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, γ-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) polymerase (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.
DEL BELLO, B., Paolicchi, A., Comporti, M., Pompella, A., Maellaro, E. (1999). Hydrogen peroxide produced during gamma-glutamyl transpeptidase activity is involved in prevention of apoptosis and maintainance of proliferation in U937 cells. THE FASEB JOURNAL, 13(1), 69-79 [10.1096/fasebj.13.1.69].
Hydrogen peroxide produced during gamma-glutamyl transpeptidase activity is involved in prevention of apoptosis and maintainance of proliferation in U937 cells
DEL BELLO, B.;COMPORTI, M.;MAELLARO, E.
1999-01-01
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, γ-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) polymerase (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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
https://hdl.handle.net/11365/3287
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