Hypoxia Regulates DPP4 Expression, Proteolytic Inactivation, and Shedding from Ovarian Cancer Cells.

Laura R Moffitt,Yiqian Chen,Magdalena Plebanski,Maree Bilandzic,Andrew N Stephens,Mark D Gorrell,Amy L Wilson,Martin K Oehler

doi:10.3390/ijms21218110

Abstract

The treatment of ovarian cancer has not significantly changed in decades and it remains one of the most lethal malignancies in women. The serine protease dipeptidyl peptidase 4 (DPP4) plays key roles in metabolism and immunity, and its expression has been associated with either pro- or anti-tumour effects in multiple tumour types. In this study, we provide the first evidence that DPP4 expression and enzyme activity are uncoupled under hypoxic conditions in ovarian cancer cells. Whilst we identified strong up-regulation of DPP4 mRNA expression under hypoxic growth, the specific activity of secreted DPP4 was paradoxically decreased. Further investigation revealed matrix metalloproteinases (MMP)-dependent inactivation and proteolytic shedding of DPP4 from the cell surface, mediated by at least MMP10 and MMP13. This is the first report of uncoupled DPP4 expression and activity in ovarian cancer cells, and suggests a previously unrecognized, cell- and tissue-type-dependent mechanism for the regulation of DPP4 in solid tumours. Further studies are necessary to identify the functional consequences of DPP4 processing and its potential prognostic or therapeutic value.

Highlights

Epithelial ovarian cancers (EOCs) remain the most lethal of gynaecological malignancies, and account for >80% of ovarian tumour diagnoses [1]
Dipeptidyl peptidase 4 (DPP4) Expression Is Upregulated by Hypoxia in Ovarian Cancer Cells
To assess the effect of hypoxic growth on DPP4 expression and abundance in ovarian cancer, cell lines OVCAR4, CaOV3, and SKOV3 were cultured under either normoxic (20% O2) or hypoxic (2% O2) conditions for 48 h

Summary

Introduction

Epithelial ovarian cancers (EOCs) remain the most lethal of gynaecological malignancies, and account for >80% of ovarian tumour diagnoses [1]. Expressed by multiple cell types, DPP4 catalyses the cleavage of N-terminal X-Pro and X-Ala dipeptides from a variety of substrates to directly modify their bioactivities [4,5]. A number of inflammatory mediators with central roles in immune suppression and tumour progression (e.g., CCL5, 11, 22; CXCL2, 6, 9–12) are potential targets for DPP4-directed cleavage [3,4,5]. DPP4 non-enzymatically regulates adhesion via interaction with extracellular matrix (ECM) proteins (e.g., collagen, fibronectin), and is involved in signalling pathways through association with FAP and CXCR4 [6]. DPP4 expression is linked with tumorigenic behaviour in a variety of cancer types (reviewed in [6])

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