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 CdCl(2) for 2 h (45% viability) caused irreversible mitotic arrest. Exposing early-G(2) cells to Cd markedly delayed mitotic exit and subsequently induced sub-G(1) 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 G(2) to mitosis. Using counterflow centrifugal elutriation and flow cytometry analysis, CL3 cells synchronized at G(1)-, S-, and G(2)/M-phases were collected and treated with CdCl(2). G(2)/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 G(1)-, S-, and G(2)/M-cells. Co-treatment early-G(2) 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-G(2) 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.
Chao
J I
JI
Molecular Carcinogenesis Laboratory, Department of Life Sciences, National Tsing Hua University, Hsinchu 300, Taiwan, Republic of China.
Yang
J L
JL
D000230:Adenocarcinoma / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects*; D002104:Cadmium / Q000633:toxicity*; D004249:DNA Damage; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D002104:Cadmium; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases