Mini-reviewProteasome inhibition: A new therapeutic strategy to cancer treatment
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].
Section snippets
Principle of actions of proteasome inhibitors
The proposed mechanisms by which proteasome inhibition mediates its antitumor effects are listed in Table 2 [11], [35]. Because of the enormity of the possible mechanisms, it is unwise to discuss each of them in detail in this review. Instead, several pathways, which are of biologic significance or novelty, will be discussed.
Induction of macroautophagy
Macroautophagy is a catabolic process by which the cell degrades its intracellular content and damaged organelles through the lysosomal system. In this capacity, macroautophagy serves complementarily with the ubiquitin–proteasome system as the two major protein degradation systems in mammalian cells [2]. The role of macroautophagy in carcinogenesis is paradoxical. As a tumor-suppressing mechanism, overactivation of macroautophagy induces cell death [110] and mutations of macroautophagy-related
Conclusive remarks
Proteasome has emerged as a novel target in cancer therapy. The use of proteasome inhibitor has yielded some success in the management of some forms of hematological malignancies and may be effective against solid tumors. It triggers a mixed repertoire of tumor-suppressing and pro-survival pathways in cancer cells. Their relative importance in the antitumor activity of and resistance to proteasome inhibitors remains to be elucidated. Combinational therapy targeting the auto-regulatory
Conflicts of interest
None declared.
Acknowledgements
This work was supported by research Grant from National Basic Research Program of China (973 Program, 2010CB529305).
References (119)
Toward an atomic model of the 26S proteasome
Curr. Opin. Struct. Biol.
(2009)- et al.
Ablation of key oncogenic pathways by RITA-reactivated p53 is required for efficient apoptosis
Cancer Cell
(2009) - et al.
Proteasome inhibitors induce death but activate NF-kappaB on endometrial carcinoma cell lines and primary culture explants
J. Biol. Chem.
(2006) - et al.
Proteasome inhibitor PSI induces apoptosis in human mesothelioma cells
Cancer Lett.
(2006) - et al.
Bortezomib-mediated proteasome inhibition as a potential strategy for the treatment of rhabdomyosarcoma
Eur. J. Cancer
(2008) - et al.
Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341
Blood
(2003) - et al.
The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and noxa activation independent of p53 status
Blood
(2006) - et al.
Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma
Blood
(2009) - et al.
Proteasome inhibitor bortezomib-induced apoptosis in natural killer (NK)-cell leukemia and lymphoma: an in vitro and in vivo preclinical evaluation
Blood
(2007) - et al.
Bortezomib induces caspase-dependent apoptosis in Hodgkin lymphoma cell lines and is associated with reduced c-FLIP expression: a gene expression profiling study with implications for potential combination therapies
Leuk. Res.
(2008)
The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications
Blood
NPI-0052, a novel proteasome inhibitor,induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells
Blood
PS-341-mediated selective targeting of multiple myeloma cells by synergistic increase in ionizing radiation-induced apoptosis
Exp. Hematol.
Phase I study of bortezomib with weekly paclitaxel in patients with advanced solid tumours
Eur. J. Cancer
Argyrin a reveals a critical role for the tumor suppressor protein p27(kip1) in mediating antitumor activities in response to proteasome inhibition
Cancer Cell
NPI-0052, a novel proteasome inhibitor, induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells
Blood
Repression of protein translation and mTOR signaling by proteasome inhibitor in colon cancer cells
Biochem. Biophys. Res. Commun.
Bortezomib overcomes tumor necrosis factor-related apoptosis-inducing ligand resistance in hepatocellular carcinoma cells in part through the inhibition of the phosphatidylinositol 3-kinase/Akt pathway
J. Biol. Chem.
Caspase-8 dependent histone acetylation by a novel proteasome inhibitor, NPI-0052: a mechanism for synergy in leukemia cells
Blood
Transcriptional repression of E2F gene by proteasome inhibitors in human osteosarcoma cells
Biochem. Biophys. Res. Commun.
Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells
Blood
Proteasome-dependent regulation of p21WAF1/CIP1 expression
Biochem. Biophys. Res. Commun.
Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor
Cell
Nuclear trafficking of cubitus interruptus in the transcriptional regulation of hedgehog target gene expression
Cell
Proteasome inhibitor MG-132 lowers gastric adenocarcinoma TMK1 cell proliferation via bone morphogenetic protein signaling
Biochem. Biophys. Res. Commun.
The ubiquitin–proteasome pathway and pathogenesis of human diseases
Annu. Rev. Med.
The roles of intracellular protein-degradation pathways in neurodegeneration
Nature
Catalytic mechanism and assembly of the proteasome
Chem. Rev.
Bortezomib: proteasome inhibition as an effective anticancer therapy
Annu. Rev. Med.
Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics
Cancer Res.
The proteasome inhibitor PS-341 (bortezomib) up-regulates DR5 expression leading to induction of apoptosis and enhancement of TRAIL-induced apoptosis despite up-regulation of c-FLIP and survivin expression in human NSCLC cells
Cancer Res.
CEP1612, a dipeptidyl proteasome, inhibitor, induces p21WAF1 and p27KIP1 expression and apoptosis and inhibits the growth of the human lung adenocarcinoma A-549 in nude mice
Cancer Res.
Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells
Mol. Cell. Biol.
Bone morphogenetic protein signalling is required for the anti-mitogenic effect of the proteasome inhibitor MG-132 on colon cancer cells
Br. J. Pharmacol.
Inhibition of proteasome function induced apoptosis in gastric cancer
Int. J. Cancer
Down-regulation of phospho-Akt is a major molecular determinant of bortezomib-induced apoptosis in hepatocellular carcinoma cells
Cancer Res.
Proteasome inhibition-induces endoplasmic reticulum dysfunction and cell death of human cholangiocarcinoma cells
World J. Gastroenterol.
Bortezomib is ineffective in an orthotopic mouse model of pancreatic adenocarcinoma
Mol. Cancer Ther.
Antitumor effects of the proteasome inhibitor bortezomib in medullary and anaplastic thyroid carcinoma cells in vitro
J. Clin. Endocrinol. Metab.
Epidermal growth factor receptor inhibition sensitizes renal cell carcinoma cells to the cytotoxic effects of bortezomib
Mol. Cancer Ther.
The proteasome inhibitor bortezomib synergizes with gemcitabine to block the growth of human 253JB-V bladder tumors in vivo
Mol. Cancer Ther.
Ubiquitin proteasome system stress underlies synergistic killing of ovarian cancer cells by bortezomib and a novel HDAC6 inhibitor
Clin. Cancer Res.
Bortezomib (PS-341, Velcade) increases the efficacy of trastuzumab (Herceptin) in HER-2-positive breast cancer cells in a synergistic manner
Mol. Cancer Ther.
Suppression of the hypoxia-inducible factor-1 response in cervical carcinoma xenografts by proteasome inhibitors
Cancer Res.
Proteasome inhibitor PS-341 down-regulates prostate-specific antigen (PSA) and induces growth arrest and apoptosis of androgen-dependent human prostate cancer LNCaP cells
Cancer Sci.
Effect of bortezomib on human neuroblastoma cell growth, apoptosis, and angiogenesis
J. Natl. Cancer Inst.
Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis in human glioblastoma multiforme (GBM)
Oncogene
Bortezomib reverses a post-translational mechanism of tumorigenesis for patched1 haplo insufficiency in medulloblastoma
Pediatr. Blood Cancer
The proteasome inhibitor bortezomib induces apoptosis in human retinoblastoma cell lines in vitro
Invest. Ophthalmol. Vis. Sci.
Antitumorigenic effect of proteasome inhibitors on insulinoma cells
Endocrinology
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