ABSTRACT
Mitochondrial dysregulation plays a central role in cancers and drives reactive oxygen species (ROS)-dependent tumor progression. We investigated the pro-tumoral roles of mitochondrial dynamics and altered intracellular ROS levels in pancreatic ductal adenocarcinoma (PDAC). We identified 'family with sequence similarity 49 member B' (FAM49B) as a mitochondria-localized protein that regulates mitochondrial fission and cancer progression. Silencing FAM49B in PDAC cells resulted in increased fission and mitochondrial ROS generation, which enhanced PDAC cell proliferation and invasion. Notably, FAM49B expression levels in PDAC cells were downregulated by the tumor microenvironment. Overall, the results of this study show that FAM49B acts as a suppressor of cancer cell proliferation and invasion in PDAC by regulating tumor mitochondrial redox reactions and metabolism.
Subject(s)
Adenocarcinoma/secondary , Biomarkers, Tumor/metabolism , Carcinoma, Pancreatic Ductal/secondary , Gene Expression Regulation, Neoplastic , Intracellular Signaling Peptides and Proteins/metabolism , Mitochondria/pathology , Mitochondrial Proteins/metabolism , Neoplasm Proteins/metabolism , Pancreatic Neoplasms/pathology , Reactive Oxygen Species/metabolism , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Animals , Apoptosis , Biomarkers, Tumor/genetics , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/metabolism , Cell Movement , Cell Proliferation , Humans , Intracellular Signaling Peptides and Proteins/genetics , Mice , Mice, Inbred NOD , Mice, SCID , Mitochondria/metabolism , Mitochondrial Proteins/genetics , Neoplasm Proteins/genetics , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Prognosis , Tumor Cells, Cultured , Xenograft Model Antitumor Assays , Pancreatic NeoplasmsABSTRACT
The development of the interendothelial tight junctions was studied in the microvessels of the otpic tectum of chick embryos, at the 14th-16th and 18th-20th incubation day (i.d.), and in post-hatching chickens, using thin sections and freeze-fracture techniques. At the 14th-16th i.d., the junctional plasmamembranes of the endothelial cells are simply apposed or fused for brief tracts showing a pentalaminar or trilaminar configuration. In the replicas the P-faces of the fractured junctional membranes are either lacking in intramembrane particles (IMPs) and characterized by finger-like depressions, or provided with discrete IMPs aligned in rows. At the 18th-20th i.d., the thin peripheral expansions of the endothelial cells are superimposed and welded by continuous pentalaminar junctions. Their fracture P-faces display junctional strands formed by parallel fibrils of fused IMPs, with or without interconnections. In the 10-day-old chickens the junctions consist of highly complex networks of fibrils. The results have made it possible to recognize precise relationships between the features of the developing endothelial junctions in the ultrathin sections and, respectively, in the replicas. Moreover, the observations suggest that tight junction formation occurs progressively in the cerebral microvessels by processes of alignment and fusion of the IMPs, which conclude with the arrangement of fibrils in networks.
