A Novel Protein-Protein Interaction between RSK3 and I kappa B alpha and a New Binding Inhibitor That Suppresses Breast Cancer Tumorigenesis

Abstract

Multiple cancer-related biological processes are mediated by protein-protein interactions (PPIs). Through interactions with a variety of factors, members of the ribosomal S6 kinase (RSK) family play roles in cell cycle progression and cell proliferation. In particular, RSK3 contributes to cancer viability, but the underlying mechanisms remain unknown. We performed a kinase library screen to find I kappa B alpha PPI binding partners and identified RSK3 as a novel I kappa B alpha binding partner using a cell-based distribution assay. In addition, we discovered a new PPI inhibitor using mammalian two-hybrid (MTH) analysis. We assessed the antitumor effects of the new inhibitor using cell proliferation and colony formation assays and monitored the rate of cell death by FACS apoptosis assay. I kappa B alpha is phosphorylated by the active form of the RSK3 kinase. A small-molecule inhibitor that targets the RSK3/I kappa B alpha complex exhibited antitumor activity in breast cancer cells and increased their rate of apoptosis. RSK3 phosphorylation and RSK3/I kappa B alpha complex formation might be functionally important in breast tumorigenesis. The RSK3/I kappa B alpha-specific binding inhibitor identified in this study represents a lead compound for the development of new anticancer drugs.