Decorin-mediated Signal Transduction in Endothelial Cells

Abstract

Endothelial cells undergoing angiogenesis express decorin, a small multifunctional proteoglycan. We have shown that decorin is causally involved in the formation of capillary-like structures and a decrease in apoptosis in endothelial cells cultured in a collagen lattice. Here we investigate signal transduction pathways mediating the effects of decorin. Reverse transcription-polymerase chain reaction demonstrated that p21 and p27, two inhibitors of cyclin-dependent kinases, were up-regulated by decorin induction. Decorin also increased protein levels of p21 and caused its translocation into the nucleus. p21 synthesis started 6 h after decorin addition and reached a plateau after 18 h, while cyclin A, which was also induced, peaked at 12 h and declined below basal levels within 24 h. These effects were mediated by the Akt/protein kinase B pathway. Akt phosphorylation at Thr-308 increased 4-fold and at Ser-473 1.4-fold within 10 min after decorin addition. Overexpression of dominant negative Akt inhibited the decorin-mediated induction of p21 and cyclin A, but had no effect on p27. These results show that decorin is a signaling molecule in sprouting endothelial cells where it acts via different pathways, one of them involving Akt/protein kinase B.

Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy

“…47 Inactivation of this pathway by drug treatment or DN Akt expression decreased levels of p21 Cip1 . 47,48 In contrast, expression of a constitutively active Akt mutant increased p21 Cip1 expression. 47 Mechanisms by which the PI3K/Akt pathway regulates p21 Cip1 protein expression were further explored by several groups.…”

“…65 However, these effects were not observed in an endothelial cell model. 48 Therefore, the effects of PI3K/Akt on p27 Kip1 expression may be cell type specific.…”

Decorin suppresses tumor cell-mediated angiogenesis

“…Because decorin has been recently implicated in playing a role in angiogenesis as either a positive (Ja¨rvela¨inen et al, 1992;Scho¨nherr et al, 1999Scho¨nherr et al, , 2001 or a negative (de Lange Davies et al, 2001) modulator of this process, we investigated the role of decorin in tumor cell-mediated angiogenesis. We utilized three different tumor cell lines stably-transfected with the full-length human decorin and efficiently secreting the proteoglycan into the conditioned medium.…”

Decorin prevents metastatic spreading of breast cancer

“…In either case, decorin causes a profound downregulation of these receptors both in vitro and in vivo, thereby providing a plausible explanation for its cytostatic effects. The cytostatic effects of decorin occur in a wide variety of tumor cell lines with a diverse histogenetic background (Santra et al, 1995(Santra et al, , 1997Nash et al, 1999) and can also affect murine tumor cells (Iozzo et al, 1999a) and normal cells such as endothelial cells (Scho¨nherr et al, 2001) and macrophages (Xaus et al, 2001). Decorin can also indirectly retard tumor growth by blocking TGF-b (Yamaguchi et al, 1990), by inhibiting tumor cell production of angiogenic factors such as VEGF (Grant et al, 2002), or by interacting with antiangiogenic compounds such as thrombospondin-1 (de Lange Davies et al, 2001).…”