revealed. Microtubule-associated protein MAP1S (originally named C19ORF5) is a widely-distributed homologue of neuronal-specific MAP1A and MAP1B with which autophagy marker light chain 3 (LC3) was originally co-purified. The MAP1S-mediated autophagy suppresses tumorigenesis as suggested in a mouse liver cancer model and in prostate cancer patients. We try to understand the relationship between TGFβ and MAP1S-mediated autophagy in pancreatic ductal adenocarcinoma

Methods

Results

Conclusion