RKIP expression in primary CRCs correlates with overall and disease-free survival, and can be useful for identifying early-stage CRC patients at risk of relapse.

Raf kinase inhibitory protein (RKIP) is a physiologic inhibitor of c-RAF kinase and nuclear factor kB signaling that represses tumor invasion and metastasis. Glycogen synthase kinase-3b (GSK3b) suppresses tumor progression by downregulating multiple oncogenic pathways including Wnt signaling and cyclin D1 activation. Here, we show that RKIP binds GSK3 proteins and maintains GSK3b protein levels and its active form. Depletion of RKIP augments oxidative stress-mediated activation of the p38 mitogen activated protein kinase, which, in turn, inactivates GSK3b by phosphorylating it at the inhibitory T390 residue. This pathway de-represses GSK3b inhibition of oncogenic substrates causing stabilization of cyclin D, which induces cell-cycle progression and b-catenin, SNAIL, and SLUG, which promote epithelial to mesenchymal transition. RKIP levels in human colorectal cancer positively correlate with GSK3b expression. These findings reveal the RKIP/GSK3 axis as both a potential therapeutic target and a prognosis-based predictor of cancer progression. Cancer Res; 71(4); 1334-43. Ó2011 AACR.