PROTEASOME INHIBITORS ACTIVATE STRESS KINASES AND INDUCE HSP72 - DIVERSE EFFECTS ON APOPTOSIS

Inhibition of the major cytosolic protease, proteasome, has been repor ted to induce programmed cell death in several cell lines, while with other lines, similar inhibition blocked apoptosis triggered by a varie ty of harmful treatments. To elucidate the mechanism of pro- and antia poptotic action of proteasome inhibitors, their effects on U937 lympho id and 293 kidney human tumor cells were tested, Treatment with peptid yl aldehyde MG132 and other proteasome inhibitors led to a steady incr ease in activity of c-Jun N-terminal kinase, JNK1, which is known to i nitiate the apoptotic program in response to certain stresses. Dose de pendence of MG132-induced JNK activation was parallel with that of apo ptosis. Furthermore, inhibition of the JNK signaling pathway strongly suppressed MG132-induced apoptosis. These data indicate that JNK is cr itical for the cell death caused by proteasome inhibitors. An antiapop totic action of proteasome inhibitors could be revealed by a short inc ubation of cells with MG132 followed by its withdrawal. Under these co nditions, the major heat shock protein Hsp72 accumulated in cells and caused suppression of JNK activation in response to certain stresses. Accordingly, pretreatment with MG132 reduced JNK-dependent apoptosis c aused by heat shock or ethanol, but it was unable to block JNK-indepen dent apoptosis induced by TNF alpha. Therefore, proteasome inhibitors activate JNK, which initiates an apoptotic program, and simultaneously they induce Hsp72, which suppresses JNK-dependent apoptosis. A balanc e between these two effects might define the fate of cells exposed to the inhibitors.