Cathepsin L Induces Proangiogenic Changes in Human Omental Microvascular Endothelial Cells via Activation of the ERK1/2 Pathway

Author(s): Md Zahidul I. Pranjol , Nicholas J. Gutowski , Michael Hannemann , Jacqueline L. Whatmore* .

Journal Name: Current Cancer Drug Targets

Volume 19 , Issue 3 , 2019

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Graphical Abstract:


Abstract:

Background: Metastasis still remains the major cause of therapeutic failure, poor prognosis and high mortality in epithelial ovarian cancer (EOC) patients. Previously, we showed that EOC cells secrete a range of factors with potential pro-angiogenic activity, in disease-relevant human omental microvascular endothelial cells (HOMECs), including the lysosomal protease cathepsin L (CathL). Thus, the aim of this study was to examine potential pro-proliferative and pro-migratory effects of CathL in HOMECs and the activated signalling pathways, and whether these proangiogenic responses are dependent on CathL-catalytic activity.

Methods: HOMECs proliferation was investigated using WST-1, BrdU and CyQUANT assays. Cell migration was examined using a Cultrex Cell 96 transwell migration assay. Enzyme activity was assayed at various pHs using the CathL-specific fluorogenic substrate FY-CHO. Activation of cell signalling pathways was tested using a commercially available phosphokinase array and intact cellbased ELISAs.

Results: We showed for the first time that CathL has a potent pro-proliferative and pro-migratory effect on HOMECs. For instance, CathL significantly increases HOMEC proliferation (134.8±14.7% vs control 100%) and migration (146.6±17.3% vs control 100%). Our data strongly suggest that these proangiogenic effects of CathL are mediated via a non-proteolytic mechanism. Finally, we show that CathL-induced activation of the ERK1/2 pathway is involved in inducing these cellular effects in HOMECs.

Conclusion: These data suggest that CathL acts as an extracellular ligand and plays an important pro-angiogenic, and thus pro-metastatic, role during EOC metastasis to the omentum, by activating the omental microvasculature, and thus can potentially be targeted therapeutically in the future.

Keywords: Cathepsin L, non-proteolytic, proliferation, migration, angiogenesis, metastasis.

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Article Details

VOLUME: 19
ISSUE: 3
Year: 2019
Page: [231 - 242]
Pages: 12
DOI: 10.2174/1568009618666180831123951
Price: $58

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