Hydrogen peroxide produced during γ‐glutamyl transpeptidase activity is involved in prevention of apoptosis and maintainance of proliferation in U937 cells

Abstract

It has been reported in several cell lines that exposure to low levels of reactive oxygen species can exert a stimulatory effect on their proliferation. We have previously shown that mild oxidative conditions can also counteract apoptotic stimuli. A constitutive cellular production of low levels of superoxide and hydrogen peroxide originates from various sources; among these, gamma-glutamyl transpeptidase (GGT), the plasma membrane-bound activity in charge of metabolizing extracellular reduced glutathione, has recently been included. Since the inhibition of GGT is a sufficient stimulus for the induction of apoptosis in selected cell lines, we investigated whether this effect might result from the suppression of the mentioned GGT-dependent prooxidant reactions, on the theory that the latter may represent a basal antiapoptotic and proliferative signal for the cell. Experiments showed that: 1) GGT activity in U937 monoblastoid cells is associated with the production of low levels of hydrogen peroxide, and two independent GGT inhibitors cause a dose-dependent decrease of such GGT-dependent production of H2O2; 2) GGT inhibition with acivicin results in cell growth arrest, and induces cell death and DNA fragmentation with the ladder appearance of apoptosis; 3) treatment of cells with catalase--and even more with Trolox C--is able to decrease their proliferative rate; 4) GGT inhibition (with suppression of H2O2 production) results in a down-regulation of poly(ADP-ribose) polimerase (PARP) activity, which precedes the proteolytic cleavage of PARP molecule, such as that typically induced by caspases. The reported data suggest that the low H2O2 levels originating as a by-product during GGT activity are able to act as sort of a 'life signal' in U937 cells, insofar as they can maintain cell proliferation and protect against apoptosis, possibly through an up-regulation of PARP activity.

In vitro antiproliferative, apoptotic and antioxidant activities of punicalagin, ellagic acid and a total pomegranate tannin extract are enhanced in combination with other polyphenols as found in pomegranate juice

“…Mild levels of reactive oxygen species (ROS) have been shown to induce proliferation in cancer cells [37,38]. Therefore, foods rich in antioxidant phytochemicals are important for the prevention of diseases related to oxidant stress such as heart disease and cancer.…”

Expression of γ-Glutamyl Transpeptidase Protects Ramos B Cells from Oxidation-induced Cell Death

“…The mechanism for this is unknown. It has recently been suggested that the high levels of GGT expressed by some cell lines generates amounts of cysteinylglycine that are pro-oxidant when the cells are exposed to artificially high levels of substrate (GSH) (30). It is not known whether this effect is observed with all cells nor whether this can be translated to a lower intracellular GSH level.…”

The CD16−CD56bright NK Cell Subset Is Resistant to Reactive Oxygen Species Produced by Activated Granulocytes and Has Higher Antioxidative Capacity Than the CD16+CD56dim Subset

“…Furthermore, H 2 O 2 may be produced by the tumor cells themselves (17)(18)(19). This study was undertaken to address whether the decreased numbers of cytotoxic CD56 dim NK cells seen during chronic inflammation may be due to selective cell death in response to exposure to ROS produced by granulocytes.…”