Defective gene expression of MnSOD in cancer cells.
Reactive oxygen species (ROS) have been frequently implicated in the initiation and promotion phases of carcinogenesis. Antioxidant enzymes, which can antagonize this process, are lowered in a number of malignancies. The enzyme most commonly decreased is the mitochondrial Mn-containing superoxide dismutase (MnSOD) encoded by a nuclear gene mapped on the band 6q21, a region frequently deleted in several human tumours. The close association of del(6q) with diminution of MnSOD has led to suggest that MnSOD might be a new type of tumour-suppressor gene. This hypothesis is also sustained by the finding that transfection of MnSOD cDNA into human melanoma cell lines suppress the malignant phenotype. There are, however, conflicting observations that tend to ascribe the deficiency of the MnSOD activity more to a defect in the expression of the gene than to its deletion. In many transformed cell lines, including some with marked del(6q), there is no change in the dosage of the MnSOD gene and the enzyme is highly inducible by various pro-oxidant agents. Transition metals (Mn, Fe) have been found to be highly deficient in human and rodent tumours. Owing to the second messenger function of ROS in activating transcription factors (NF-kB, AP-1) and to the ability of Mn to facilitate the dismutation of O2- to H2O2 and of Fe to participate in the Fenton reaction, we propose that in the early stage of carcinogenesis an impairment of the signal transduction machinery, related to the metal deficiency, might limit the binding to DNA of transcription factors and cause the defect in the MnSOD gene expression.
Borrello
S
S
Institute of General Pathology, Catholic University, Rome, Italy.
De Leo
M E
ME
Galeotti
T
T
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000473:pathology; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D015870:Gene Expression; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008113:Liver Neoplasms / Q000201:enzymology* / Q000473:pathology; D008345:Manganese / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011912:Rats, Inbred ACI; D011915:Rats, Inbred BUF; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013482:Superoxide Dismutase / Q000096:biosynthesis*
D012333:RNA, Messenger; D008345:Manganese; D013482:Superoxide Dismutase