The transcription factor NF-κB plays a critical role in regulation of survival-related genes, particularly in the case of malignant hematopoietic cells. For example, inappropriate activation of NF-κB has been implicated in the pathogenesis of AML (and in the viability of AML stem cells), as well as the ABCsubtype of diffuse large B-cell lymphoma and multiple myeloma. Under normal conditions, NF-κB is sequestered in the cytoplasm by the inhibitory protein IκBα, itself an NF-κB-dependent protein. Upon stimulation by cytokines (e.g., TNFα), IκBα kinases (IKKs) are activated, resulting in IκBα phosphorylation, ubiquitination, and proteasomal degradation. This unleashes NF-κB, allowing it to translocate to the nucleus, where it binds to DNA and promotes transcription of anti-apoptotic genes. Significantly, multiple myeloma cells are characterized by a wide array of NF-κB-activating chromosomal and genetic abnormalities, which presumably contribute to their survival advantage over their normal counterparts.1
These considerations have prompted the development of agents capable of interrupting the NF-κB pathway, exemplified by the proteasome inhibitor bortezomib, which has shown remarkable activity in patients with refractory multiple myeloma. The common wisdom is that bortezomib and similar agents act by blocking the proteasomal degradation of IκBα, which is allowed to accumulate and trap NF-κB in the cytoplasm, thereby attenuating its prosurvival activities.
However, the results of a recent study by Hideshima et al., from Ken Anderson’s group at Dana Farber, casts doubt on this commonly accepted model of proteasome inhibitor action. This group studied the effects of proteasome inhibitors on NF-κB activation status in multiple myeloma cells both in vitro and in vivo. Contrary to expectations, they found that bortezomib and similar agents failed to inhibit NF-κB activity; instead, they actually appeared to activate NF-κB, an event associated with IκBα down-regulation. Interestingly, inhibitors of IKKs, which block phosphorylation of IκBα, prevented NF-κB activation by bortezomib and potentiated its lethality. The authors concluded that the lethality of bortezomib in myeloma cells cannot be solely attributed to interruption of NF-κB activation, as has conventionally been assumed.
In Brief
The results of this study have implications not only for our understanding of the mechanism of action of bortezomib in multiple myeloma and other hematologic malignancies, but also for how such agents might best be used in the future. The question of how a proteasome inhibitor would be able to activate NF-κB and down-regulate IκBα expression remains unanswered. One possibility is that this phenomenon might reflect the complex and dynamic nature of the NF-κB network, in which multiple reciprocal interactions occur.2 For example, initial inactivation of NF-κB might result in down-regulation of NF-κB-dependent proteins, including IκBα. Alternatively, proteasome inhibitors such as bortezomib have numerous other activities, including disruption of protein disposition, induction of ER stress, and interference with DNA repair, all of which could potentially serve as triggers for NF-κB activation. Lastly, it is important to note that discrepancies between this and earlier reports may stem from two facts: 1) that the latter often examined effects of proteasome inhibitors on cytokine-induced NF-κB activation and 2) that mechanisms involved in this setting may differ from those operative under basal, unstimulated conditions. However, it is important to note that whatever its effects on unstimulated cells, bortezomib and similar agents may still block NF-κB activation induced by other agents and thereby enhance lethality. Whatever the answers to these questions, the results of this study could have a profound impact on the way we view (and use) proteasome inhibitors in the future.
References
Competing Interests
Dr. Grant indicated no relevant conflicts of interest.
