WIF1 can effectively co-regulate pro-apoptotic activity through the combination with DKK1

Abstract

Wnt inhibitory factor-1 (WIF1) is a conserved lipid-binding protein that interrupts Wnt ligands by interacting with their Frizzled receptors. Thus, they may suppress the activation of the Wnt/β-catenin triggered signaling cascade. Recently, we found that WIF1 can effectively co-regulate pro-apoptotic activity through the combination with Dickkopf-1 (DKK1). The tumor suppressor p53 protein expression was remarkably increased in the WIF1- and DKK1-transfected cells, along with p21. In contrast, expressions of the anti-apoptotic proteins, c-Myc and Bcl-2, were noticeably reduced. In addition, WIF1 and/or DKK1 significantly activated the transcription of p21 and p53, whereas c-Myc and Bcl-2 activities were remarkably reduced. The tumor suppressor WIF1 was also found to be capable of suppressing tumor growth through the inhibition of tumor angiogenesis in the cellular biological/physiological condition through the targeting of the PI3K/Akt/mTOR signaling pathway, while also being recognized as a Wnt antagonist factor in the Wnt cascade. Consistently, WIF1 conspicuously decreased the VEGF-induced phosphorylation of the PI3K/Akt signaling cascade components, including PDK1, mTOR, TSC-2, GSK-3β, and the p70S6K protein. Collectively, our results indicate for the first time that the tumor suppressor WIF1 is involved in angiogenesis and supplies a possible molecular target for the treatment of distinct malignant cancers, as well as several other associated diseases.