Cathepsin D non-proteolytically induces proliferation and migration in human omental microvascular endothelial cells via activation of the ERK1/2 and PI3K/AKT pathways

Biochim Biophys Acta Mol Cell Res. 2018 Jan;1865(1):25-33. doi: 10.1016/j.bbamcr.2017.10.005. Epub 2017 Oct 10.

Abstract

Epithelial ovarian cancer (EOC) frequently metastasises to the omentum, a process that requires pro-angiogenic activation of human omental microvascular endothelial cells (HOMECs) by tumour-secreted factors. We have previously shown that ovarian cancer cells secrete a range of factors that induce pro-angiogenic responses e.g. migration, in HOMECs including the lysosomal protease cathepsin D (CathD). However, the cellular mechanism by which CathD induces these cellular responses is not understood. The aim of this study was to further examine the pro-angiogenic effects of CathD in HOMECs i.e. proliferation and migration, to investigate whether these effects are dependent on CathD catalytic activity and to delineate the intracellular signalling kinases activated by CathD. We report, for the first time, that CathD significantly increases HOMEC proliferation and migration via a non-proteolytic mechanism resulting in activation of ERK1/2 and AKT. These data suggest that EOC cancer secreted CathD acts as an extracellular ligand and may play an important pro-angiogenic, and thus pro-metastatic, role by activating the omental microvasculature during EOC metastasis to the omentum.

Keywords: Angiogenesis; Cathepsin D; Migration; Non-proteolytic; Proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Ovarian Epithelial
  • Cathepsin D / genetics
  • Cathepsin D / physiology*
  • Cell Movement / genetics*
  • Cell Proliferation / genetics*
  • Cells, Cultured
  • Endothelial Cells / cytology
  • Endothelial Cells / physiology*
  • Female
  • Humans
  • MAP Kinase Signaling System / physiology
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Neoplasm Metastasis
  • Neoplasms, Glandular and Epithelial / metabolism
  • Neoplasms, Glandular and Epithelial / pathology
  • Omentum / blood supply
  • Omentum / cytology*
  • Omentum / pathology
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Peritoneal Neoplasms / genetics
  • Peritoneal Neoplasms / metabolism
  • Peritoneal Neoplasms / secondary
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / physiology

Substances

  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 3
  • CTSD protein, human
  • Cathepsin D