Inhibition of PTEN and activation of Akt by menadione

Abstract

Menadione (vitamin K(3)) has been shown to activate Erk in several cell lines. This effect has been shown to be due to the activation of EGF receptors (EGFR) as a result of inhibition of some protein tyrosine phosphatases. In the present study, we examined the effects of menadione on Akt in Chinese hamster ovary cells. The phosphorylation of Akt by menadione was not inhibited by AG1478, an inhibitor of EGFR. Menadione inhibited the lipid phosphatase activity of PTEN in a cell-free system. In an intact cell system, menadione inhibited the effect of transfected PTEN on Akt. Thus, one mechanism of its action was considered the accelerated activation of Akt through inhibition of PTEN. This was not the sole mechanism responsible for the EGFR-independent activation of Akt, because menadione attenuated the rate of Akt dephosphorylation even in PTEN-null PC3 cells. The decelerated inactivation of Akt, probably through inhibition of some tyrosine phosphatases, was considered another mechanism of its action.

Essential roles of PIKfyve and PTEN on phagosomal phosphatidylinositol 3‐phosphate dynamics

“…S4). Treatment of the control cells with menadione (vitamin K 3 ), which we have reported to inhibit PTEN in both cell‐free and intact‐cell systems [32], increased the life span of the fluorescence (Fig. 3B).…”

The TERE1 protein interacts with mitochondrial TBL2: Regulation of trans‐membrane potential, ROS/RNS and SXR target genes

“…Since the electron transport chain is an abundant source of mitochondrial superoxide radicals [Castello et al, 2006;Poyton et al, 2009;Cardoso et al, 2012], and menaquinone is known to undergo redox-cycling and generate reactive oxygen species [ Benz et al, 2006;Klaus et al, 2010], we conducted studies that demonstrate that ectopic TERE1 and TBL2 expression can affect the cellular levels of oxidative stress as evidenced by oxidation of the CellROX fluorogenic probe. TERE1 may be involved in phospho-activation of oxidative stress responsive signaling cascades as was previously shown for EGFR, ERK, ErbB2, and AKT in response to vitamin K-3 and attributed to inhibition of protein tyrosine phosphatases [Yoshikawa et al, 2007;Klaus et al, 2010]. This shows that TERE1 expression can mimic some of the reported effects of pharmacological dosing of vitamins K-2 and K-3 that lead to different types of growth inhibition, autoschizis, necrosis, or apoptosis in different tumor cell lines [Lamson and Plaza, 2003;Shibayama-Imazu et al, 2008;Jamison et al, 2010].…”

Rash from EGFR inhibitors: Opportunities and challenges for palliation

“…They demonstrated that inhibition of phosphatase by menadione resulted in net activation of the EGFR inhibitor. Yoshikawa et al [ 25 ] observed that among a variety of cell lines, menadione activates the EGFR, which in turn activates the extracellular signal-related kinase (ERK) cascade. Finally, Klotz and colleagues [ 26 ] showed that exposing rat liver epithelial cells to menadione resulted in a dramatic increase in tyrosine phosphorylation on cell membranes with immunohistochemistry as well as ERK activation via the EGFR pathway.…”