Black tea polyphenols induce human leukemic cell cycle arrest by inhibiting Akt signaling: possible involvement of Hsp90, Wnt/β-catenin signaling and FOXO1

Abstract

Tea polyphenols have potent biological activities against human cancer cells. A major causative factor in malignancies is disregulation of cell-cycle kinetics. In this study, we observed that black tea polyphenols, theaflavins (TF) and thearubigins (TR) induced cell-cycle arrest at the G(0) /G(1) phase in human leukemic U937 and K562 cells. Our objective was to understand the underlying molecular mechanism of cell-cycle inhibition by TF and TR. During elucidation, we observed that both TF and TR treatment augmented expression of p19, p21 and p27, while ablating cylcin-dependent kinase (CDK)2, CDK4, CDK6 and cyclin D1 levels. Our experimental results further determined that Akt signaling suppression by TF and TR played a major role in this process. Moreover, suppression of glycogen synthase kinase-3β, β-catenin and amplification of forkhead transcription factor 1 (FOXO1) expression were associated with regulation of certain key components of the cell-cycle machinery. In addition, depletion of heat shock protein (Hsp) 90 by TF and TR also had a pivotal role in cell-cycle arrest. More specifically, inhibition of Akt signaling by TF and TR correlated with the depletion of its downstream targets like Wnt/β-catenin signaling, cyclin D1 and increase of FOXO1, p27 levels. Inhibition of upstream Hsp90 by TF and TR consequently attenuated Akt signaling and reduced the level of CDK2. These results suggest possible mechanisms for the chemopreventive effect of TF and TR on human leukemic cells. To our knowledge, this is the first report of such a detailed molecular mechanism for TF and the less-investigated polyphenol TR-mediated cell-cycle inhibition in human leukemic U937 and K562 cells.