Opposite roles of ERK and p38 mitogen-activated protein kinases in cadmium-induced genotoxicity and mitotic arrest

The roles of extracellular signal-regulated kinase (ERK) and p38 mitogen-activation protein kinase (MAPK) in guarding genome stability and regulating cell cycle progression were explored in CL3 human lung adenocarcinoma cells treated with cadmium (Cd), a human carcinogen. Exposing asynchronous cells to CDCl₂ for 2 h (45% viability) caused irreversible mitotic arrest. Exposing early-G₂ cells to Cd markedly delayed mitotic exit and subsequently induced sub-G₁ populations; however, this did not alter, the levels of Cdc₂ and cyclin B1. These results suggest that Cd elicits mitotic arrest without affecting the progression of G₂ to mitosis. Using counterflow centrifugal elutriation and flow cytometry analysis, CL3 cells synchronized at G₁-, S-, and G₂/M-phases were collected and treated with CDCl₂. G₂/M was the most sensitive cell cycle phase to Cd for the induction of ERK and p38 MAPK activities, cytotoxicity, apoptosis, micronucleus, and intracellular peroxide; despite that similar Cd accumulation was observed in G₁-, S-, and G₂/M-cells. Co-treatment early-G₂ cells with Cd and SB202190, an inhibitor of p38 MAPK, significantly decreased the induction of micronucleus, mitotic arrest, and apoptosis. Conversely, PD98059, an inhibitor of the ERK upstream activators MKK1/2, enhanced micronucleus and apoptosis in Cd-treated early-G₂ cells. Together, the results suggest that intracellular peroxide may participate in the activation of ERK and p38 MAPK by Cd; also, the activated-p38 MAPK may contribute to mitotic arrest and genome instability, whereas the activated-ERK may help to maintain genome integrity and survival.