Abstract
Carcinogenesis is a multi‐step process that is frequently associated with p53 inactivation. The class 1 carcinogen Cd causes renal cancer and is known to inactivate p53. G2/mitosis(M) arrest contributes to stabilization of p53‐deficient mutated cells, but its role and regulation in Cd exposed p53‐deficient renal cells is unknown. Using the Comet assay, DNA damage was induced by Cd (50–100 μM) within 1–6 h in p53‐inactivated kidney proximal tubule (PT) cells. This was associated with peak formation of reactive oxygen species (ROS) at 1–3 h, measured with dihydrorhodamine 123, and G2/M cell cycle arrest at 6 h, which were both abolished by the antioxidant α‐tocopherol (100μM). G2/M arrest by Cd was enhanced ~2‐fold upon release from cell synchronization (double thymidine block or nocodazole) and resulted in ~2‐fold increase of apoptosis, indicating that G2/M arrest mirrors DNA damage and toxicity. The Chk1/2 kinase inhibitor UCN‐01 (0.3μM) abolished Cd‐induced G2/M arrest, increased apoptosis, and prevented Cd‐induced cyclin‐dependent kinase cdc2 phosphorylation at tyrosine15, shown by immunofluorescence microscopy and immunoblotting. The data indicate that in p53‐inactivated PT cells Cd‐induced ROS formation and DNA damage trigger signaling of check‐point activating kinases ATM/ATR to cause G2/M arrest. This may promote survival of pre‐malignant PT cells and Cd carcinogenesis. Funded by DFG TH 345/10–1.
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