Modulation of GST P1-1 activity by polymerization during apoptosis

Abstract

Glutathione S-transferases (GSTs, EC 2.5.1.18) belong to a large family of functionally different enzymes that catalyze the S-conjugation of glutathione with a wide variety of electrophilic compounds including carcinogens and anticancer drugs. Drug resistance may result from reduction in apoptosis of neoplastic cells when exposed to antineoplastic drugs. The c-Jun N-terminal Kinase (JNK) belongs to the family of stress kinases and has been shown to be required for the maximal induction of apoptosis by DNA-damaging agents. Recently, an inhibition of JNK activity by GST P1-1, which was reversed by polymerization induced by oxidative stress, has been reported in 3T3-4A mouse fibroblast cell lines. The finding that GST P1-1 might inhibit JNK activity and that it is frequently highly expressed in tumor tissues suggests its possible implication in "apoptosis resistance" during antineoplastic therapy. We investigated the modulation of GST P1-1 during apoptosis in a neoplastic T-cell line (Jurkat) induced by hydrogen peroxide and etoposide. Apoptosis was paralleled by the appearance of a dimeric form of GST P1-1 on western blotting, associated with an increase in the Km(GSH) and a reduction in GST P1-1 specific activity toward 1-chloro-2,4-dinitrobenzene, which reached statistical significance only in H(2)O(2)-treated cells. Our data seem to suggest that H(2)O(2) and etoposide may partly act through a process of partial inactivation of the GST P1-1, possibly involving the "G" site in the process of dimerization, and thus favoring programmed cell death.

Reactive oxygen species mediated apoptosis of esophageal cancer cells induced by marine triprenyl toluquinones and toluhydroquinones

“…September 2007 endogenous JNK inhibitors has already been documented (29,30), providing a plausible pathway for the induction of c-Jun observed here. Our results strongly implicated JNK/ c-Jun signaling in mediating KLM155-induced apoptosis, considering the induction of c-Jun subsequent to treatment with KLM155 and the observation that the JNK inhibitor abrogated KLM155-induced apoptosis.…”

Endogenous Inhibition of Histone Deacetylase 1 by Tumor-Suppressive Maspin

“…GST-mediated protein modification may have a profound effect because numerous proteins, including transcription factors p53 (47) and HDAC1 (42) and signaling molecules such as c-Jun NH 2 -terminal kinase (48), are regulated by sulfide hydrogenation or disulfide bond formation. In the case of HDAC1, an active conformation may be induced by a divalent cation, preferably Zn 2+ , that binds to the sulfide groups of oxidized cysteine residue residing in catalytic site (41).…”

Prognostic Significance of Glutathione S-Transferase-Pi in Invasive Breast Cancer

“…It is reported to be variably expressed in breast cancer (3) and is associated with estrogen receptor level expressed by the tumor (4,5). Down-regulation of GST-pi activity in a T-cell line study appears to favor apoptosis (6) and inhibition of GST-pi function induces apoptosis in rat hepatoma cells (7).…”