LACTACYSTIN, A SPECIFIC INHIBITOR OF THE PROTEASOME, INDUCES APOPTOSIS IN HUMAN MONOBLAST U937 CELLS

Lactacystin, originally isolated from a microbe as an inducer of neuri togenesis, targets the catalytic beta-subunit of the proteasome, and a rrests the cell cycle. Here we report for the first time that lactacys tin induces apoptotic cell death in human monoblastic U937 cells. When U937 cells were cultured with lactacystin, their nuclei were shrunken , a morphological change typical of apoptosis, and cell viability was decreased. Electrophoretic analysis revealed that chromosomal DNAs fro m lactacystin-treated cells were cleaved in an internucleosomal ladder -like pattern, indicating that cell death occurs through an apoptotic process, which was also confirmed by DNA fragmentation analysis using flow cytometry. These findings suggest that inhibition of the proteaso me during proliferation results in apoptotic cell death, and that the proteasome is a key enzyme in the course of the cell cycle that destin es the cell to proliferate, differentiate or die. (C) 1995 Academic Pr ess, Inc.