GSTP1 determines cis-platinum cytotoxicity in gastric adenocarcinoma MGC803 cells: regulation by promoter methylation and extracellular regulated kinase signaling

Abstract

Detoxification mechanisms can play a pivotal role in determining tumor cell responses to platinum-based chemotherapy. Glutathione S-transferase-pi (GSTP1) belongs to a supergene family of detoxifying enzymes involved in the prevention of DNA damage and subsequent platinum resistance in numerous cancers. The role of GSTP1 in gastric cancer sensitivity to chemotherapy is, however, not known. In this study, we found that the human gastric cancer cell line MGC803 was significantly more sensitive to cis-platinum (CDDP) than the other gastric cancer lines examined (BGC823 and SGC7901). To explore the potential role of GSTP1 in drug resistance, we measured GSTP1 expression in these cells. GSTP1 mRNA and protein were not detectable in MGC803 cells; both were present in BGC823 and SGC7901 cells. GSTP1 CpG island DNA methylation was examined. We report that promoter hypermethylation was associated with the absence of GSTP1 expression in MGC803 cells. Treatment of these cells with 5-aza-2′-deoxycytidine, a DNA methyltransferase inhibitor, restored GSTP1 expression and suppressed sensitivity to CDDP. The selective mitogen-activated protein kinase/extracellular regulated kinase (ERK) pathway inhibitor PD98059 decreased GSTP1 expression in 5-aza-2′-deoxycytidine-treated cells. A similar decrease was observed in the BGC823 and SGC7901 cell lines, suggesting that mitogen-activated protein kinase/ERK signaling stimulates GSTP1 expression. CDDP sensitivity was also enhanced by PD98059. These observations indicate that somatic promoter hypermethylation and impaired ERK signaling are associated with decreased GSTP1 expression and CDDP sensitivity in gastric cancer cell lines. Evaluation of promoter methylation and ERK activity may be useful for predicting tumor sensitivity to platinum-based chemotherapeutics.