Abstract
Paxillin (PXN), a key component of the focal adhesion complex, has been associated with cancer progression, but the underlying mechanisms are poorly understood. The purpose of this study was to elucidate mechanisms by which PXN affects cancer growth and progression, which we addressed using cancer patient data, cell lines, and orthotopic mouse models. We demonstrated a previously unrecognized mechanism whereby nuclear PXN enhances angiogenesis by transcriptionally regulating SRC expression. SRC, in turn, increases PLAT expression through NF-ĸB activation; PLAT promotes angiogenesis via LRP1 in endothelial cells. PXN silencing in ovarian cancer mouse models reduced angiogenesis, tumor growth, and metastasis. These findings provide a new understanding of the role of PXN in regulating tumor angiogenesis and growth.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Apoptosis
-
Biomarkers, Tumor / genetics
-
Biomarkers, Tumor / metabolism*
-
Cell Nucleus / metabolism*
-
Cell Proliferation
-
Disease Progression
-
Female
-
Gene Expression Regulation, Neoplastic*
-
Humans
-
Male
-
Mice
-
Mice, Nude
-
Neovascularization, Pathologic / genetics
-
Neovascularization, Pathologic / metabolism
-
Neovascularization, Pathologic / pathology*
-
Ovarian Neoplasms / blood supply*
-
Ovarian Neoplasms / genetics
-
Ovarian Neoplasms / metabolism
-
Paxillin / antagonists & inhibitors
-
Paxillin / genetics
-
Paxillin / metabolism*
-
Prognosis
-
Survival Rate
-
Tissue Plasminogen Activator / genetics
-
Tissue Plasminogen Activator / metabolism
-
Tumor Cells, Cultured
-
Xenograft Model Antitumor Assays
-
src-Family Kinases / genetics
-
src-Family Kinases / metabolism
Substances
-
Biomarkers, Tumor
-
PXN protein, human
-
Paxillin
-
src-Family Kinases
-
PLAT protein, human
-
Tissue Plasminogen Activator