Potential Inhibition of PDK1/Akt Signaling by Phenothiazines Suppresses Cancer Cell Proliferation and Survival

Abstract

3'-Phosphoinositide-dependent kinase-1 (PDK1) has been identified for its ability to phosphorylate and activate Akt. Accumulated studies have shown that the activation of the PDK1Akt pathway plays a pivotal role in cell survival, proliferation, and tumorigenesis. Therefore, the PDK1Akt pathway is believed to be a critical target for cancer intervention. In this paper, we report the discovery of a new function of phenothiazines, widely known as antipsychotics, inhibiting PDK1/Akt pathway. Upon epidermal growth factor (EGF) stimulation, phenothiazines specifically suppressed the kinase activity of PDK1 and the phosphorylation level of Akt. The inhibition of PDK1Akt kinase resulted in suppression of EGF-induced cell growth and induction of apoptosis in human ovary cancer cells. In particular, phenothiazines were highly selective for downstream targets of PDK1Akt and did not inhibit the activation of phosphatidylinositol 3-kinase (PI3K), EGFR, or extracellular signal-regulated kinase 1/2 (ERK1/2). In particular, phenothiazines effectively suppressed tumor growth in nude mice of human cancer cells. Taken together, these findings provide strong evidence for novel function of phenothiazines, pharmacologically targeting PDK1Akt for anticancer drug discovery.