Ascorbate up-regulates MLH1 (Mut L homologue-1) and p73: implications for the cellular response to DNA damage
Copyright policy )Ascorbate up-regulates MLH1 (Mut L homologue-1) and p73: implications for the cellular response to DNA damage
We have found previously that ascorbic acid (vitamin C), as well as acting as a radical scavenger, may modulate the expression of several genes [i.e. fra-1, glutathione S-transferase Pi (GSTpi) and Mut L homologue-1 (MLH1)] in human keratinocytes. In the present paper, we demonstrate that MLH1, as well as its downstream target p73, can be positively modulated by this antioxidant vitamin, indeed, up-regulation of the two mRNAs was observed after just 2h, and increased further up to 16h of treatment. Modulation of MLH1 and p73 gene expression improves cellular susceptibility to apoptosis triggered by the DNA-damaging agent cisplatin. Indeed, in ascorbate-supplemented cells, increased cisplatin-induced apoptosis was seen, involving activation of the MLH1/c-Abl/p73 signalling cascade. Our results were further confirmed by studies performed on genetically defined mutants, i.e. mouse embryo fibroblasts derived from knock-out animals for c-Abl or p53, as well as human colon carcinoma cell lines deficient in MLH1. The increased sensitivity to cisplatin observed in ascorbate-loaded cells appeared to be dependent exclusively on MLH1 and c-Abl expression, and independent of p53. These data suggest a potential mechanism accounting for the anti-carcinogenic and anti-cancer activities of vitamin C.
- University of Rome Tor Vergata Italy
- University of California, Los Angeles United States
- University of Chieti-Pescara Italy
- Roma Tre University Italy
- Sapienza University of Rome Italy
Cell death, c-Abl; Cell death; Cisplatin; Vitamin C, Ascorbic Acid, c-Abl, Cell Line, Mice, Bacterial Proteins, Animals, Humans, Genes, Tumor Suppressor, Vitamin C, DNA Primers, Adenosine Triphosphatases, Mice, Knockout, Base Sequence, Cell Death, Reverse Transcriptase Polymerase Chain Reaction, Escherichia coli Proteins, Nuclear Proteins, Tumor Protein p73, DNA-Binding Proteins, MutL Proteins, c-abl; cell death; cisplatin; vitamin c, Cisplatin, Settore MED/35 - MALATTIE CUTANEE E VENEREE, DNA Damage
Cell death, c-Abl; Cell death; Cisplatin; Vitamin C, Ascorbic Acid, c-Abl, Cell Line, Mice, Bacterial Proteins, Animals, Humans, Genes, Tumor Suppressor, Vitamin C, DNA Primers, Adenosine Triphosphatases, Mice, Knockout, Base Sequence, Cell Death, Reverse Transcriptase Polymerase Chain Reaction, Escherichia coli Proteins, Nuclear Proteins, Tumor Protein p73, DNA-Binding Proteins, MutL Proteins, c-abl; cell death; cisplatin; vitamin c, Cisplatin, Settore MED/35 - MALATTIE CUTANEE E VENEREE, DNA Damage
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