Deregulated manganese superoxide dismutase expression and resistance to oxidative Injury in p53-deficient cells

• Published in: Cancer research (Chicago, Ill.) Vol. 60; no. 16; pp. 4654 - 4660
• Main Authors: PANI, G, BEDOGNI, B, ANZEVINO, R, COLAVITTI, R, PALAZZOTTI, B, BORRELLO, S, GALEOTTI, T
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.08.2000
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - physiology; Biological and medical sciences; Cell Line, Transformed; Cell physiology; Cell Survival - physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Down-Regulation; Doxorubicin - pharmacology; Fibroblasts - drug effects; Fibroblasts - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Enzymologic; HeLa Cells; Humans; Mice; Mice, Inbred C57BL; Mitochondria - enzymology; Molecular and cellular biology; Oxidative Stress - physiology; Paraquat - pharmacology; Reactive Oxygen Species - metabolism; Superoxide Dismutase - biosynthesis; Superoxide Dismutase - genetics; Transcriptional Activation - physiology; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - physiology; Cell proliferation; Oxidative stress; Transformed cell; Cytotoxicity; Superoxide dismutase; Carcinogenesis; Free radical; TP53 Gene; Transfection; Malignant transformation; Established cell line; Mechanism of action; Tumor cell; Tumor suppressor gene; Human; Enzyme; Rodentia; Antioxidant; Gene expression; In vitro; Vertebrata; Mammalia; Sensitivity resistance; Mouse; Animal; Oxidoreductases; Fibroblast; Manganese
• ISSN: 0008-5472; 1538-7445

Loss of function of the tumor suppressor protein p53 represents a very frequent event in human carcinogenesis, but the molecular mechanisms linking impaired p53 activity to increased cell malignancy are still incompletely understood. p53 is normally involved in both cell cycle control and the induction of cell death and is involved in the latter mainly through the transcriptional regulation of pro- and antiapoptotic proteins. Reactive oxygen species are known to be powerful inducers of p53 activity; moreover, they play a role in the execution of p53-dependent apoptosis. Here we show that transformed mouse fibroblasts lacking p53 are significantly more resistant than wild-type (wt) controls to the cytotoxic effect of a number of pro-oxidant treatments. Interestingly, these cells also exhibit deregulated expression of the antioxidant enzyme manganese superoxide dismutase (MnSOD), a protein known to protect cancer cells from the oxidative injury inflicted by antitumoral cytokines and anticancer drugs. MnSOD activity was also increased in liver tissue from p53-deficient mice in comparison with wt tissue. Transient transfection of wt p53 in HeLa cells led to a significant reduction in steady-state MnSOD mRNA levels and enzymatic activity, confirming that the expression of this antioxidant enzyme is negatively regulated by p53. Forced expression of MnSOD rendered HeLa cells resistant to p53-dependent cytotoxic treatments and, in cotransfection experiments, counteracted the growth-inhibitory effect of p53. Taken together, these data identify MnSOD as a potential target for tumor suppressor protein p53 and underscore the relevance of MnSOD modulation in the context of normal p53 functions because it is consistent with many reports of abnormally increased MnSOD expression in human cancers.