Open AccessDetermination of cell uptake pathways for tumor inhibitor lysyl oxidase propeptide
Author(s) -
Ozdener Gokhan Baris,
Bais Manish V.,
Trackman Philip C.
Publication year - 2016
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1016/j.molonc.2015.07.005
Subject(s) - pinocytosis , lysyl oxidase , endosome , microbiology and biotechnology , intracellular , chemistry , endocytosis , pi3k/akt/mtor pathway , cytosol , biochemistry , biology , cell , signal transduction , extracellular matrix , enzyme
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.