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 PDK1/Akt pathway plays a pivotal role in cell survival, proliferation, and tumorigenesis. Therefore, the PDK1/Akt 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 PDK1/Akt 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 PDK1/Akt 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 PDK1/Akt for anticancer drug discovery.

• Authors: Jang Hyun Choi, Yong Ryoul Yang, Seul Ki Lee, Sun-Hee Kim, Yun-Hee Kim, Joo-Young Cha, Se-Woong Oh, Jong-Ryul Ha, Sung Ho Ryu, Pann-Ghill Suh
• Journal: Annals of the New York Academy of Sciences (Ann N Y Acad Sci) Vol. 1138 Pg. 393-403 (Sep 2008) ISSN: 1749-6632 [Electronic] United States
• PMID: 18837915 (Publication Type: Journal Article)

Chemical References

• PDK1 protein, human
• Pdk1 protein, mouse
• Phenothiazines
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Humans
• Mice
• Phenothiazines (pharmacology)
• Phosphorylation
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Signal Transduction
• Transplantation, Heterologous