Catalase regulates the growth of human promyelocytic cells HL60 via the ERK1/2 cascade

Catalase is located at the peroxisome and is a major enzyme which scavenges hydrogen peroxide (H2O2). Reactive oxygen species (ROS) including H2O2 are constitutively generated in mammalian cells; high levels of ROS are associated with cytotoxicity. However, non-toxic levels of ROS are components of the signal transduction cascade involved in various cellular responses. Because of their relatively long life and high permeability across the membranes, H2O2 is thought to be one of the important second messengers. In the present study, we investigated the role of catalase in the cell growth using a H2O2-resistant variant HP100-1 of the human promyelocytic cells HL60. HP100-1 cells had a 4-fold higher activity of catalase than HL60 cells without differences in levels of other antioxidant enzymes such as glutathione peroxydase (GSH-Px), manganese superoxide dismutase (MnSOD), and copper-zinc SOD (CuZnSOD). HP100-1 cells had a high proliferavable activity than HL60 cells; the higher level of c-myc was expressed in HP100-1 cells than in HL60 cells. Treatment with catalase or introduction of catalase cDNA into HL60 cells stimulated the growth. Exposure of HP100-1 cells to a catalase inhibitor resulted in suppression of the cell growth with concomitant increased levels of intracellular H2O2. Moreover, exogenously added H2O2 or depletion of a glutathione suppressed the cell growth in HL60 cells. The p38 mitogen-activated protein kinase (p38MAPK) and the extracelluar signal regulated kinase1/2 (ERK1/2) were constitutively phosphorylated in HP100-1, but not in HL60 cells. Inhibition of the ERK1/2 pathway suppressed the growth of HP100-1 cells, but that of p38MAPK did not affect the growth. Moreover, inhibition of catalase blocked the phosphorylation of ERK1/2, but not p38MAPK in HP100-1 cells. Thus, our results suggest that catalase activates the growth of HL60 cells through dismutation of H2O2 leading to activation of the ERK1/2 pathway; H2O2 is an important regulator of the growth in HL60 cells.94ｔｈ Ａｎｎｕａｌ Ｍｅｅｔｉｎｇ