Oncogenic Regulators and Substrates of the Anaphase Promoting Complex/Cyclosome Are Frequently Overexpressed in Malignant Tumors

Department of Pathology, MC5324, Stanford University, Stanford, CA, USA.
American Journal Of Pathology (Impact Factor: 4.59). 06/2007; 170(5):1793-805. DOI: 10.2353/ajpath.2007.060767
Source: PubMed

ABSTRACT The fidelity of cell division is dependent on the accumulation and ordered destruction of critical protein regulators. By triggering the appropriately timed, ubiquitin-dependent proteolysis of the mitotic regulatory proteins securin, cyclin B, aurora A kinase, and polo-like kinase 1, the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase plays an essential role in maintaining genomic stability. Misexpression of these APC/C substrates, individually, has been implicated in genomic instability and cancer. However, no comprehensive survey of the extent of their misregulation in tumors has been performed. Here, we analyzed more than 1600 benign and malignant tumors by immunohistochemical staining of tissue microarrays and found frequent overexpression of securin, polo-like kinase 1, aurora A, and Skp2 in malignant tumors. Positive and negative APC/C regulators, Cdh1 and Emi1, respectively, were also more strongly expressed in malignant versus benign tumors. Clustering and statistical analysis supports the finding that malignant tumors generally show broad misregulation of mitotic APC/C substrates not seen in benign tumors, suggesting that a "mitotic profile" in tumors may result from misregulation of the APC/C destruction pathway. This profile of misregulated mitotic APC/C substrates and regulators in malignant tumors suggests that analysis of this pathway may be diagnostically useful and represent a potentially important therapeutic target.

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Available from: Norman L Lehman, Sep 29, 2015
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    • "APC/C is a multi-subunit ubiquitin E3 ligase protein that plays a distinct role in cell cycle transitions [11], [12]. Previous studies showed that misregulation of APC/C and its substrates correlates with tumor progression [13]. We identified a novel class of small molecule inhibitors (SMIs) of CARP-1 binding with APC/C subunit APC2. "
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    ABSTRACT: Neuroblastomas (NBs) are a clinically heterogeneous group of extra cranial pediatric tumors. Patients with high-risk, metastatic NBs have a long-term survival rate of below 40%, and are often resistant to current therapeutic modalities. Due to toxic side effects associated with radiation and chemotherapies, development of new agents is warranted to overcome resistance and effectively treat this disease in clinic. CARP-1 functional mimetics (CFMs) are an emerging class of small molecule compounds that inhibit growth of diverse cancer cell types. Here we investigated NB inhibitory potential of CFMs and the molecular mechanisms involved. CFM-1, -4, and -5 inhibited NB cell growth, in vitro, independent of their p53 and MYCN status. CFM-4 and -5 induced apoptosis in NB cells in part by activating pro-apoptotic stress-activated kinases (SAPKs) p38 and JNK, stimulating CARP-1 expression and cleavage of PARP1, while promoting loss of the oncogenes C and N-myc as well as mitotic cyclin B1. Treatments of NB cells with CFM-4 or -5 also resulted in loss of Inhibitory κB (IκB) α and β proteins. Micro-RNA profiling revealed upregulation of XIAP-targeting miR513a-3p in CFM-4-treated NB, mesothelioma, and breast cancer cells. Moreover, exposure of NB and breast cancer cells to CFM-4 or -5 resulted in diminished expression of anti-apoptotic XIAP1, cIAP1, and Survivin proteins. Expression of anti-miR513a-5p or miR513a-5p mimic, however, interfered with or enhanced, respectively, the breast cancer cell growth inhibition by CFM-4. CFMs also impacted biological properties of the NB cells by blocking their abilities to migrate, form colonies in suspension, and invade through the matrix-coated membranes. Our studies indicate anti-NB properties of CFM-4 and 5, and suggest that these CFMs and/or their future analogs have potential as anti-NB agents.
    PLoS ONE 07/2014; 9(7):e102567. DOI:10.1371/journal.pone.0102567 · 3.23 Impact Factor
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    • "The Anaphase Promoting Complex/Cyclosome (APC/C) is a multiprotein complex with E3 ubiquitin ligase activity [13]. Dysregulation of APC/C may be associated with tumorigenesis since many APC/C-targeting/activating molecules such as securin, polo-like kinase, aurora kinase, and SnoN are potential oncogenes [14]. A yeast-two-hybrid (Y2H) screening assay revealed CARP-1 interaction with APC-2 protein. "
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    ABSTRACT: Malignant pleural mesothelioma (MPM) is an asbestos-related thoracic malignancy that is characterized by late metastases, and resistance to therapeutic modalities. The toxic side-effects of MPM therapies often limit their clinical effectiveness, thus necessitating development of new agents to effectively treat and manage this disease in clinic. CARP-1 functional mimetics (CFMs) are a novel class of compounds that inhibit growth of diverse cancer cell types. Here we investigated MPM cell growth suppression by the CFMs and the molecular mechanisms involved. CFM-1, -4, and -5 inhibited MPM cell growth, in vitro, in part by stimulating apoptosis. Apoptosis by CFM-4 involved activation of pro-apoptotic stress-activated protein kinases (SAPKs) p38 and JNK, elevated CARP-1 expression, cleavage of PARP1, and loss of the oncogene c-myc as well as mitotic cyclin B1. Treatments of MPM cells with CFM-4 resulted in depletion of NF-κB signaling inhibitor ABIN1 and Inhibitory κB (IκB)α and β, while increasing expression of pro-apoptotic death receptor (DR) 4 protein. CFM-4 enhanced expression of serine-phosphorylated podoplanin and cleavage of vimetin. CFMs also attenuated biological properties of the MPM cells by blocking their abilities to migrate, form colonies in suspension, and invade through the matrix-coated membranes. Both podoplanin and vimentin regulate processes of cell motility and invasion, and their expression often correlates with metastatic disease, and poor prognosis. The fact that phosphorylation of serines in the cytoplasmic domain of podoplanin interferes with processes of cellular motility, CFM-4-dependent elevated phosphorylated podoplanin and cleavage of vimentin underscore a metastasis inhibitory property of these compounds, and suggest that CFMs and/or their future analogs have potential as anti-MPM agents.
    PLoS ONE 03/2014; 9(3):e89146. DOI:10.1371/journal.pone.0089146 · 3.23 Impact Factor
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    • "In the current study, significantly altered values of PTTG1 were observed by treatment with OA, showing an increase in expression levels compared to control at 3 and 24 h and a decrease at 48 h of OA exposure (Fig. 1b). Despite the fact that a PTTG1 overexpression is often found in tumours of different tissue origins (Lehman et al., 2007), low PTTG1 expression level can also induce mitotic disruption and cell growth abnormalities, since securin function is important for cell division (Jallepalli et al., 2001). Besides, PTTG-null mice exhibited a variety of abnormalities including aberrant cell cycle progression and premature centromere division (Wang et al., 2001). "
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    Ecotoxicology and Environmental Safety 04/2013; 92. DOI:10.1016/j.ecoenv.2013.03.009 · 2.76 Impact Factor
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