title: Determination of cell uptake pathways for tumor inhibitor lysyl oxidase propeptide.
abstract: The lysyl oxidase propeptide (LOX-PP) is derived from pro-lysyl oxidase (Pro-LOX) by extracellular biosynthetic proteolysis. LOX-PP inhibits breast and prostate cancer xenograft tumor growth and has tumor suppressor activity. Although, several intracellular targets and molecular mechanisms of action of LOX-PP have been identified, LOX-PP uptake pathways have not been reported. Here we demonstrate that the major uptake pathway for recombinant LOX-PP (rLOX-PP) is PI3K-dependent macropinocytosis in PWR-1E, PC3, SCC9, MDA-MB-231 cell lines. A secondary pathway appears to be dynamin- and caveola dependent. The ionic properties of highly basic rLOX-PP provide buffering capacity at both high and low pHs. We suggest that the buffering capacity of rLOX-PP, which serves to limit endosomal acidification, sustains PI3K-dependent macropinocytosis in endosomes which in turn is likely to facilitate LOX-PP endosomal escape into the cytoplasm and its observed interactions with cytoplasmic targets and nuclear uptake.
authors: Boston University, Department of Molecular and Cell Biology, Boston, MA 02118, United States.
authors: Gokhan Baris
authors: GB
authors: Ozdener
authors: Boston University, Department of Molecular and Cell Biology, Boston, MA 02118, United States.
authors: Manish V
authors: MV
authors: Bais
authors: Boston University, Department of Molecular and Cell Biology, Boston, MA 02118, United States. Electronic address: trackman@bu.edu.
authors: Philip C
authors: PC
authors: Trackman
mesh_terms: D045744:Cell Line, Tumor; D034281:Dynamins / Q000378:metabolism; D004705:Endocytosis; D006801:Humans; D010455:Peptides / Q000737:chemistry*; D008249:Protein-Lysine 6-Oxidase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D010455:Peptides; D008249:Protein-Lysine 6-Oxidase; D034281:Dynamins
keywords: Endocytosis; Lysyl oxidase; Macropinocytosis; Propeptide; Tumor suppressor