Glutathione Transferase P1–1 Expression in Human Melanoma Metastases: Correlation to N-RAS mutations and expression

Abstract

Expression of the detoxication enzyme glutathione transferase P1–1 (GST P1–1) at elevated levels has been noted in many types of human tumors, including melanomas. The products of the human H-RAS, K-RAS and N-RAS genes play a key role in intracellular signal transduction leading to transcriptional activation of AP-1 (Fos/Jun) responsive genes. The oncogenic mutated forms of the ras proteins are constitutively active and interfere with normal signal transduction. Mutated RAS genes as well as increased expression of wild-type ras proteins are common features in human tumors including melanoma. We have characterized 30 melanoma metastases from 23 melanoma patients with reference to N-RAS expression and mutation as well as to GST P1 expression (immunohistochemistry and genetic analysis). Twenty-three of 30 samples (70%) had high N-Ras p21 and/or N-RAS codon 61 mutations and 18 of these 23 samples also had high GST P1–1 immunoreactivity. Seven of 30 (23%) samples had low N-Ras p21 immunoreactivity and no detectable N-RAS codon 61 mutations. Six of these 7 samples (86%) also had low GST P1–1 immunoreactivity. The results indicate a statistically significant correlation (Spearman correlation coefficient, r = 0.56, p = 0.001, 2–tailed test) and provide, for the first time, indirect evidence for a possible coregulation of N-RAS and GST P1 in human malignant melanoma which should be further evaluated.