Myeloid cell leukemia-1 (Mcl-1) protein is a member of the Bcl-2 family of apoptotic regulatory proteins that is dysregulated in a variety of hematopoietic malignancies, including multiple myeloma, non-Hodgkin lymphoma, and mantle cell lymphoma. It has also been associated with resistance to certain chemotherapeutic agents. Consequently, Mcl-1 has been the focus of considerable interest as a potential target in these diseases. For example, the short half-life of this protein has prompted the use of cyclin-dependent kinase inhibitors such as flavopiridol, which in preclinical studies act as transcriptional repressors, in Mcl-1 overexpressing malignancies (e.g., multiple myeloma). However, the effectiveness of such strategies has yet to be clearly demonstrated.
The ubiquitin-proteasome system (UPS) provides a mechanism by which cells rid themselves of unwanted or misfolded proteins. Such proteins are targeted for elimination following polyubiquitination by sequential action of ubiquitin activating, conjugating, and ligating enzymes, after which they are directed to the 20S catalytic core of the proteasome for degradation. Proteasome inhibitors such as bortezomib disrupt this process by inhibiting proteasomal enzyme activities, particularly chymotrypsin-like activity, although the precise mechanism by which these agents selectively induce malignant cell death remains to be determined. Whatever its mechanism of action, bortezomib’s efficacy in patients with refractory multiple myeloma or mantle cell lymphoma attests to the validity of this approach. However, the ability of proteasome inhibitors to interfere with protein degradation carries with it certain intrinsic theoretical disadvantages. For example, proteasome inhibition can also trigger the accumulation of anti-apoptotic proteins such as Mcl-1, which has been shown to oppose bortezomib lethality.1 Consequently, interfering with the UPS in a way that does not lead to Mcl-1 up-regulation could provide a potential advantage over the use of conventional proteasome inhibitors.
Results of the study by Schwickart et al. from Genentech suggest the feasibility of such an approach. These investigators exploited the initial requirement of proteins targeted for degradation to be polyubiquitinated by ubiquitin processing enzymes. This process is reciprocally regulated by an opposing group of deubiquitinases, one of which, USP9X, appears to be specifically related to Mcl-1 disposition. Notably, the authors observed that in follicular and diffuse large B-cell lymphomas, increased USP9X levels correlated strongly with increased Mcl-1 expression and, in the case of myeloma, were associated with a poor prognosis. Significantly, genetic manipulation of USP9X (i.e., by shRNA knockdown) resulted in markedly enhanced Mcl-1 polyubiquitination and down-regulation. The therapeutic implications of these observations were highlighted by the observation that interference with USP9X function and resulting down-regulation of Mcl-1 dramatically increased the sensitivity of cells to ABT-737, a BH3 mimetic whose analog ABT-263 is currently undergoing clinical trials and whose activity has been shown to be inversely related to Mcl-1 expression.2
In Brief
The findings in this report have potentially important implications for the identification of predictive response indicators in hematologic malignancies characterized by dysregulation of Mcl-1, as well as for the future development of novel agents targeting non-traditional components of the ubiquitin-proteasome system. Although increased expression of proteins such as Mcl-1, which can confer resistance to therapy, often reflects alterations in gene expression, the present findings highlight the possibility that such events may represent secondary phenomena resulting from post-translational mechanisms, as in the case of dysregulated USP9X. A corollary of this notion is that targeting proteins responsible for Mcl-1 disposition may prove to be more feasible than direct strategies designed to block Mcl-1 transcription. An additional implication of these findings is that while targeting the catalytic core of the proteasome, i.e., by agents such as bortezomib, has clearly been successful in certain hematologic malignancies, generic strategies that block protein degradation can theoretically lead to the undesirable accumulation of anti-apoptotic proteins such as Mcl-1. This consideration has prompted intense interest in more selective targeting of components of the ubiquitin-proteasome system, e.g., by selective E3-ubiquitin ligases. The results of the present study raise the intriguing possibility that targeting deubiquitinases such as USP9X may represent an alternative and potentially effective approach to down-regulation of the expression of resistance-conferring anti-apoptotic proteins like Mcl-1. The development of such agents could have significant implications for the therapy of diverse hematologic malignancies, and their arrival is eagerly awaited.
References
Competing Interests
Dr. Grant indicated no relevant conflicts of interest.
