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

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.

Antiproliferative and Antimetastatic Effects of Praeruptorin C on Human Non–Small Cell Lung Cancer through Inactivating ERK/CTSD Signalling Pathways

“…Depletion of CTSD gene expression by RNA interference decreases proliferative response and invasive potential in human breast cancer cell through suppressing the activation of EKR1/2 pathway [45]. Epithelial ovarian cancer(EOC)-secreted CTSD acts as an extracellular ligand and induces proliferation and migration in human omental microvascular endothelial cells (HOMECs) through activation of ERK1/2 and PI3K/AKT pathways [46]. Based on our observation, we found that PC cotreated with U0126 does not affect cell viability in A549 and H1299 cells.…”

New Insights into the Occurrence of Matrix Metalloproteases -2 and -9 in a Cohort of Breast Cancer Patients and Proteomic Correlations

“…Cathepsin D, CATD (CTSD) is an acid protease that is active in the breakdown of intracellular proteins, which has been reported to be involved in the pathogenesis of several diseases, such as breast cancer and possibly Alzheimer’s disease via non-proteolytic pathways [ 64 , 65 ]. The postulated direct correlation between CTSD and MMP-2 is an interesting observation which needs further insight.…”

Cathepsin-sensitive nanoscale drug delivery systems for cancer therapy and other diseases

“…Hence, the intimate relationships between Cathepsins and cancer stimulated the conception of (macro)molecules sensitive to the presence of Cathepsins for enhanced therapeutic effect. [71][72][73][74][75][76][77] In the following, we have covered Cathepsin-sensitive drug delivery systems for anticancer therapy, by distinguishing five different types of systems: (i) polymeric; (ii) inorganic; (iii) dendritic/comb-like; (iv) lipidic and (v) protein-based/peptidic.…”