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By behaving as molecular hubs, scaffold proteins can assemble a large number of signaling molecules and organize complicated intracellular signaling networks in time and space. Owing to their crucial role in mediating intracellular signaling related to tumor cell growth and migration, recent studies have highlighted the relevance of scaffold proteins in human cancers and indicated that interfering with their expression and/or their ability to bind effector proteins can inhibit cancer progression. Here, we show that receptor for activated C-kinase 1 (RACK1), a ubiquitously expressed scaffolding protein, plays a crucial regulatory role in tumor growth. Using an RNA silencing approach, we found that downregulation of RACK1 expression in HeLa and A673 tumor cells markedly suppressed the proliferation and invasion of these cells in vitro and tumor development in vivo. Consequently, we found that significant suppression of constitutive phosphorylation of Akt and MAPK by RACK1 silencing may contribute to the inhibition of tumor growth. Moreover, RACK1 silencing significantly attenuated tumor-associated angiogenesis by, at least in part, inhibiting the expression of two critical angiogenic factors, namely vascular endothelial growth factor-B and fibroblast growth factor 2. The results of the present study show that RACK1 is a potent enhancer of tumor growth and, thus, a potential anti-cancer therapeutic target. (Cancer Sci 2011; 102: 2007–2013)