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Defective gene expression of MnSOD in cancer cells
S Borrello1, M E De Leo, T Galeotti
1Institute of General Pathology, Catholic University, Rome, Italy.
Abstract:
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.
Insights
Mitochondrial manganese superoxide dismutase (MnSOD) is often deficient in cancers. This study suggests that metal deficiency, not gene deletion, may impair MnSOD expression and contribute to cancer development.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Reactive oxygen species (ROS) play a role in carcinogenesis.
- Antioxidant enzymes, like manganese superoxide dismutase (MnSOD), are often reduced in malignancies.
- MnSOD deficiency is linked to chromosome 6q deletions in some tumors, suggesting a tumor-suppressor role.
Purpose of the Study:
- To investigate the reasons for MnSOD deficiency in cancer.
- To explore the role of metal deficiency in MnSOD gene expression and cancer initiation.
Main Methods:
- Analysis of MnSOD gene dosage and expression in transformed cell lines.
- Investigation of MnSOD inducibility by pro-oxidant agents.
- Assessment of transition metal levels in tumors.
Main Results:
- MnSOD deficiency in cancer may result from impaired gene expression rather than deletion.
- Some cell lines with chromosome 6q deletions show normal MnSOD gene dosage.
- Transition metals (Mn, Fe) are deficient in human and rodent tumors.
- ROS act as second messengers in signal transduction pathways.
Conclusions:
- Metal deficiency, particularly manganese and iron, may impair signal transduction.
- This impairment could limit transcription factor binding to DNA, leading to defective MnSOD gene expression.
- Defective MnSOD expression might contribute to the early stages of carcinogenesis.