Glypican 1 Stimulates S Phase Entry and DNA Replication in Human Glioma Cells and Normal Astrocytes

Abstract

c Malignant gliomas are highly lethal neoplasms with limited treatment options. We previously found that the heparan sulfate proteoglycan glypican 1 (GPC1) is universally and highly expressed in human gliomas. In this study, we investigated the biological activity of GPC1 expression in both human glioma cells and normal astrocytes in vitro. Expression of GPC1 inactivates the G 1 /S checkpoint and strongly stimulates DNA replication. Constitutive expression of GPC1 causes DNA rereplication and DNA damage, suggesting a mutagenic activity for GPC1. GPC1 expression leads to a significant downregulation of the tumor suppressors pRb, Cip/Kip cyclin-dependent kinase inhibitors (CKIs), and CDH1, and upregulation of the pro-oncogenic proteins cyclin E, cyclin-dependent kinase 2 (CDK2), Skp2, and Cdt1. These GPC1-induced changes are accompanied by a significant reduction in all types of D cyclins, which is independent of serum supplementation. It is likely that GPC1 stimulates the so-called Skp2 autoinduction loop, independent of cyclin D-CDK4/6. Knockdown of Skp2, CDK2, or cyclin E, three key elements within the network modulated by GPC1, results in a reduction of the S phase and aneuploid fractions, implying a functional role for these regulators in GPC1-induced S phase entry and DNA rereplication. In addition, a significant activation of both the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways by GPC1 is seen in normal human astrocytes even in the presence of growth factor supplement. Both pathways are constitutively activated in human gliomas. The surprising magnitude and the mitogenic and mutagenic nature of the effect exerted by GPC1 on the cell cycle imply that GPC1 may play an important role in both glioma tumorigenesis and growth.

Glypican-1 nanoliposomes for potentiating growth factor activity in therapeutic angiogenesis

“…It can act as a co-receptor/modulator for many angiogenic factors including members of the FGF and VEGF growth factor families [40, 44–47]. Several studies also have shown that glypican-1 can stimulate cell cycle progression in endothelial cells [43, 48]. In this work, we show that glypican-1 is lost in the blood vessels of skin samples from human patients with type 2 diabetes.…”

“…A hallmark of gliomas is vigorous angiogenic response to the tumor that drives neovascularization through multiple mechanisms [30–33]. Glypican-1 has a key role in the growth, metastasis and angiogenic properties of gliomas [40–43]. In addition, glypican-1 is the most prevalent member of the glypican family expressed in endothelial cells and the vascular system [44].…”

Overexpression of glypican-1 implicates poor prognosis and their chemoresistance in oesophageal squamous cell carcinoma

“…GPC1 is a member of the glypican family, which comprises HSPGs, linked via a glycosyl-phosphatidylinositol (GPI) anchor to the extracellular membrane. GPC1 functions in angiogenesis, cell-cycle promotion and mitogenic growth in cancer cells ( Qiao et al , 2008 , 2012 , 2013 ). Other reports have shown that GPC1 is essential for mitogenic signalling promoted by FGF2 and HB-EGF, and plays a crucial role in neoplastic transformation and tumour progression in some cancers ( Kleeff et al , 1998 , 1999 ; Gengrinovitch et al , 1999 ; Matsuda et al , 2001 ; Ding et al , 2005 ; Su et al , 2006 ; Aikawa et al , 2008 ; Okolicsanyi et al , 2014 ).…”

Autophagy Induction by Endothelial-Monocyte Activating Polypeptide II Contributes to the Inhibition of Malignant Biological Behaviors by the Combination of EMAP II with Rapamycin in Human Glioblastoma

“…Furthermore, PI3K/Akt/mTOR is a critical regulatory pathway in autophagy response ( Takeuchi et al, 2005 ; Guertin and Sabatini, 2007 ). Recent study revealed that PI3K/Akt/mTOR signal pathway would be commonly activated in human glioma cells ( Qiao et al, 2013 ; Shin et al, 2013 ; Xu et al, 2013 ). To further investigate the possible mechanism involved in this process, we studied the effect of EMAP II on P13K, Akt, and mTOR signal molecules.…”