Table 1.

Different molecular pathways targeted by PEDF in different types of diseases

Molecular pathway	Function	Diseases involved	Role of PEDF
uPA/uPAR (urokinase plasminogen activator and its receptor)	The binding of uPA to uPAR activates proteolytic cascades resulting to blood vessel invasion of tumour cells leading in metastasis. Serpins plasminogen activator inhibitor-1 and -2 (PAI-1 and PAI-2) are known inhibitors of the interaction of uPA to uPAR.	Osteosarcoma	PEDF in combination with uPAR downregulation showed a decrease in osteosarcoma invasion, growth and metastasis, The presence of PEDF internalized the distribution of uPA/uPAR from the surface of the cell hence, reducing the ability of the osterosarcoma cells to migrate [10]
		Prostate cancer	PAI-2 is upregulated by PEDF inhibiting the activity of uPA and uPAR [11]
		Lung cancer	Reduced lung cancer cell adhesion and motility [11]
VEGF/VEGFR (vascular endothelial growth factor)	Overexpression generates leaky blood vessels allowing recruitment of endothelial cells forming new blood vessels, uneven distribution of oxygen and nutrients. For cancer, the effects of VEGF overexpression can influence tumour growth and survival, and can leak out delivered chemotherapeutic drugs.	Cardiovascular disease	PEDF inhibited VEGF-induced uPA/uPAR activation affecting vascular permeability [40]
		Diabetic retinopathy	PEDF downregulated VEGF expression at the transcription level. PEDF was also shown to compete against VEGF in binding to VEGF receptor 2 [41]
		Lung cancer, prostate cancer,	PEDF resulted in a reduced tumour microvessel density, and reduced tumour growth and weight [11]
		Melanoma	Tumour growth, tumour cell survival and microvessel density is decreased [11]
		Pancreatic cancer	Microvessel density is decreased, tumour growth is inhibited and the proliferation and migration of endothelial cells decreased [11]
Fas/FasL	Fas ligand when bound to Fas creates an activator complex activating caspase 8, The activation of caspase 8 and its release in the cytosol allows the activation of other caspases, which leads to cell apoptosis.	Melanoma	PEDF lead to increased levels of apoptosis which was prevented after the addition of neutralizing FasL antibodies [11]
p53/PPARγ	p53 is a tumour suppressor protein which, upon signals of DNA damage, is involved in arresting cell cycling activity or initiates apoptosis. PPARγ, a transcription factor, which upon activation by its ligand, 15d-PGJ2, activates caspase-mediated endothelial cell apoptosis.	Choroidal neovascularisation	PEDF increased the expression of PPARγ in human umbilical vein endothelial cells (HUVECs) initiating endothelial cell apoptosis and upon the inhibition of PPARγ activity using PPARγ antagonists, abolished the apoptotic effect of PEDF. PEDF also induced overexpression of p53 for apoptosis. Inhibition of either PPARγ or p53 attenuates apoptosis [23]
c-jun N-terminal kinase (JNK)	JNK responses to inflammatory cytokines, growth factors and environmental stress. JNK plays a role in cell differentiation, apoptosis, and inflammation, to name a few. It modifies proteins acting in the nucleus or in the mitochondria to regulate cell function and protein synthesis.	Neovascularization	PEDF regulated the expression of JNK leading to the apoptosis of endothelial cell inhibiting neovascularisation and tumour growth [42]
		Obesity	PEDF activated JNK in the muscle and liver resulting to insulin expression inhibition [43]