Heparan sulfate proteoglycans as trastuzumab targets in anoikis-resistant endothelial cells.

Abstract

Anoikis is a form of programmed cell death induced by loss of contact from neighboring cells or from their extracellular matrix (ECM). Many tumorigenic cells are anoikis resistant, facilitating cancer progression and metastasis. Trastuzumab is a monoclonal antibody used for the treatment of breast and gastric cell cancer, but its mechanism of action is not well elucidated and its target molecules not well defined. Heparan sulfate proteoglycans (HSPGs) and glycosaminoglycans (GAGs) play important roles in tumor development and in response of cancer cells to drugs. This study investigates the effect of trastuzumab on the expression of HSPGs and sulfated glycosaminoglycans (SGAGs) in anoikis-resistant endothelial cells. After trastuzumab treatment, endothelial cells resistant to anoikis show an increase in adhesion to fibronectin followed by a decrease in invasion, proliferation, and angiogenic capacity. In addition, a significant increase in the number of cells in the S phase of the cell cycle was also observed. In relation to HSPGs and SGAGs expression, we observed a decrease in syndecan-4 and perlecan expression, as well as in the heparan sulfate biosynthesis in anoikis-resistant endothelial cells after exposure to trastuzumab. Our results suggest that trastuzumab interacts with GAGs and proteoglycans of the cell surface and ECM and through this interaction controls cellular events in anoikis-resistant endothelial cells.

• Authors: Jessica Oyie Sousa Onyeisi, Paulo Castanho de Almeida Pernambuco Filho, Silvana de Araujo Lopes, Helena Bonciani Nader, Carla Cristina Lopes
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 120 Issue 8 Pg. 13826-13840 (08 2019) ISSN: 1097-4644 [Electronic] United States
• PMID: 30945340 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Wiley Periodicals, Inc.

Chemical References

• Angiogenesis Inhibitors
• Heparan Sulfate Proteoglycans
• perlecan
• Chondroitin Sulfates
• Heparitin Sulfate
• Trastuzumab

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Anoikis (drug effects)
• Cell Adhesion (drug effects)
• Cell Cycle (drug effects)
• Cell Line
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Chondroitin Sulfates (metabolism)
• Endothelial Cells (drug effects, metabolism)
• Gene Expression Regulation (drug effects)
• Heparan Sulfate Proteoglycans (metabolism)
• Heparitin Sulfate (metabolism)
• Rabbits
• Trastuzumab (pharmacology)