Carcinogenesis Advance Access published online on March 28, 2003
Carcinogenesis, doi:10.1093/carcin/bgg042
© 2003 by Oxford University Press
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CANCER BIOLOGY
1 The Heart Research Institute, Iron Metabolism and Chelation Group, 145 Missenden Rd, Camperdown, Sydney, New South Wales, 2050, AUSTRALIA; Children's Cancer Institute Australia for Medical Research, Iron Metabolism and Chelation Program, High St (PO Box 81), Randwick, Sydney, New South Wales, 2031, AUSTRALIA
* Corresponding author. E-mail: d.richardson{at}ccia.org.au.
Received 18 December 2002
; revised 4 March 2003
; accepted 6 March 2003
Iron (Fe) chelators are potential anti-tumor agents. Cellular Fe depletion results in a G1/S arrest but the precise molecular mechanisms involved remain unclear. Recent studies have shown that this process is complex with multiple cell cycle molecules being involved (Gao, J. and Richardson, D.R. (2001) Blood 98, 842-850). We previously showed that Fe chelators such as 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) were far more potent anti-tumor agents than the clinically used ligand, desferrioxamine (DFO). To further characterize the effects of chelators on cell cycle arrest, we compared their activity to the DNA-damaging agents, actinomycin D (Act D) and cisplatin (CP). These latter two compounds increase the expression of p53 and its target genes such as the universal cyclin-dependent kinase inhibitor, p21CIP1/WAF1. Incubation of normal and neoplastic cells with all agents resulted in increased nuclear p53, the effect being pronounced for Act D and CP. As expected, both Act D and CP also markedly increased nuclear p21CIP1/WAF1 protein levels, while DFO and 311 caused a significant (p < 0.0004) decrease. This latter effect was surprising, as these chelators markedly increased mRNA levels of this molecule. Immunofluorescence studies showed that Act D and CP caused nuclear localization of p21CIP1/WAF1. In contrast, the chelators prevented translation of p21CIP1/WAF1. This did not appear to be due to a general effect of the chelators on preventing translation, as the transferrin receptor 1 was markedly up-regulated 15-21-fold by DFO or 311. Combination of 311 with Act D or CP prevented translation of p21CIP1/WAF1 and its nuclear localization observed with these DNA-damaging agents. Significantly, the effect of chelation on reducing nuclear p21CIP1/WAF1 was reversed by the Fe-donor, ferric ammonium citrate, indicating that p21CIP1/WAF1 translation was dependent on intracellular Fe levels. This study demonstrates that while Fe chelators markedly up-regulate the mRNA levels of p21CIP1/WAF1 they paradoxically inhibit translation.
Potent iron chelators increase the mRNA levels of the universal cyclin-dependent kinase inhibitor, p21CIP1/WAF1, but paradoxically inhibit its translation: a potential mechanism of cell cycle dysregulation
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