Stanniocalcin-1 acts in a negative feedback loop in the prosurvival ERK1/2 signaling pathway during oxidative stress

Abstract

Mammalian Stanniocalcin-1 (STC1) is a glycoprotein that has been implicated in various biological processes including angiogenesis. Aberrant STC1 expression has been reported in breast, ovarian and prostate cancers, but the significance of this is not well understood. Here, we report that oxidative stress caused a 40-fold increase in STC1 levels in mouse embryo fibroblasts (MEFs). STC1À/À MEFs were resistant to growth inhibition and cell death induced by H 2 O 2 or by 20% O 2 (which is hyperoxic for most mammalian cells); this is the first phenotype reported for STC1-null cells. STC1À/À cells had higher levels of activated MEK and ERK1/2 than their wild-type (WT) counterparts, and these levels were all reduced by stable expression of exogenous STC1 in STC1À/À cells. Furthermore, pharmacological inhibition by PD98059 or UO126 of MEK and therefore of ERK1/2 activation restored sensitivity of STC1À/À cells to oxidative stress. We also found that H 2 O 2 -induced STC1 expression in WT cells was abolished by inhibition of ERK1/2 activation. Thus, the ERK1/2 signaling pathway upregulates STC1 expression, which in turn downregulates the level of activated MEK and consequently ERK1/2 in a novel negative feedback loop. Therefore, STC1 expression downregulates prosurvival ERK1/2 signaling and reduces survival under conditions of oxidative stress.

Synergistic effect of p53 on TSA-induced stanniocalcin 1 expression in human nasopharyngeal carcinoma cells, CNE2

“…Other studies have demonstrated that TSA could promote apoptosis induced by Dox treatment (Karagiannis et al 2004, Rho et al 2005 via the activation of p53-signaling pathway (Magnelli et al 1995, Brantley-Finley et al 2003, Wang et al 2004. Human STC1 has been suggested to be a putative p53 downstream target and is involved in apoptosis (Wu et al 2006, Lai et al 2007, Law et al 2008, Nguyen et al 2009. In this study, the data of western blotting, real-time PCR, and p53-luciferase reporter assays showed that p53 was activated in the Dox-treated cells.…”

“…Our previous study has demonstrated the epigenetic regulation of STC1 gene expression in apoptotic cancer cells treated with histone deacetylase (HDAC) inhibitors (Law et al 2008). The possible roles of STC1 in apoptosis have been reported by different laboratories (Zhang et al 2000, Wu et al 2006, Lai et al 2007, Block et al 2009, Nguyen et al 2009). The transcriptional relationship between p53 (TP53) and STC1 has also been suggested (Lai et al 2007); however, the underlying regulatory mechanism is not clear.…”

STC1 Expression By Cancer-Associated Fibroblasts Drives Metastasis of Colorectal Cancer

“…2B). Previous studies have reported that proliferation rate of STC1À/À MEFs is increased as compared with wild-type MEFs (35).…”

“…This poorly characterized, secreted hypoxiainduced protein was recently linked to ovarian cancer (32). Furthermore, earlier studies have also linked this protein to progression of colorectal cancer (33,34), although negative effect on prosurvival signaling pathways has also been observed (35).…”

“…Previously isolated and characterized MEFs from STC1 knockout mice (30,35) were used to analyze the contribution of STC1 to the PDGF-induced paracrine effects. These cells were observed to have similar levels of expression, and ligandinduced phosphorylation, of PDGF b-receptor as wild-type MEFs (Fig.…”