Hypoxia regulates DPP4 expression and proteolytic shedding of inactive enzyme from the surface of ovarian cancer cells

Moffitt LR1,2, Bilandzic M1,2, Wilson A1,2, Chen Y1,2, Plebanski M3, Gorrell MD4 and Stephens AN1,2,5

  1. Monash University, VIC, Australia.
  2. Hudson Institute of Medical Research, VIC, Australia.
  3. RMIT University, VIC, Australia.
  4. University of Sydney, NSW, Australia.
  5. Epworth Research Institute, VIC, Australia.

Ovarian cancer is the leading cause of death from a gynaecological malignancy. There is an urgent need to develop targeted therapies to improve outcomes for patients. Dipeptidyl peptidase 4 (DPP4) is a serine protease with a diverse role in tumour progression; involving mediating cell-cell interactions, immune modulation and degradation of the extracellular matrix. DPP4 is overexpressed within the hypoxic microenvironment of solid ovarian tumours and tumour-derived spheroids, which drive metastasis of the disease. Whilst DPP4 and its activity is regulated by hypoxia in other cell types, the mechanism is cell-type dependent and has never been investigated in ovarian cancer. In this study we examined the effect of hypoxic growth on DPP4 expression and activity in human ovarian cancer cell lines OVCAR4, SKOV3 and CaOV3. Cells grown under chronic hypoxic stress exhibited upregulation of DPP4, which was correlated with an increase in enzyme release from the cell surface. DPP4 in culture media was inactive, however, and its presence correlated with simultaneous increases in mRNA and protein expression of the matrix metalloproteinases; MMP-1, MMP-10 and MMP-13. We provide the first evidence of the hypoxic regulation of DPP4 in ovarian cancer cell lines and identify MMP-1, MMP-10 and MMP-13 as possible mediators for the shedding of inactive DPP4 from the cell surface. Our study offers a novel insight into the potential role of DPP4 in epithelial ovarian cancer, and highlights some possible therapeutic approaches targeting DPP4 expression or activity.