Identification of a Novel Inhibitor of Differentiation-1 (ID-1) Binding Partner, Caveolin-1, and Its Role in Epithelial-Mesenchymal Transition and Resistance to Apoptosis in Prostate Cancer Cells

Abstract

Recently, ID-1 (inhibitor of differentiation/DNA binding) is suggested as an oncogene and is reported to promote cell proliferation, invasion, and survival in several types of human cancer cells through multiple signaling pathways. However, how Id-1 interacts with these pathways and the immediate downstream effectors of the Id-1 protein are not known. In this study, using a yeast two-hybrid screening technique, we identified a novel Id-1-interacting protein, caveolin-1 (Cav-1), a cell membrane protein, and a positive regulator of cell survival and metastasis in prostate cancer. Using an immunoprecipitation method, we found that the helix-loop-helix domain of the Id-1 protein was essential for the physical interaction between Id-1 and Cav-1. In addition, we also demonstrated that the physical interaction between Id-1 and Cav-1 played a key role in the epithelial-mesenchymal transition and increased cell migration rate as well as resistance to taxol-induced apoptosis in prostate cancer cells. Furthermore, our results revealed that this effect was regulated by Id-1-induced Akt activation through promoting the binding activity between Cav-1 and protein phosphatase 2A. Our study demonstrates a novel Id-1 binding partner and suggests a molecular mechanism that mediates the function of Id-1 in promoting prostate cancer progression through activation of the Akt pathway leading to cancer cell invasion and resistance to anticancer drug-induced apoptosis.

Id-1 activates Akt-mediated Wnt signaling and p27Kip1 phosphorylation through PTEN inhibition

“…Activation of the Akt-mediated Wnt/TCF pathway by Id-1 overexpression in MCF7 cells A recent study showed that Id-1-induced Akt-mediated EMT and enhanced cell migration (Zhang et al, 2007). Consistently, our data showed Id-1-induced Akt activation, GSK-3b phosphorylation and b-catenin and cyclin D1 expressions (Figure 1a).…”

“…Recently, it was reported that Id-1 inhibits protein phosphatase 2A activity, which led to Akt dephosphorylation (Zhang et al, 2007). Here, our data provide the first evidence that Id-1 can control PTEN as a novel negative regulator that activates the Akt pathway.…”

“…Id-1 is also involved in tumor angiogenesis and invasion/ metastasis (Ling et al, 2006). Recently, it has been reported that the interaction of Id-1 with Cav-1 resulted in suppression of epithelial marker expression, enhancement of mesenchymal marker expression and cell migration (Zhang et al, 2007). Here we found that Id-1 activated the Akt-mediated Wnt/TCF signaling pathway through PTEN inhibition, suggesting that Id-1 is implicated in tumor invasion and progression through the PTEN/Akt pathway and could be an important part of the modulation of EMT.…”

“…Recently, Li et al (2007) reported that Id-1 activated the PI3K/Akt/NF-kB pathway, which is implicated in cell proliferation and apoptosis. Furthermore, a recent study showed that Id-1-induced Akt-mediated epithelialmesenchymal transition (EMT) and enhanced cell migration through interacting with caveolin-1 (Cav-1) in prostate cancer (Zhang et al, 2007). However, the mechanism of Akt activation by Id-1 has not yet been elucidated.…”

Prostate cancer cells modulate osteoblast mineralisation and osteoclast differentiation through Id-1

“…Most importantly, Id-1 has been shown to promote metastasis of prostate cancer. Id-1 promotes angiogenesis through upregulation of VEGF , while it also binds to caveolin-1 to induce epithelial -mesenchymal transition in prostate cancer cells (Zhang et al, 2007a). In addition, increased expression of Id-1 is significantly associated with shorter survival of prostate cancer patients (Forootan et al, 2007).…”