Markedly enhanced colon tumorigenesis in Apc ^Min mice lacking glutathione S-transferase Pi

Abstract

Glutathione transferases are a multigene family of proteins that catalyze the conjugation of toxic electrophiles and carcinogens to glutathione. Glutathione transferase Pi (GSTP) is commonly overexpressed in human tumors and there is emerging evidence that the enzyme has additional cellular functions in addition to its role in drug and carcinogen detoxification. To investigate the unique functions of this enzyme, we have crossed Gstp null mice with an initiated model of colon cancer, the Apc Min mouse. In contrast to the Apc Min/؉ Gstp1/p2 ؉/؉ (Gstp-wt Apc Min ) mice, which rarely develop colonic tumours, Apc Min/؉ Gstp1/p2 ؊/؊ (Gstp-null Apc Min ) mice had a 6-fold increase in colon adenoma incidence, and a 50-fold increase in colorectal adenoma multiplicity, relative to Gstp-wt Apc Min . This increase was associated with early tumor onset and decreased survival. Analysis of the biochemical changes in the colon tissue of Gstp-null Apc Min mice demonstrated a marked induction of many inflammatory genes, including IL-6, IL-4, IFN-␥, and inducible nitric oxide synthase. In support of the induction of inducible nitric oxide synthase, a profound induction of nitrotyrosine adducts was observed. Gstp therefore appears to play a role in controlling inflammatory responses in the colon, which would explain the change in tumor incidence observed. These data also suggest that individual variation in GSTP levels may be a factor in colon cancer susceptibility.cancer ͉ colorectal ͉ inflammation G lutathione S-transferases play a key role in chemical detoxification by catalyzing the conjugation of reduced glutathione to reactive electrophiles (1). In a genetic approach to study GST functions, we have generated mice nulled at the glutathione transferase Pi (GSTP) Gstp gene locus (2). These mice develop normally, are fertile, and show no obvious abnormalities. Topical application of the tumor initiator 7,12-dimethylbenz[a]anthracene, followed by the promoting agent 12-0-tetradecanoylphorbol-13-acetate, resulted in a significant increase in the number of papillomas in null animals (2). Similarly, increased adenoma formation in the lungs of Gstp-null mice relative to wild-type mice was also observed following dosing with benzo[a]pyrene, 3-methylcholanthene and urethane (3). In recent studies we have obtained evidence that this protein can also modulate toxicological or carcinogenic response in a manner distinct from its role in chemical detoxification (4). Further evidence of unique GSTP function is demonstrated by its ability to form protein-protein interactions and regulate the activities of several cellular proteins (JNK and TRAF2) independently of its catalytic function (5, 6). GSTP has also been shown to potentiate S-glutathionylation reactions following oxidative and nitrosative stress in vitro and in vivo (7).To further evaluate the role of GSTP in disease processes, we have investigated whether GSTP can alter colon cancer susceptibility in the Apc Min mouse. Mutations in the Apc gene is a major initiating factor in the aet...

Expression of CYP1A1 and GSTP1 in Human Brain Tumor Tissues in Pakistan

“…In current study statistically significant downregulation of GSTP1 was observed in brain tumor samples compared to control samples. Similar results have also been observed in breast cancer (Erlap et al, 2013), prostate cancer (Okino et al, 2007;Re et al, 2011) and colon cancer (Ritchie et al, 2009).Whereas conflicting results for GSTP1 expression pattern have been reported in some of other studies (Masood et al, 2011;Uchida et al, 2013). In present study, significant down-regulation of GSTP1 was observed in more advance grade of brain tumor samples when compared with early grade of brain tumor.…”

Thiazolide-induced apoptosis in colorectal cancer cells is mediated via the Jun kinase–Bim axis and reveals glutathione-S-transferase P1 as Achilles’ heel

“…It is thus more likely that the product of GSTP1-converted thiazolides promotes the activation of the different MAP kinase pathways, rather than via inhibition of GSTP1. Along these lines is the surprising observation that GSTP1-deficient mice develop increased numbers of intestinal tumors in the APC min/ þ model (Ritchie et al, 2009), rather than having reduced tumor burden. This could indicate that even in vivo GSTP1 may enzymatically convert inactive endogenous or bacterial substances to tumoricidal products, which limits the growth and development of intestinal tumors.…”

Unusual Intronic Variant in GSTP1 in Head and Neck Cancer in Pakistan

“…Nevertheless, few studies have suggested increased expression of GSTP1 as an indicator of premalignant and malignant changes (Aliya et al, 2003;Usarek et al, 2004) while others have suggested expression of GSTP1 as a sign of carcinogen exposure in the endothelial and oral tissues (Gajewska et al, 2007;Conklin et al, 2009). Few studies have also reported that loss of GSTP1 expression is suggestive of carcinogenesis (Okino et al, 2007;Ritchie et al, 2009). GSTP1 is genetically polymorphic, and two GSTP1 non-…”