title: L-asparaginase inhibits invasive and angiogenic activity and induces autophagy in ovarian cancer.
abstract: Recent work identified L-asparaginase (L-ASP) as a putative therapeutic target for ovarian cancer. We suggest that L-ASP, a dysregulator of glycosylation, would interrupt the local microenvironment, affecting the ovarian cancer cell-endothelial cell interaction and thus angiogenesis without cytotoxic effects. Ovarian cancer cell lines and human microvascular endothelial cells (HMVEC) were exposed to L-ASP at physiologically attainable concentrations and subjected to analyses of endothelial tube formation, invasion, adhesion and the assessment of sialylated proteins involved in matrix-associated and heterotypic cell adhesion. Marked reduction in HMVEC tube formation in vitro, HMVEC and ovarian cancer cell invasion, and heterotypic cell-cell and cell-matrix adhesion was observed (P < 0.05-0.0001). These effects were associated with reduced binding to ß1integrin, activation of FAK, and cell surface sialyl Lewis(X) (sLe(x)) expression. No reduction in HMVEC E-selectin expression was seen consistent with the unidirectional inhibitory actions observed. L-ASP concentrations were non-toxic to either ovarian cancer or HMVEC lines in the time frame of the assays. However, early changes of autophagy were observed in both cell types with induction of ATG12, beclin-1, and cleavage of LC-3, indicating cell injury did occur. These data and the known mechanism of action of L-ASP on glycosylation of nascent proteins suggest that L-ASP reduces of ovarian cancer dissemination and progression through modification of its microenvironment. The reduction of ovarian cancer cell surface sLe(x) inhibits interaction with HMVEC and thus HMVEC differentiation into tubes, inhibits interaction with the local matrix reducing invasive behaviour, and causes cell injury initiating autophagy in tumour and vascular cells.
authors.affiliation: Molecular Signaling Section, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Minshu
authors.initials: M
authors.lastname: Yu
authors.forename: Ryan
authors.initials: R
authors.lastname: Henning
authors.forename: Amanda
authors.initials: A
authors.lastname: Walker
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Kim
authors.forename: Alyssa
authors.initials: A
authors.lastname: Perroy
authors.forename: Riccardo
authors.initials: R
authors.lastname: Alessandro
authors.forename: Victoria
authors.initials: V
authors.lastname: Virador
authors.forename: Elise C
authors.initials: EC
authors.lastname: Kohn
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D001215:Asparaginase / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D021982:Cell-Matrix Junctions; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000473:pathology; D009844:Oligosaccharides / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D000080506:Sialyl Lewis X Antigen
chemical_list: D020533:Angiogenesis Inhibitors; D019040:E-Selectin; D019012:Integrin beta1; D009844:Oligosaccharides; D000080506:Sialyl Lewis X Antigen; D001215:Asparaginase