Proteasome Inhibitors Activate Stress Kinases and Induce Hsp72

Abstract

Inhibition of the major cytosolic protease, proteasome, has been reported to induce programmed cell death in several cell lines, while with other lines, similar inhibition blocked apoptosis triggered by a variety of harmful treatments. To elucidate the mechanism of proand antiapoptotic action of proteasome inhibitors, their effects on U937 lymphoid and 293 kidney human tumor cells were tested. Treatment with peptidyl aldehyde MG132 and other proteasome inhibitors led to a steady increase in activity of c-Jun N-terminal kinase, JNK1, which is known to initiate the apoptotic program in response to certain stresses. Dose dependence of MG132-induced JNK activation was parallel with that of apoptosis. Furthermore, inhibition of the JNK signaling pathway strongly suppressed MG132-induced apoptosis. These data indicate that JNK is critical for the cell death caused by proteasome inhibitors. An antiapoptotic action of proteasome inhibitors could be revealed by a short incubation of cells with MG132 followed by its withdrawal. Under these conditions, 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 caused by heat shock or ethanol, but it was unable to block JNK-independent apoptosis induced by TNF␣. Therefore, proteasome inhibitors activate JNK, which initiates an apoptotic program, and simultaneously they induce Hsp72, which suppresses JNK-dependent apoptosis. A balance between these two effects might define the fate of cells exposed to the inhibitors.

Prostate carcinoma cell death resulting from inhibition of proteasome activity is independent of functional Bcl-2 and p53

“…This result stands in variance to a recent report by Meriin et al, (1998). Their studies indicate that the catalytic activity of JNK1 can be stimulated in human U937 lymphoid tumor cells and human 293 kidney tumor cells.…”

“…The most direct data implicating the requisite function of the JNK stress pathway in proteasome inhibitor-induced cell death comes from Meriin et al, (1998) who reported that ectopic expression of either a catalytically defective mutant version of JNKK (SEK1) or a transcriptionally incompetent c-jun protein blocks the cleavage of a co-expressed fragment of the U1 ribonucleoprotein. In this report cell death induction was not reported on a per cell basis (i.e.…”

NF-κB pathway inhibitors preferentially inhibit breast cancer stem-like cells

“…To study the sensitivity of breast cancer stem-like cell to NF-κB pathway inhibitors, 11 compounds targeting different steps of the NF-κB pathway, including antioxidants Curcumin [32]; PDTC [33]; DETC [34]; Quercetin [35], NF-κB phosphorylation inhibitors Sulfasalazine [36]; Sulindac [37]; Ibuprofen [38]; PTL [39] and NF-κB degradation inhibitors MG-132 [40]; Cyclosporin A [41]; Genistein [42], were tested in this study. MCF7 sphere cells were used as a model of breast cancer stem-like cells [16,43].…”

The proteasome: a protein‐destroying machine

“…For one possible explanation for these diverse effects, it was recently proposed that proteasome inhibitors activate c-Jun N-terminal kinase (JNK), which initiates an apoptotic programme, while they simultaneously induce Hsp72, which suppresses JNKdependent apoptosis. Consequently, a balance between these two effects might define the fate of cells exposed to the inhibitors (Meriin et al 1998). …”