Proteasome inhibition: A new therapeutic strategy to cancer treatment

Abstract

The ubiquitin–proteasome system is a major pathway for protein degradation. Targeting this pathway using proteasome inhibitors represents a novel approach for the treatment of cancer. Proteasome inhibitors lower cell proliferation and induce apoptosis in solid and hematologic malignancies through multiple mechanisms, including stabilization of cell cycle regulators and pro-apoptotic factors, stimulation of bone morphogenetic protein signaling, inhibition of protein translation, and sensitization to ligand-induced apoptosis. In this connection, proteasome inhibition activates macroautophagy, a compensatory protein degradation system, as well as other pro-survival signaling pathways. Inhibition of these auto-protective responses sensitizes cancer cells to the anti-proliferative effects of proteasome inhibitors.

Introduction

The ubiquitin–proteasome system is the major catabolic pathway for degradation of short-lived and misfolded proteins [1]. Proteins to be degraded through this pathway first undergo polyubiquitination followed by recognition and proteolysis by proteasome, a barrel-shaped multimeric protein complex. The process of ubiquitination involves several enzymes: E1 (ubiquitin-activating), E2 (ubiquitin-conjugating) and E3 (ubiquitin-ligase) enzymes (Fig. 1). The E1 enzyme hydrolyses ATP and forms a thioester linkage with the ubiquitin molecule. The activated ubiquitin is then transferred to the E2 enzyme. However, it is the E3 enzyme, which determines the substrate specificity, transfers the ubiquitin to the lysine residue on the target protein. The ubiquitin then serves as the substrate for another round of ubiquitination, forming a polyubiquitin chain on the target protein. Chain of four or more ubiquitin molecules allows the target protein to be shuttled to proteasome for degradation [2]. The 26S proteasome consists of one 20S core structure and two 19S regulatory caps. The 20S core structure is composed of four stacked rings made of different α (structural) and β (catalytic) subunits while the 19S regulatory cap consists of 19 subunits divided into a 10-protein α ring and a 9-protein ubiquitin-binding lid [3], [4]. In mammalian cells, β1, β2, and β5 subunits of the 20S core structure account for the caspase-like, trypsin-like and chymotrypsin-like activities of proteasome, respectively [4].

The increasing interest in the role of the ubiquitin–proteasome system in carcinogenesis has led to the discovery that many proteins involved in the regulation of cell proliferation and apoptosis are degraded through this pathway [5]. It therefore comes as no surprise that inhibition of the ubiquitin–proteasome system substantially alters cancer growth. In this respect, the ubiquitin–proteasome system can be targeted at different points, such as the E1 enzyme or specific E3 enzyme [6], [7]. Nevertheless, prevention of proteasomal degradation of ubiquitinated proteins by proteasome inhibitors remains the most common approach. Therapeutically, proteasome inhibitors display a broad-spectrum anti-proliferative or pro-apoptotic activity in vitro against different types of hematological and solid malignancies (Table 1) [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45]. Proteasome inhibitors also sensitize cancer cells to the antitumor effects of conventional chemotherapeutics [46] and novel targeted cancer therapy [47], [48] as well as irradiation [49]. Clinically, the proteasome inhibitor bortezomib has been FDA-approved for the treatment of multiple myeloma and mantle cell lymphoma [50]. Clinical trials evaluating the efficacies of proteasome inhibitors for the treatment of solid tumors and other hematological malignancies are in progress [5], [51], [52]. However, it is worthwhile to notice that solid tumors in general, with the exception of prostate cancer and non-small cell lung carcinoma, do not respond too well to bortezomib and further studies are needed. The most common adverse drug reactions associated with proteasome inhibitors include peripheral neuropathy and myelosuppression, which are usually self-limiting and mild relative to treatment options available to advanced cancer patients [52].