Up-regulation of thioredoxin and thioredoxin reductase in human malignant pleural mesothelioma

Thioredoxin (Trx) with a redoxactive dithiol together with NADPH and thiore doxin reductase (TrxR) is a major disulfide reductase regulating cellular r edox state and cell proliferation and possibly contributing to the drug res istance of malignant cells, We assessed the Trx system in malignant pleural mesothelioma cell lines, in nonmalignant pleural mesothelium and in biopsi es of malignant pleural mesothelioma, The mRNA and immunoreactive proteins of Trx and cytosolic and mitochondrial TrxR were positive in all four human mesothelioma cell lines investigated. Six cases of nonmalignant, histologi cally healthy pleural mesothelium showed no Trx or TrxR immunoreactivity, w hereas immunohistochemistry on 26 biopsies of human malignant pleural mesot helioma showed positive Trx in all cases and positive TrxR in 23 (88%) of t he cases. Moderate or strong immunoreactivity for Trx or TrxR was detected in 85% (22 cases) and 61% (14 cases) of the mesothelioma cases, respectivel y. Both Trx and TrxR staining patterns were mainly diffuse and cytoplasmic, but in 39% of the mesothelioma cases prominent nuclear staining could also be detected. Although staining for Trx and TrxR was seen in tumor cells, n o significant association could be demonstrated between Trx or TrxR express ion and tumor tell proliferation or apoptosis in the biopsies of mesothelio ma. There was no significant association between the intensity of Trx or Tr xR immunoreactivity and patient survival, which may possibly be related to moderate or intense Trx and TrxR reactivity in most of the cases. Although the Trx system may have an important role in the drug resistance of maligna nt mesothelioma. these studies also suggest that multiple factors contribut e to the promotion, cell proliferation and apoptosis of malignant mesotheli oma cells in vivo. (C) 2001 Wiley-Liss, Inc.