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

International Journal of Molecular Sciences

Mark D Gorrell¹  Martin K Oehler²  Andrew N Stephens³  Maree Bilandzic³  Amy L Wilson³  Yiqian Chen³  Laura R Moffitt³  Magdalena Plebanski⁴ 

[1] Centenary Institute, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2006, Australia;Department of Gynaecological Oncology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia;Department of Molecular and Translational Sciences, Monash University, Clayton, VIC 3168, Australia;School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3082, Australia;

关键词: ovarian cancer;    DPP4;    hypoxia;    MMP;    tumour microenvironment;   

DOI  :  10.3390/ijms21218110

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown