Abstract
Carfilzomib (CFZ) is a second generation proteasome inhibitor approved for the treatment of patients with multiple myeloma. It induces apoptosis in human cancer cells; but the underlying mechanisms remain undefined. In the present study, we show that CFZ decreases the survival of several human cancer cell lines and induces apoptosis. Induction of apoptosis by CFZ occurs, at least in part, due to activation of the extrinsic apoptotic pathway, since FADD deficiency protected cancer cells from undergoing apoptosis. CFZ increased total and cell surface levels of DR5 in different cancer cell lines; accordingly it enhanced TRAIL-induced apoptosis. DR5 deficiency protected cancer cells from induction of apoptosis by CFZ either alone or in combination with TRAIL. These data together convincingly demonstrate that DR5 upregulation is a critical mechanism accounting for CFZ-induced apoptosis and enhancement of TRAIL-induced apoptosis. CFZ inhibited the degradation of DR5, suggesting that DR5 stabilization contributes to CFZ-induced DR5 upregulation. In summary, the present study highlights the important role of DR5 upregulation in CFZ-induced apoptosis and enhancement of TRAIL-induced apoptosis in human cancer cells.
Highlights
Ubiquitin/proteasome-mediated protein degradation represents a critical post-translational mechanism for the regulation of protein levels
To understand the mechanism by which CFZ activates extrinsic apoptosis, we examined the effects of CFZ on the expression of death receptor 4 (DR4) and DR5, which are important cell surface death receptors that activate extrinsic apoptotic signaling though recruitment of FADD
We found that total and cell surface levels of DR5 were strongly elevated by CFZ across the tested cancer cell lines, in comparison with a relatively modest increase in DR4
Summary
Ubiquitin/proteasome-mediated protein degradation represents a critical post-translational mechanism for the regulation of protein levels. This process primarily involves polyubiquitination of substrate proteins and subsequent proteolytic degradation by the macromolecular 26S proteasome complex. Carfilzomib (CFZ; known as PR-171), a second-generation irreversible proteasome inhibitor, is approved by the FDA for the treatment of multiple myeloma. It is a cell-permeable tetrapeptide epoxyketone analog of epoxomicin (Figure 1A) that is structurally distinct from bortezomib and irreversibly binds to and inhibits the chymotrypsin-like site of the proteasome [4, 5]. In addition to hematologic malignancies, CFZ is being evaluated in clinical trials against solid tumors including small-cell lung cancer, non-small cell lung cancer, refractory renal cell cancer, and metastatic prostate cancer [2]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
