Ubiquitin-specific protease 14 expression in colorectal cancer is associated with liver and lymph node metastases

Shinji, Seiichi; Naito, Zenya; Ishiwata, Shunji; Ishiwata, Toshiyuki; Tanaka, Noritake; Furukawa, Kiyonori; Suzuki, Hideyuki; Seya, Tomoko; Matsuda, Akihisa; Katsuta, Miwako; Tajiri, Takashi

doi:10.3892/or.15.3.539

Cited by 53 publications

(54 citation statements)

References 15 publications

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“…[29][30][31] Although USP14 and UCHL5 have been implicated in the tumorigenesis and progression of colorectal cancer and esophageal squamous cell carcinoma, 14,19 their role in MM is undefined. Consistent with previous studies, 15,16,21 we found that USP14 and UCHL5 are highly expressed in MM cells vs normal plasma cells and PBMCs, suggesting a role of USP14 and UCHL5 in MM pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance

Tian

D’Arcy

Wang

et al. 2014

Blood

270

269

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Key Points• Deubiquitylating enzymes USP14 and UCHL5 are involved in the tumorigenesis of MM.• b-AP15 is a specific USP14 and UCHL5 inhibitor, which blocks growth and induces apoptosis in MM cells.Proteasome inhibitors have demonstrated that targeting protein degradation is effective therapy in multiple myeloma (MM). Here we show that deubiquitylating enzymes (DUBs) USP14 and UCHL5 are more highly expressed in MM cells than in normal plasma cells. USP14 and UCHL5 short interfering RNA knockdown decreases MM cell viability. A novel 19S regulatory particle inhibitor b-AP15 selectively blocks deubiquitylating activity of USP14 and UCHL5 without inhibiting proteasome activity. b-AP15 decreases viability in MM cell lines and patient MM cells, inhibits proliferation of MM cells even in the presence of bone marrow stroma cells, and overcomes bortezomib resistance. Anti-MM activity of b-AP15 is associated with growth arrest via downregulation of CDC25C, CDC2, and cyclin B1 as well as induction of caspase-dependent apoptosis and activation of unfolded protein response. In vivo studies using distinct human MM xenograft models show that b-AP15 is well tolerated, inhibits tumor growth, and prolongs survival. Combining b-AP15 with suberoylanilide hydroxamic acid, lenalidomide, or dexamethasone induces synergistic anti-MM activity. Our preclinical data showing efficacy of b-AP15 in MM disease models validates targeting DUBs in the ubiquitin proteasomal cascade to overcome proteasome inhibitor resistance and provides the framework for clinical evaluation of USP14/UCHL5 inhibitors to improve patient outcome in MM. (Blood. 2014;123(5):706-716)

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Section: Discussionmentioning

confidence: 99%

A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance

Tian

D’Arcy

Wang

et al. 2014

Blood

270

269

View full text Add to dashboard Cite

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“…Although neither USP14 nor UCHL5 appears to be essential for cell survival alone, dual knockdown using RNA interference has been shown to lead to the accumulation of polyubiquitinated substrates and loss of cell viability (Koulich et al, 2008;Tian et al, 2013;Wang et al, 2014). Interestingly several reports have shown that USP14 is consistently overexpressed in solid tumours of lung and ovarian origin and associated with metastases in colorectal carcinoma suggesting a potential role in oncogenesis (Shinji et al, 2006;Wang et al, 2015;Wu et al, 2013). Considering that USP14 and UCHL5 belong to different classes of DUBs, dual inhibition of these enzymes by small molecules would a priori be expected to be possible only in the context of broad-spectrum DUB inhibition.…”

Section: Proteasomal Dubs As Drug Targets For Cancer Therapymentioning

confidence: 99%

Inhibition of proteasome deubiquitinase activity: a strategy to overcome resistance to conventional proteasome inhibitors?

Selvaraju

Mazurkiewicz

Wang

et al. 2015

Drug Resistance Updates

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The ubiquitin-proteasome system (UPS) is the primary mechanism controlling the degradation of damaged, unwanted or short-lived proteins in eukaryotic cells. In addition to protein homeostasis, the UPS has also emerged as a critical node in the regulation of signalling pathways implicated in the growth and survival of cancer cells. The absolute dependency of cancer cells on a functioning UPS has been exploited in the development of anti-cancer therapies as exemplified by development of proteasome inhibitors for the treatment of certain leukemic malignancies.Deubiquitinases (DUBs) are enzyme components of the UPS that catalyse re-editing of poly ubiquitin chains and/or removal of ubiquitin en bloc from target substrates leading to alterations in protein stability and/or downstream signalling. There is a growing recognition that targeting DUB activity may be a feasible option for the development of novel anti-cancer therapies. In particular inhibition of proteasomal cysteine DUBs (i.e. USP14 and UCHL5) has been shown to be particularly cytotoxic to cancer cells leading to the accumulation of ubiquitinated proteins and proteotoxic stress. In this review we focus on the mechanisms of action of proteasome DUB inhibitors as well as the potential of such compounds to circumvent acquired drug resistance in cancer patients.

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“…IU1 treatment enhanced proteasome efficiency in vitro, with resultant degradation of the tau protein in initial studies. The clinical utility of a specific USP14 inhibitor may merit more attention, as new studies indicate that USP14 activity is necessary for WNT/ β-catenin signaling that is active in some cancers, and that high levels of USP14 correlate with gastrointestinal cancer severity and lung cancer mortality (54,55). To this end, bAP-15 is a recently developed compound that antagonizes USP14 and another proteasome-associated DUB, USP5, and displays antiproliferative activity in vitro and tumoricidal activity in animal models (56).…”

Section: Therapeuticsmentioning

confidence: 99%

Emerging therapies targeting the ubiquitin proteasome system in cancer

Weathington¹,

Mallampalli²

2014

J. Clin. Invest.

112

104

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The ubiquitin proteasome system (UPS) is an essential metabolic constituent of cellular physiology that tightly regulates cellular protein concentrations with specificity and precision to optimize cellular function. Inhibition of the proteasome has proven very effective in the treatment of multiple myeloma, and this approach is being tested for utility in other malignancies. New pharmaceuticals targeting the proteasome itself or specific proximal pathways of the UPS are in development as antiproliferatives or immunomodulatory agents. In this article, we discuss the biology of UPS-targeting drugs, their use as therapy for neoplasia, and the state of clinical and preclinical development for emerging therapeutics. IntroductionA new era in myeloma therapy. At the turn of the millennium, targeted molecular therapeutics against hematologic malignancies initiated a shift in our perspective on treatment, prognosis, and survival for patients with some of the most aggressive and fatal neoplasms. Bortezomib (branded and marketed as Velcade by Millennium Pharmaceuticals) entered the armamentarium of new antiproliferative therapies with approval in May 2003 for the hematologic malignancy multiple myeloma (MM), in which B cellderived plasma cells clonally proliferate and produce large quantities of monoclonal antibody. MM can be a devastating disease, with renal failure, blood hyperviscosity, and bone marrow invasion seen clinically. Before 2000, there were few life-prolonging therapies for the disease. Bortezomib blocks the proteolytic activity of the 26S proteasome, a cellular structure whose role in cell metabolism has now been meticulously characterized; indeed, bortezomib is the first agent available for use in humans that inhibits the activity of this system. Bortezomib quickly proved effective in refractory MM (1), and its inclusion in initial MM treatment was superior to the conventional cytotoxic chemotherapy regimen alone (2).During this time thalidomide, an agent that produced deformities in infants of mothers prescribed the drug during pregnancy, further suppressed myeloma plasma cell proliferation when added to the regimen. A decade of careful clinical trials since these first breakthrough observations has revealed that therapeutic combinations including bortezomib with thalidomide or related compounds (collectively called immunomodulatory drugs, or IMiDs) and steroids confer a very favorable prognosis compared with historic therapy, greatly prolonging the median survival time from diagnosis over this period (3). When this therapy is implemented in conjunction with autologous bone marrow stem cell transplant, recent clinical trials show a three-year progression-free survival of 60% and overall survival of 90% for patients eligible for stem cell transplant (4), compared with only 48% three-year relative survival for patients diagnosed in 1999 (5). Multiple clinical trials for this new generation of MM molecular therapies are underway, with median survival projected by some to exceed 10 years in the post-bortezomib...

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Ubiquitin-specific protease 14 expression in colorectal cancer is associated with liver and lymph node metastases

Cited by 53 publications

References 15 publications

A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance

A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance

Inhibition of proteasome deubiquitinase activity: a strategy to overcome resistance to conventional proteasome inhibitors?

Emerging therapies targeting the ubiquitin proteasome system in cancer

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