The 26S proteasome complex: An attractive target for cancer therapy

Abstract

The 26S proteasome complex engages in an ATP-dependent proteolytic degradation of a variety of oncoproteins, transcription factors, cell cycle specific cyclins, cyclin-dependent kinase inhibitors, ornithine decarboxylase, and other key regulatory cellular proteins. Thus, the proteasome regulates either directly or indirectly many important cellular processes. Altered regulation of these cellular events is linked to the development of cancer. Therefore, the proteasome has become an attractive target for the treatment of numerous cancers. Several proteasome inhibitors that target the proteolytic active sites of the 26S proteasome complex have been developed and tested for anti-tumor activities. These proteasome inhibitors have displayed impressive anti-tumor functions by inducing apoptosis in different tumor types. Further, the proteasome inhibitors have been shown to induce cell cycle arrest, and inhibit angiogenesis, cell-cell adhesion, cell migration, immune and inflammatory responses, and DNA repair response. A number of proteasome inhibitors are now in clinical trials to treat multiple myeloma and solid tumors. Many other proteasome inhibitors with different efficiencies are being developed and tested for anti-tumor activities. Several proteasome inhibitors currently in clinical trials have shown significantly improved anti-tumor activities when combined with other drugs such as histone deacetylase (HDAC) inhibitors, Akt (protein kinase B) inhibitors, DNA damaging agents, Hsp90 (heat shock protein 90) inhibitors, and lenalidomide. The proteasome inhibitor bortezomib is now in the clinic to treat multiple myeloma and mantle cell lymphoma. Here, we discuss the 26S proteasome complex in carcinogenesis and different proteasome inhibitors with their potential therapeutic applications in treatment of numerous cancers.

BAG3 induction is required to mitigate proteotoxicity via selective autophagy following inhibition of constitutive protein degradation pathways

“…As inhibition of protein degradation is considered as an attractive anticancer strategy, 10 further insights into the mechanisms that regulate sensitivity and resistance of cancer cells to inhibitors of PQC pathways will be critical to exploit this strategy in human cancers. By identifying the BAG3-mediated selective autophagy pathway as a novel mechanism of acquired resistance that compensates for inhibition of the constitutive protein degradation systems, our findings suggest that interfering with this inducible escape mechanism may potentiate the efficacy of protein degradation inhibitors.…”

“…8 Given the importance of proper PQC to maintain cell viability, these pathways have been exploited as therapeutic targets in oncology. 10 For example, Bortezomib, a reversible proteasome inhibitor, demonstrated potent in vitro and in vivo antitumor activity against various hematological malignancies and solid cancers, and is approved for the treatment of certain tumors, for example, multiple myeloma. 10 However, several cancers exhibit primary or acquired resistance to Bortezomib-based therapies, thus calling for new strategies to bypass this resistance.…”

“…10 For example, Bortezomib, a reversible proteasome inhibitor, demonstrated potent in vitro and in vivo antitumor activity against various hematological malignancies and solid cancers, and is approved for the treatment of certain tumors, for example, multiple myeloma. 10 However, several cancers exhibit primary or acquired resistance to Bortezomib-based therapies, thus calling for new strategies to bypass this resistance. For example, engagement of the aggresome-autophagy system has been encountered as a defense mechanism to compensate as alternative constitutive PQC pathway for inhibition of the UPS.…”

Potential use of chymotrypsin-like proteasomal activity as a biomarker for prostate cancer

“…In the present study, the expression of proteasome target proteins was also assessed, including p27, which functions in cell cycle progression; Bax, which is associated with apoptosis; and IκB-α, which is part of the nuclear factor (NF)-κB pathway (29). The expression levels of all three substrates were decreased in prostate cancer cells and xenograft tumor tissue in the present study.…”

Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

“…Bortezomib is a modified dipeptidyl boronic acid authorized for the treatment of multiple myeloma and mantle cell lymphoma [11][12][13]. Recently, thalidomide has received a great deal of attention due to its remarkable therapeutic efficacy in the treatment of multiple myeloma [14].…”