MANGANESE SUPEROXIDE-DISMUTASE IN HEALTHY-HUMAN PLEURAL MESOTHELIUM AND IN MALIGNANT PLEURAL MESOTHELIOMA

We hypothesized that manganese superoxide dismutase (MnSOD), known to be induced in rat mesothelial cells by asbestos fibers, cytokines, and hyperoxia, may also be induced in asbestos-related pleural diseases s uch as mesothelioma. MnSOD was assessed in healthy human pleural mesot helium (n = 6), in biopsy samples of human pleural mesothelioma (n = 7 ), in transformed nonmalignant human mesothelial cells (Met5A), and in two human mesothelioma cell lines (M14K and M38K) established from th e tumor tissue of mesothelioma patients. There was no MnSOD immunoreac tivity in five of the six samples of healthy pleural mesothelium, wher eas MnSOD immunoreactivity was high in the tumor cells in all the meso thelioma samples. Northern blotting, immunohistochemistry, Western blo tting, and specific activity measurements showed lower MnSOD in the no nmalignant MetSA mesothelial cells than in the M14K and M38K mesotheli oma cells. In additional experiments the mesothelial and mesothelioma cells were exposed to menadione, which generates superoxide intracellu larly, and to epirubicin, a cytotoxic drug commonly used to treat meso thelioma. The M38K mesothelioma cells were most resistant to menadione and epirubicin when assessed by LDH release or by adenine nucleotide (ATP, ADP, and AMP) depletion. These same cells showed not only the hi ghest MnSOD levels, but also the highest mRNA levels and activities of catalase, whereas glutathione peroxidase and glutathione reductase le vels did not differ significantly. We conclude that MnSOD expression i s low in healthy human pleural mesothelium and high in human malignant mesothelioma. The most resistant mesothelioma cells contained coordin ated induction of MnSOD and catalase.