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Yang W, Wang S, Tong S, Zhang WD, Qin JJ. Expanding the ubiquitin code in pancreatic cancer. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166884. [PMID: 37704111 DOI: 10.1016/j.bbadis.2023.166884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/23/2023] [Accepted: 09/06/2023] [Indexed: 09/15/2023]
Abstract
The ubiquitin-proteasome system (UPS) is a fundamental regulatory mechanism in cells, vital for maintaining cellular homeostasis, compiling signaling transduction, and determining cell fates. These biological processes require the coordinated signal cascades of UPS members, including ubiquitin ligases, ubiquitin-conjugating enzymes, deubiquitinases, and proteasomes, to ubiquitination and de-ubiquitination on substrates. Recent studies indicate that ubiquitination code rewriting is particularly prominent in pancreatic cancer. High frequency mutation or aberrant hyperexpression of UPS members dysregulates ferroptosis, tumor microenvironment, and metabolic rewiring processes and contribute to tumor growth, metastasis, immune evasion, and acquired drug resistance. We conduct an in-depth overview of ubiquitination process in pancreatic cancer, highlighting the role of ubiquitin code in tumor-promoting and tumor-suppressor pathways. Furthermore, we review current UPS modulators and analyze the potential of UPS modulators as cancer therapy.
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Affiliation(s)
- Wenyan Yang
- College of Pharmaceutical Science, Zhejiang University of Technology, Huzhou 313200, China; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China
| | - Shiqun Wang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China
| | - Shengqiang Tong
- College of Pharmaceutical Science, Zhejiang University of Technology, Huzhou 313200, China
| | - Wei-Dong Zhang
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Jiang-Jiang Qin
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou 310022, China.
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DDTC-Cu(I) based metal-organic framework (MOF) for targeted melanoma therapy by inducing SLC7A11/GPX4-mediated ferroptosis. Colloids Surf B Biointerfaces 2023; 225:113253. [PMID: 36934611 DOI: 10.1016/j.colsurfb.2023.113253] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 02/22/2023] [Accepted: 03/06/2023] [Indexed: 03/09/2023]
Abstract
Disulfiram (DSF), a drug for alcohol withdrawal, has attracted extensive scientific attention due to its potential to treat cancer. The metabolite of DSF, diethyl dithiocarbamate (DDTC), forms a Cu-DDTC complex in vivo with copper ions, which has been shown to be a proteasome inhibitor with high antitumor activity. However, the in vivo stability of Cu-DDTC complexes remains a challenge. In this study, the nanomedicine Cu-BTC@DDTC with high antitumor activity was prepared by using the nanoscale metal-organic framework (MOF) Cu-BTC as a carrier and loading diethyldithiocarbamate (DDTC) through coordination interaction. The results showed that Cu-BTC@DDTC had high drug loading and adequate stability, and exhibited DDTC-Cu(I) chemical valence characteristics and polycrystalline structure features. In vitro cytocompatibility investigation and animal xenograft tumor model evaluation demonstrated the anti-cancer potential of Cu-BTC@DDTC, especially the combination of Cu-BTC@DDTC with low-dose cisplatin showed significant antitumor effect and biosafety. This study provides a feasible protocol for developing antitumor drugs based on the drug repurposing strategy.
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Yang Y, Li Y, Yang Q, Liu Z, Chang X, Yang H, Liu J, Li Z, Zuo D. FAT4 activation inhibits epithelial-mesenchymal transition (EMT) by promoting autophagy in H2228/Cer cells. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 40:64. [PMID: 36576661 DOI: 10.1007/s12032-022-01934-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 12/16/2022] [Indexed: 12/29/2022]
Abstract
As a tumor suppressor in lung cancer, FAT atypical cadherin 4 (FAT4) has a critical role in epithelial-mesenchymal transition (EMT). However, the role of FAT4 in ceritinib-resistant anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) EMT has not been reported. It is necessary to discuss the role of FAT4 in this process and its potential mechanism of interaction. We found that the expression level of FAT4 was downregulated markedly in ceritinib-resistant NCI-H2228 (H2228/Cer) cells. Jujuboside A, a FAT4 activator, diminished EMT and metastasis of H2228/Cer cells. Importantly, autophagy inhibition inverted the inhibitory effect of FAT4 activation on EMT. Furthermore, we found the regulatory action of FAT4 on autophagy was related to proteasome 26S subunit ubiquitin receptor and non-ATPase 4 (PSMD4) and proteasome 20S subunit beta 4 (PSMB4), and the inhibitory effect of autophagy on EMT might be related to ROS/NF-κB/IκB-α and Wnt/β-catenin pathways. In conclusion, FAT4 activation can inhibit the process of EMT in H2228/Cer cells by promoting autophagy, which provides a potential target for ceritinib-resistant ALK positive NSCLC therapy.
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Affiliation(s)
- Yuying Yang
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenhe District, 103 Wenhua Road, Shenyang, 110016, China
| | - Yang Li
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenhe District, 103 Wenhua Road, Shenyang, 110016, China
| | - Qian Yang
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenhe District, 103 Wenhua Road, Shenyang, 110016, China
| | - Zi Liu
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenhe District, 103 Wenhua Road, Shenyang, 110016, China
| | - Xing Chang
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenhe District, 103 Wenhua Road, Shenyang, 110016, China
| | - Huan Yang
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenhe District, 103 Wenhua Road, Shenyang, 110016, China
| | - Jingang Liu
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenhe District, 103 Wenhua Road, Shenyang, 110016, China
| | - Zengqiang Li
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenhe District, 103 Wenhua Road, Shenyang, 110016, China
| | - Daiying Zuo
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenhe District, 103 Wenhua Road, Shenyang, 110016, China.
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Agrawal MY, Gaikwad S, Srivastava S, Srivastava SK. Research Trend and Detailed Insights into the Molecular Mechanisms of Food Bioactive Compounds against Cancer: A Comprehensive Review with Special Emphasis on Probiotics. Cancers (Basel) 2022; 14:cancers14225482. [PMID: 36428575 PMCID: PMC9688469 DOI: 10.3390/cancers14225482] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 10/26/2022] [Accepted: 11/04/2022] [Indexed: 11/09/2022] Open
Abstract
In an attempt to find a potential cure for cancer, scientists have been probing the efficacy of the food we eat and its bioactive components. Over the decades, there has been an exponentially increasing trend of research correlating food and cancer. This review explains the molecular mechanisms by which bioactive food components exhibit anticancer effects in several cancer models. These bioactive compounds are mainly plant based or microbiome based. While plants remain the primary source of these phytochemicals, little is known about probiotics, i.e., microbiome sources, and their relationships with cancer. Thus, the molecular mechanisms underlying the anticancer effect of probiotics are discussed in this review. The principal mode of cell death for most food bioactives is found to be apoptosis. Principal oncogenic signaling axes such as Akt/PI3K, JAK/STAT, and NF-κB seem to be modulated due to these bioactives along with certain novel targets that provide a platform for further oncogenic research. It has been observed that probiotics have an immunomodulatory effect leading to their chemopreventive actions. Various foods exhibit better efficacy as complete extracts than their individual phytochemicals, indicating an orchestrated effect of the food components. Combining bioactive agents with available chemotherapies helps synergize the anticancer action of both to overcome drug resistance. Novel techniques to deliver bioactive agents enhance their therapeutic response. Such combinations and novel approaches are also discussed in this review. Notably, most of the food components that have been studied for cancer have shown their efficacy in vivo. This bolsters the claims of these studies and, thus, provides us with hope of discovering anticancer agents in the food that we eat.
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Affiliation(s)
- Manas Yogendra Agrawal
- Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
- Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
| | - Shreyas Gaikwad
- Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
- Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
| | | | - Sanjay K. Srivastava
- Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
- Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
- Correspondence: ; Tel.: +1-325-696-0464; Fax: +1-325-676-3875
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Cha HS, Lee HK, Park SH, Nam MJ. Acetylshikonin induces apoptosis of human osteosarcoma U2OS cells by triggering ROS-dependent multiple signal pathways. Toxicol In Vitro 2022; 86:105521. [DOI: 10.1016/j.tiv.2022.105521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/18/2022] [Accepted: 11/15/2022] [Indexed: 11/19/2022]
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Pereira M, Vale N. Saquinavir: From HIV to COVID-19 and Cancer Treatment. Biomolecules 2022; 12:biom12070944. [PMID: 35883499 PMCID: PMC9313067 DOI: 10.3390/biom12070944] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/01/2022] [Accepted: 07/04/2022] [Indexed: 11/25/2022] Open
Abstract
Saquinavir was the first protease inhibitor developed for HIV therapy, and it changed the standard of treatment for this disease to a combination of drugs that ultimately led to increased survival of this otherwise deadly condition. Inhibiting the HIV protease impedes the virus from maturing and replicating. With this in mind, since the start of the COVID-19 outbreak, the research for already approved drugs (mainly antivirals) to repurpose for treatment of this disease has increased. Among the drugs tested, saquinavir showed promise in silico and in vitro in the inhibition of the SARS-CoV-2 main protease (3CLpro). Another field for saquinavir repurposing has been in anticancer treatment, in which it has shown effects in vitro and in vivo in several types of cancer, from Kaposi carcinoma to neuroblastoma, demonstrating cytotoxicity, apoptosis, inhibition of cell invasion, and improvement of radiosensibility of cancer cells. Despite the lack of follow-up in clinical trials for cancer use, there has been a renewed interest in this drug recently due to COVID-19, which shows similar pharmacological pathways and has developed superior in silico models that can be translated to oncologic research. This could help further testing and future approval of saquinavir repurposing for cancer treatment.
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Affiliation(s)
- Mariana Pereira
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal;
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
| | - Nuno Vale
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal;
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
- Department of Community Medicine, Information and Health Decision Sciences (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- Correspondence:
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Koltai T, Reshkin SJ, Carvalho TMA, Di Molfetta D, Greco MR, Alfarouk KO, Cardone RA. Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma: A Physiopathologic and Pharmacologic Review. Cancers (Basel) 2022; 14:2486. [PMID: 35626089 PMCID: PMC9139729 DOI: 10.3390/cancers14102486] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a poor prognosis and inadequate response to treatment. Many factors contribute to this therapeutic failure: lack of symptoms until the tumor reaches an advanced stage, leading to late diagnosis; early lymphatic and hematic spread; advanced age of patients; important development of a pro-tumoral and hyperfibrotic stroma; high genetic and metabolic heterogeneity; poor vascular supply; a highly acidic matrix; extreme hypoxia; and early development of resistance to the available therapeutic options. In most cases, the disease is silent for a long time, andwhen it does become symptomatic, it is too late for ablative surgery; this is one of the major reasons explaining the short survival associated with the disease. Even when surgery is possible, relapsesare frequent, andthe causes of this devastating picture are the low efficacy ofand early resistance to all known chemotherapeutic treatments. Thus, it is imperative to analyze the roots of this resistance in order to improve the benefits of therapy. PDAC chemoresistance is the final product of different, but to some extent, interconnected factors. Surgery, being the most adequate treatment for pancreatic cancer and the only one that in a few selected cases can achieve longer survival, is only possible in less than 20% of patients. Thus, the treatment burden relies on chemotherapy in mostcases. While the FOLFIRINOX scheme has a slightly longer overall survival, it also produces many more adverse eventsso that gemcitabine is still considered the first choice for treatment, especially in combination with other compounds/agents. This review discusses the multiple causes of gemcitabine resistance in PDAC.
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Affiliation(s)
| | - Stephan Joel Reshkin
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Tiago M. A. Carvalho
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Daria Di Molfetta
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Khalid Omer Alfarouk
- Zamzam Research Center, Zamzam University College, Khartoum 11123, Sudan;
- Alfarouk Biomedical Research LLC, Temple Terrace, FL 33617, USA
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
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Zheng X, Wang Y, Wang D, Wan J, Qin X, Mu Z, Hu N. PSMC2 is overexpressed in glioma and promotes proliferation and anti-apoptosis of glioma cells. World J Surg Oncol 2022; 20:84. [PMID: 35287689 PMCID: PMC8922849 DOI: 10.1186/s12957-022-02533-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 02/18/2022] [Indexed: 11/19/2022] Open
Abstract
Background This study aims to investigate the effect of PSMC2 expression on the clinical prognosis of glioma patients and its molecular mechanism. Methods TCGA multi-tumor screening and survival analysis were combined to explore the differential expression of PSMC2 in multi-tumor. PSMC2 expression in glioma and normal tissues was detected by Western blot and RT-qPCR. Kaplan-Meier survival curve was used to visualize the effect of PSMC2 expression on the overall survival rate and disease-free survival rate of patients with glioma. The highly expressed cell line U343MG was selected to construct a PSMC2 knockdown model by siRNA transfection, and the effect of PSMC2 knockdown on cell proliferation ability was evaluated by CCK-8 assay. Gene-set enrichment analysis of PSMC2 co-expression genes was carried out to predict the molecular mechanism of their regulation of tumor cell phenotypes, and the analysis results were verified by flow cytometry and Western blot. Results Through broad-spectrum screening of 31 kinds of tumors, we found that PSMC2 was upregulated in most tumors, but PSMC2 was most significantly overexpressed in gliomas and correlated with poor prognosis in glioma patients. The results of Western blot and qRT-PCR showed that PSMC2 was significantly overexpressed in glioma tissues. Further survival analysis revealed that the overall survival and disease-free survival of patients with low PSMC2 expression were significantly better than that of patients with high PSMC2 expression. The proliferation of U343MG cells was significantly inhibited after PSMC2 knockdown. Enrichment analysis of PSMC2 co-expression genes indicated that PSMC2 affected the apoptosis process. The expression of apoptosis-related proteins also significantly changed following PSMC2 knockdown. Conclusions PSMC2 promotes the proliferation of glioma cells and inhibits the apoptosis, which is expected to be a potential therapeutic target for glioma. Supplementary Information The online version contains supplementary material available at 10.1186/s12957-022-02533-1.
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Mitra S, Anand U, Jha NK, Shekhawat MS, Saha SC, Nongdam P, Rengasamy KRR, Proćków J, Dey A. Anticancer Applications and Pharmacological Properties of Piperidine and Piperine: A Comprehensive Review on Molecular Mechanisms and Therapeutic Perspectives. Front Pharmacol 2022; 12:772418. [PMID: 35069196 PMCID: PMC8776707 DOI: 10.3389/fphar.2021.772418] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 11/18/2021] [Indexed: 12/26/2022] Open
Abstract
Piperine and piperidine are the two major alkaloids extracted from black pepper (Piper nigrum); piperidine is a heterocyclic moiety that has the molecular formula (CH2)5NH. Over the years, many therapeutic properties including anticancer potential of these two compounds have been observed. Piperine has therapeutic potential against cancers such as breast cancer, ovarian cancer, gastric cancer, gliomal cancer, lung cancer, oral squamous, chronic pancreatitis, prostate cancer, rectal cancer, cervical cancer, and leukemia. Whereas, piperidine acts as a potential clinical agent against cancers, such as breast cancer, prostate cancer, colon cancer, lung cancer, and ovarian cancer, when treated alone or in combination with some novel drugs. Several crucial signalling pathways essential for the establishment of cancers such as STAT-3, NF-κB, PI3k/Aκt, JNK/p38-MAPK, TGF-ß/SMAD, Smac/DIABLO, p-IκB etc., are regulated by these two phytochemicals. Both of these phytochemicals lead to inhibition of cell migration and help in cell cycle arrest to inhibit survivability of cancer cells. The current review highlights the pharmaceutical relevance of both piperine and piperidine against different types of cancers.
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Affiliation(s)
- Sicon Mitra
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
| | - Uttpal Anand
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
| | - Mahipal S Shekhawat
- Department of Plant Biology and Biotechnology, Kanchi Mamunivar Government Institute for Postgraduate Studies and Research, Lawspet, India
| | - Suchismita Chatterjee Saha
- Department of Zoology, Nabadwip Vidyasagar College (Affiliated to the University of Kalyani), Nabadwip, India
| | | | - Kannan R R Rengasamy
- Green Biotechnologies Research Centre of Excellence, University of Limpopo, Sovenga, South Africa
| | - Jarosław Proćków
- Department of Plant Biology, Institute of Environmental Biology, Wrocław University of Environmental and Life Sciences, Wrocław, Poland
| | - Abhijit Dey
- Ethnopharmacology and Natural Product Research Laboratory, Department of Life Sciences, Presidency University, Kolkata, India
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Golonko A, Pienkowski T, Swislocka R, Lazny R, Roszko M, Lewandowski W. Another look at phenolic compounds in cancer therapy the effect of polyphenols on ubiquitin-proteasome system. Eur J Med Chem 2019; 167:291-311. [PMID: 30776692 DOI: 10.1016/j.ejmech.2019.01.044] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 01/21/2019] [Accepted: 01/21/2019] [Indexed: 12/26/2022]
Abstract
Inhibitors of the ubiquitin-proteasome system (UPS) have been the object of research interests for many years because of their potential as anti-cancer agents. Research in this field is aimed at improving the specificity and safety of known proteasome inhibitors. Unfortunately, in vitro conditions do not reflect the processes taking place in the human body. Recent reports indicate that the components of human plasma affect the course of many signaling pathways, proteasome activity and the effectiveness of synthetic cytostatic drugs. Therefore, it is believed that the key issue is to determine the effects of components of the human diet, including effects of chemically active polyphenols on the ubiquitin-proteasome system activity in both physiological and pathological (cancerous) states. The following article summarizes the current knowledge on the direct and indirect synergistic and antagonistic effects between polyphenolic compounds present in the human diet and the efficiency of protein degradation via the UPS.
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Affiliation(s)
- Aleksandra Golonko
- Department of Food Analysis, Institute of Agricultural and Food Biotechnology, Rakowiecka 36, 02-532, Warsaw, Poland
| | - Tomasz Pienkowski
- Bialystok University of Technology, Faculty of Civil Engineering and Environmental Engineering, Department of Chemistry, Biology and Biotechnology, Wiejska 45E, 15-351, Bialystok, Poland
| | - Renata Swislocka
- Bialystok University of Technology, Faculty of Civil Engineering and Environmental Engineering, Department of Chemistry, Biology and Biotechnology, Wiejska 45E, 15-351, Bialystok, Poland
| | - Ryszard Lazny
- Institut of Chemistry, University of Bialystok, Ciolkowskiego 1K, 15-245, Bialystok, Poland
| | - Marek Roszko
- Department of Food Analysis, Institute of Agricultural and Food Biotechnology, Rakowiecka 36, 02-532, Warsaw, Poland
| | - Wlodzimierz Lewandowski
- Department of Food Analysis, Institute of Agricultural and Food Biotechnology, Rakowiecka 36, 02-532, Warsaw, Poland.
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Wongprayoon P, Govitrapong P. Melatonin attenuates methamphetamine-induced neuroinflammation through the melatonin receptor in the SH-SY5Y cell line. Neurotoxicology 2015; 50:122-30. [DOI: 10.1016/j.neuro.2015.08.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 08/07/2015] [Accepted: 08/10/2015] [Indexed: 01/13/2023]
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12
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Jiang X, Kanda T, Wu S, Nakamoto S, Nakamura M, Sasaki R, Haga Y, Wakita T, Shirasawa H, Yokosuka O. Hepatitis C Virus Nonstructural Protein 5A Inhibits MG132-Induced Apoptosis of Hepatocytes in Line with NF-κB-Nuclear Translocation. PLoS One 2015; 10:e0131973. [PMID: 26133378 PMCID: PMC4489642 DOI: 10.1371/journal.pone.0131973] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Accepted: 06/09/2015] [Indexed: 12/21/2022] Open
Abstract
Background Hepatitis C virus (HCV) infection is one of the major causes of cirrhosis and hepatocellular carcinoma. HCV nonstructural protein 5A (NS5A) is an attractive antiviral target and plays an important role in HCV replication as well as hepatocarcinogenesis. The aim of this study was to assess the effect of HCV NS5A protein in the abrogation of apoptotic cell death induced by the proteasome inhibitor MG132. Methods Apoptotic responses to MG132 and the expression of molecules involved in NF-κB signaling pathways in human hepatocytes were investigated with or without the expression of HCV NS5A. Results HCV NS5A protected HepG2 cells against MG132-induced apoptosis, in line with NF-κB-nuclear translocation. A similar NF-κB-nuclear translocation was observed in Huh7 cells infected with HCV JFH1. In agreement with this, after treatment with MG132, HCV NS5A could elevate the transcription of several NF-κB target genes such as BCL2 and BCLXL to inhibit MG132-induced apoptosis in hepatocytes. HCV HCV NS5A also enhanced phosphorylation of IκBα. Consistent with a conferred prosurvival advantage, HCV NS5A reduced MG132-induced poly(adenosine diphosphate-ribose) polymerase cleavage. Conclusions HCV NS5A expression enhances phosphorylation of IκBα, liberates NF-κB for nuclear translocation and downregulates MG132-induced apoptotic pathways in human hepatocytes. It is possible that the disruption of proteasome-associated apoptosis plays a role in the pathogenesis of HCV infection.
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Affiliation(s)
- Xia Jiang
- Departments of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Tatsuo Kanda
- Departments of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
- * E-mail:
| | - Shuang Wu
- Departments of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Shingo Nakamoto
- Departments of Molecular Virology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Masato Nakamura
- Departments of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Reina Sasaki
- Departments of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Yuki Haga
- Departments of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hiroshi Shirasawa
- Departments of Molecular Virology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Osamu Yokosuka
- Departments of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
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13
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The PERKs of damage-associated molecular patterns mediating cancer immunogenicity: From sensor to the plasma membrane and beyond. Semin Cancer Biol 2015; 33:74-85. [PMID: 25882379 DOI: 10.1016/j.semcancer.2015.03.010] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Revised: 03/17/2015] [Accepted: 03/19/2015] [Indexed: 12/20/2022]
Abstract
Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are emerging as key adaptation mechanisms in response to loss of proteostasis, with major cell autonomous and non-autonomous functions impacting cancer progression and therapeutic responses. In recent years, vital physiological roles of the ER in maintenance of proteostasis, Ca(2+) signaling and trafficking through the secretory pathway have emerged. Some of these functions have been shown to be decisive for mobilizing certain signals from injured/dying cancer cells in response to certain anticancer treatments, toward the plasma membrane and ultimately emit them into the extracellular environment, where they may act as danger signals. The spatiotemporally defined emission of these signals, better known as damage-associated molecular patterns (DAMPs), distinguishes this type of cancer cell death from physiological apoptosis, which is tolerogenic in nature, thereby enabling these dying cancer cells to alert the immune system and "re-activate" antitumor immunity. The emission of DAMPs, decisive for immunogenic cell death (ICD) and which include the ER chaperone calreticulin and ATP, is reliant on a danger signaling module induced by certain assorted anticancer treatments through oxidative-ER stress. The main focus of this review is to discuss the emerging role of ER-stress regulated pathways and processes in danger signaling thereby regulating the cancer cell-immune cell interface by the extracellular emission of DAMPs. In particular, we discuss signaling contexts existing upstream and around PERK, a major ER-stress sensor in ICD context, which have not been emphatically discussed in the context of antitumor immunity and ICD up until now. Finally, we briefly discuss the pros and cons of targeting PERK in the context of ICD.
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Yadav VR, Sahoo K, Awasthi V. Preclinical evaluation of 4-[3,5-bis(2-chlorobenzylidene)-4-oxo-piperidine-1-yl]-4-oxo-2-butenoic acid, in a mouse model of lung cancer xenograft. Br J Pharmacol 2014; 170:1436-48. [PMID: 24102070 DOI: 10.1111/bph.12406] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Revised: 07/30/2013] [Accepted: 08/29/2013] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND AND PURPOSE 4-[3,5-Bis(2-chlorobenzylidene)-4-oxo-piperidine-1-yl]-4-oxo-2-butenoic acid CLEFMA is a new anti-cancer molecule. Here, we investigated changes in apoptosis and inflammatory markers during CLEFMA-induced tumour suppression. EXPERIMENTAL APPROACH Lung adenocarcinoma H441 and A549, and normal lung fibroblast CCL151 cell lines were used, along with a xenograft model of H441 cells implanted in mice. Tumour tissues were analysed by immunoblotting, immunohistochemistry and/or biochemical assays. The ex vivo results were confirmed by performing selected assays in cultured cells. KEY RESULTS CLEFMA-induced cell death was associated with cleavage of caspases 3/9 and PARP. In vivo, CLEFMA treatment resulted in a dose-dependent suppression of tumour growth and (18) F-fluorodeoxyglucose uptake in tumours, along with a reduction in the expression of the proliferation marker Ki-67. In tumour tissue homogenates, the anti-apoptotic markers (cellular inhibitor of apoptosis protein-1(cIAP1), Bcl-xL, Bcl-2, and survivin) were inhibited and the pro-apoptotic Bax and BID were up-regulated. Further, CLEFMA decreased translocation of phospho-p65-NF-κB into the nucleus. In vitro, it inhibited the DNA-binding and transcriptional activity of NF-κB. It also reduced the expression of COX-2 in tumours and significantly depressed serum TNF-α and IL-6 levels. These effects of CLEFMA were accompanied by a reduced transcription and/or translation of the invasion markers VEGF, MMP9, MMP10, Cyclin D1 and ICAM-1. CONCLUSIONS AND IMPLICATIONS Overall, CLEFMA inhibited growth of lung cancer xenografts and this tumour suppression was associated with NF-κB-regulated anti-inflammatory and anti-metastatic effects.
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Affiliation(s)
- Vivek R Yadav
- Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
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15
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The role of Src protein in the process formation of PC12 cells induced by the proteasome inhibitor MG-132. Neurochem Int 2013; 63:413-22. [DOI: 10.1016/j.neuint.2013.07.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Revised: 07/05/2013] [Accepted: 07/23/2013] [Indexed: 11/20/2022]
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Han J, Liu L, Yue X, Chang J, Shi W, Hua Y. A binuclear complex constituted by diethyldithiocarbamate and copper(I) functions as a proteasome activity inhibitor in pancreatic cancer cultures and xenografts. Toxicol Appl Pharmacol 2013; 273:477-83. [PMID: 24060341 DOI: 10.1016/j.taap.2013.09.009] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Revised: 09/07/2013] [Accepted: 09/12/2013] [Indexed: 01/01/2023]
Abstract
It is a therapeutic strategy for cancers including pancreatic to inhibit proteasome activity. Disulfiram (DSF) may bind copper (Cu) to form a DSF-Cu complex. DSF-Cu is capable of inducing apoptosis in cancer cells by inhibiting proteasome activity. DSF is rapidly converted to diethyldithiocarbamate (DDTC) within bodies. Copper(II) absorbed by bodies is reduced to copper(I) when it enters cells. We found that DDTC and copper(I) could form a binuclear complex which might be entitled DDTC-Cu(I), and it had been synthesized by us in the laboratory. This study is to investigate the anticancer potential of this complex on pancreatic cancer and the possible mechanism. Pancreatic cancer cell lines, SW1990, PANC-1 and BXPC-3 were used for in vitro assays. Female athymic nude mice grown SW1990 xenografts were used as animal models. Cell counting kit-8 (cck-8) assay and flow cytometry were used for analyzing apoptosis in cells. A 20S proteasome assay kit was used in proteasome activity analysis. Western blot (WB) and immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were used in tumor sample analysis. The results suggest that DDTC-Cu(I) inhibit pancreatic cancer cell proliferation and proteasome activity in vitro and in vivo. Accumulation of ubiquitinated proteins, and increased p27 as well as decreased NF-κB expression were detected in tumor tissues of DDTC-Cu(I)-treated group. Our data indicates that DDTC-Cu(I) is an effective proteasome activity inhibitor with the potential to be explored as a drug for pancreatic cancer.
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Affiliation(s)
- Jinbin Han
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Clinical Center, Chinese Academy of Sciences/Xuhui Central Hospital, Shanghai 200031, China.
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Bu R, Hussain AR, Al-Obaisi KAS, Ahmed M, Uddin S, Al-Kuraya KS. Bortezomib inhibits proteasomal degradation of IκBα and induces mitochondrial dependent apoptosis in activated B-cell diffuse large B-cell lymphoma. Leuk Lymphoma 2013; 55:415-24. [PMID: 23697845 DOI: 10.3109/10428194.2013.806799] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Activated B-cell type lymphoma (ABC), a subgroup of diffuse large B-cell lymphoma (DLBCL), has a worse survival after upfront chemotherapy and is characterized by constitutive activation of the anti-apoptotic nuclear factor-κB (NFκB) pathway. The implication of NFκB inhibition in ABC has not yet been fully explored as a potential therapeutic target. Therefore, a panel of ABC cell lines was used to examine the effect of bortezomib, a proteasome inhibitor which blocks degradation of IκBα and consequently inhibits NFκB activity. Our data showed that bortezomib caused a dose-dependent growth inhibition and induction of apoptosis in all cell lines studied. We next determined the status of the NFκB pathway following bortezomib treatment and found that there was accumulation of IκBα without affecting its phosphorylation status at an early time point. Electrophoretic mobility shift assay showed that bortezomib treatment inhibited constitutive nuclear NFκB in ABC cell lines. Furthermore, treatment of ABC cell lines with bortezomib for 48 h also down-regulated the expression of NFκB-regulated gene products, such as IκBα, Bcl-2, Bcl-Xl, XIAP and survivin, leading to apoptosis via the mitochondrial apoptotic pathway. Altogether, these results suggest that NFκB may be a potential target for therapeutic intervention in DLBCL using proteasomal inhibitors such as bortezomib.
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Affiliation(s)
- Rong Bu
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center , Riyadh , Saudi Arabia
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18
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Benson EA, Goebl MG, Yang FC, Kapur R, McClintick J, Sanghani S, Clapp DW, Harrington MA. Loss of SIMPL compromises TNF-alpha-dependent survival of hematopoietic progenitors. Exp Hematol 2009; 38:71-81. [PMID: 19941935 DOI: 10.1016/j.exphem.2009.11.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2009] [Revised: 11/14/2009] [Accepted: 11/16/2009] [Indexed: 11/29/2022]
Abstract
OBJECTIVE Emerging work has revealed an integral role of the tumor necrosis factor-alpha (TNF-alpha) nuclear factor (NF)-kappaB pathway in the regulation of hematopoiesis. TNF-alpha inhibition of hematopoietic stem/progenitor cell growth involves type I TNF-alpha receptor (TNF-RI) and type II TNF-alpha receptor (TNF-RII). However, the role of TNF-RI vs TNF-RII in mediating this response is less clear. Full induction of NF-kappaB-dependent gene expression through TNF-RI requires the transcriptional coactivator SIMPL (substrate that interacts with mouse pelle-like kinase). To address the role of SIMPL in TNF-alpha-dependent signaling in hematopoiesis, endothelial cells and hematopoietic progenitors expressing SIMPL short hairpin RNA were characterized. MATERIAL AND METHODS In vitro gene expression and progenitor assays employing SIMPL short hairpin RNA were used to examine the requirement for SIMPL in TNF-alpha-dependent effects upon cytokine gene expression and hematopoietic progenitor cell growth. Competitive repopulation studies were used to extend these studies in vivo. RESULTS SIMPL is required for full TNF-RI-dependent expression of NF-kappaB-controlled cytokines in endothelial cells. Hematopoietic progenitor cell expansion is not affected if progenitors lacked SIMPL or if progenitors are treated with human TNF-alpha, which signals through TNF-RI. In the absence of SIMPL, human TNF-alpha leads to a dramatic decrease in progenitor cell expansion that is not due to apoptosis. Loss of SIMPL does not affect the activity of transforming growth factor-beta1 and interferon-gamma, other known suppressors of hematopoiesis. CONCLUSIONS Suppression of myeloid progenitor cell expansion requires signaling through TNF-RI and TNF-RII. Signals transduced through the TNF-alpha-TNF-RI-SIMPL pathway support hematopoietic progenitor cell survival, growth and differentiation.
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Affiliation(s)
- Eric A Benson
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5122, USA
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Uddin S, Ahmed M, Hussain AR, Jehan Z, Al-Dayel F, Munkarah A, Bavi P, Al-Kuraya KS. Bortezomib-mediated expression of p27Kip1 through S-phase kinase protein 2 degradation in epithelial ovarian cancer. J Transl Med 2009; 89:1115-27. [PMID: 19636294 DOI: 10.1038/labinvest.2009.75] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
S-phase kinase protein 2 (SKP2), an F-box protein, targets cell-cycle regulators including cyclin-dependent kinase inhibitor p27Kip1 through ubiquitin-mediated degradation. SKP2 is frequently overexpressed in variety of cancers. We investigated the function of SKP2 and its ubiquitin-proteasome pathway in a large series (156) of epithelial ovarian cancer (EOC) patient samples, using a panel of cell lines, and nude mouse model. Using immunohistochemistry, we detected SKP2 in 13.2% tumor samples and found that it was inversely associated with p27Kip1. EOC subset with high level of SKP2 and low level of p27Kip1 showed a strong association with proliferative marker Ki167 (P<0.0014). Treatment of EOC cell lines with bortezomib or expression of siRNA of SKP2 causes downregulation of SKP2 and accumulation of p27Kip1. In addition, co-treatment of EOC with bortezomib and cisplatin causes more pronounced effect on cell proliferation, apoptosis and downregulation of SKP2 leading to accumulation of p27kip1. Bortezomib treatment of EOC cells causes apoptosis by involving mitochondrial pathway, activation of caspases and downregulation of XIAP, and survivin. Finally, treatment of EOC cell line xenografts with bortezomib resulted in growth inhibition of tumors in nude mice through downregulation of SKP2 and accumulation of p27Kip1. Altogether, our results suggest that SKP2 and ubiquitin-proteasome pathway may be a potential target for therapeutic intervention for treatment of EOC.
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Affiliation(s)
- Shahab Uddin
- Department of Human Cancer Genomic Research, King Fahad National Centre for Children's Cancer and Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
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20
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Uddin S, Hussain A, Ahmed M, Belgaumi A, Al‐Dayel F, Ajarim D, Bavi P, Al‐Kuraya KS. S‐phase kinase protein 2 is an attractive therapeutic target in a subset of diffuse large B‐cell lymphoma. J Pathol 2008; 216:483-94. [PMID: 18850583 DOI: 10.1002/path.2433] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- S Uddin
- Department of Human Cancer Genomic Research, Research Center, King Fahad National Center for Children's Cancer & Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - A Hussain
- Department of Human Cancer Genomic Research, Research Center, King Fahad National Center for Children's Cancer & Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - M Ahmed
- Department of Human Cancer Genomic Research, Research Center, King Fahad National Center for Children's Cancer & Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - A Belgaumi
- Paediatric Haematology‐Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - F Al‐Dayel
- Department of Pathology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - D Ajarim
- King Faisal Cancer Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - P Bavi
- Department of Human Cancer Genomic Research, Research Center, King Fahad National Center for Children's Cancer & Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - KS Al‐Kuraya
- Department of Human Cancer Genomic Research, Research Center, King Fahad National Center for Children's Cancer & Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
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Uddin S, Ahmed M, Bavi P, El-Sayed R, Al-Sanea N, AbdulJabbar A, Ashari LH, Alhomoud S, Al-Dayel F, Hussain AR, Al-Kuraya KS. Bortezomib (Velcade) induces p27Kip1 expression through S-phase kinase protein 2 degradation in colorectal cancer. Cancer Res 2008; 68:3379-88. [PMID: 18451165 DOI: 10.1158/0008-5472.can-07-6109] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
S-phase kinase protein 2 (SKP2), an F-box protein, targets cell cycle regulators including cycle-dependent kinase inhibitor p27Kip1 via ubiquitin-mediated degradation. SKP2 is frequently overexpressed in a variety of cancers. We investigated the role of SKP2 and its ubiquitin-proteasome pathway in colorectal carcinoma using a panel of cell lines, clinical samples, and the NUDE mouse model. Using immunohistochemical analysis on a large tissue microarray of 448 samples, an inverse association of SKP2 expression with p27Kip1 protein levels was seen. A colorectal cancer (CRC) subset with high level of SKP2 and low level of p27Kip1 showed a decreased overall survival (P = 0.0057). Treatment of CRC cell lines with bortezomib or expression of small interfering RNA of SKP2 causes down-regulation of SKP2 and accumulation of p27Kip1. Furthermore, treatment of CRC cells with bortezomib causes apoptosis by involving the mitochondrial pathway and activation of caspases. In addition, treatment of CRC cells with bortezomib down-regulated the expression of XIAP, cIAP1, and survivin. Finally, treatment of CRC cell line xenografts with bortezomib resulted in growth inhibition of tumors in NUDE mice via down-regulation of SKP2 and accumulation of p27Kip1. Altogether, our results suggest that SKP2 and the ubiquitin-proteasome pathway may be potential targets for therapeutic intervention for treatment of CRC.
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Affiliation(s)
- Shahab Uddin
- Department of Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital, Riyadh, Saudi Arabia
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Abstract
Pancreatic cancer is one of the leading causes of cancer mortality in the United States. Current therapy for pancreatic cancer involves surgery, chemotherapy, and radiation therapy; however, the 5-year survival rate remains less than 5%. New strategies for treating pancreatic cancer include targeting intracellular signaling that provides survival advantages to cancer cells. One of these targets is the transcription factor nuclear factor (NF) kappaB, which is activated by a variety of mechanisms. Data demonstrate that increased NF-kappaB activity can promote growth and tumorigenesis, inhibit apoptosis, promote angiogenesis, promote invasion and metastasis, and promote chemoresistance in pancreatic cancer. This review explores the roles of NF-JB in these processes and examines the evidence that different NF-kappaB-inhibiting drugs can improve the treatment of pancreatic cancer.
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Weiss YG, Bromberg Z, Raj N, Raphael J, Goloubinoff P, Ben-Neriah Y, Deutschman CS. Enhanced heat shock protein 70 expression alters proteasomal degradation of IkappaB kinase in experimental acute respiratory distress syndrome. Crit Care Med 2007; 35:2128-38. [PMID: 17855826 DOI: 10.1097/01.ccm.0000278915.78030.74] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES Acute respiratory distress syndrome is a common and highly lethal inflammatory lung syndrome. We previously have shown that an adenoviral vector expressing the heat shock protein (Hsp)70 (AdHSP) protects against experimental sepsis-induced acute respiratory distress syndrome in part by limiting neutrophil accumulation in the lung. Neutrophil accumulation and activation is modulated, in part, by the nuclear factor-kappaB (NF-kappaB) signal transduction pathway. NF-kappaB activation requires dissociation/degradation of a bound inhibitor, IkappaBalpha. IkappaBalpha degradation requires phosphorylation by IkappaB kinase, ubiquitination by the SCFbeta-TrCP (Skp1/Cullin1/Fbox beta-transducing repeat-containing protein) ubiquitin ligase, and degradation by the 26S proteasome. We tested the hypothesis that Hsp70 attenuates NF-kappaB activation at multiple points in the IkappaBalpha degradative pathway. DESIGN Laboratory investigation. SETTING University medical center research laboratory. SUBJECTS Adolescent (200 g) Sprague-Dawley rats and murine lung epithelial-12 cells in culture. INTERVENTIONS Lung injury was induced in rats via cecal ligation and double puncture. Thereafter, animals were treated with intratracheal injection of 1) phosphate buffer saline, 2) AdHSP, or 3) an adenovirus expressing green fluorescent protein. Murine lung epithelial-12 cells were stimulated with tumor necrosis factor-alpha and transfected. NF-kappaB was examined using molecular biological tools. MEASUREMENTS AND MAIN RESULTS Intratracheal administration of AdHSP to rats with cecal ligation and double puncture limited nuclear translocation of NF-kappaB and attenuated phosphorylation of IkappaBalpha. AdHSP treatment reduced, but did not eliminate, phosphorylation of the beta-subunit of IkappaB kinase. In vitro kinase activity assays and gel filtration chromatography revealed that treatment of sepsis-induced lung injury with AdHSP induced fragmentation of the IkappaB kinase signalosome. This stabilized intermediary complexes containing IkappaB kinase components, IkappaBalpha, and NF-kappaB. Cellular studies indicate that although ubiquitination of IkappaBalpha was maintained, proteasomal degradation was impaired by an indirect mechanism. CONCLUSIONS Treatment of sepsis-induced lung injury with AdHSP limits NF-kappaB activation. This results from stabilization of intermediary NF-kappaB/IkappaBalpha/IkappaB kinase complexes in a way that impairs proteasomal degradation of IkappaBalpha. This novel mechanism by which Hsp70 attenuates an intracellular process may be of therapeutic value.
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Affiliation(s)
- Yoram G Weiss
- Department of Anesthesiology and Critical Care Medicine and the Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University School of Medicine, Jerusalem, Israel.
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Sun X, Gulyás M, Hjerpe A, Dobra K. Proteasome inhibitor PSI induces apoptosis in human mesothelioma cells. Cancer Lett 2006; 232:161-9. [PMID: 16458112 DOI: 10.1016/j.canlet.2005.02.022] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2004] [Revised: 01/09/2005] [Accepted: 02/12/2005] [Indexed: 11/27/2022]
Abstract
Malignant mesothelioma is an increasingly common tumor with an almost 100% mortality rate. It is refractory to conventional treatment. We have previously shown with SSH and microarray that the mRNA expression level of proteasome is higher in epithelioid mesothelioma cell lines than in sarcomatoid ones. This study evaluates the differential apoptotic effect of proteasome inhibitors on both of these mesothelioma sub-lines. Proteasome inhibitors show substantial anti-tumor activity in some tumor cells in vitro and in vivo, but the effects on mesothelioma cells has not been studied. The viability of mesothelioma cells was reduced in a dose- and time-dependent manner by the proteasome inhibitors tested; PSI was effective with a low dose, but higher concentrations were needed for calpain inhibitor I. The epithelioid mesothelioma cells are more sensitive to the inhibitors than the sarcomatoid ones, their IC50 after 24 h of treatment with PSI being 4 and 16 microm, respectively. Other mesothelioma cell lines show similar sensitivity. PSI seemed to decrease mesothelioma viability by inducing apoptosis, as verified by cell morphology, Western blotting analysis of caspase 3 cleavage, and flow-cytometric analysis. In conclusion, PSI, a representative agent that reduces viability and induces apoptosis of mesothelioma cells, might be useful in the treatment of patients with mesothelioma, especially of epithelioid phenotype.
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Affiliation(s)
- Xiaojuan Sun
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, F-46, Karolinska University Hospital, S-141 86 Huddinge, Stockholm, Sweden.
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Alberts SR, Foster NR, Morton RF, Kugler J, Schaefer P, Wiesenfeld M, Fitch TR, Steen P, Kim GP, Gill S. PS-341 and gemcitabine in patients with metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group (NCCTG) randomized phase II study. Ann Oncol 2005; 16:1654-61. [PMID: 16085692 DOI: 10.1093/annonc/mdi324] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND PS-341 is a proteasome inhibitor with preclinical activity in pancreatic cancer tumor models and synergistic activity with gemcitabine. This randomized phase II study determined the tumor response rate (RR) for PS-341 alone and the 6-month survival and RR for the combination of gemcitabine and PS-341 in patients with metastatic pancreatic adenocarcinoma. PATIENTS AND METHODS Patients were randomized to receive 3-week cycles of either arm A: PS-341 1.5 mg/m(2) i.v. bolus (over 3--5 s) on days 1, 4, 8 and 11 or arm B: PS-341 1.0 mg/m(2) (same as arm A otherwise) plus gemcitabine 1,000 mg/m(2) i.v. on days 1 and 8. Patients progressing on arm A were allowed to receive arm B treatment. RESULTS Arm A: 42 evaluable patients were enrolled with a confirmed RR of 0% (95% CI 0% to 8%), median survival of 2.5 months (95% CI 2.0-3.3), and median time to progression (TTP) of 1.2 months (95% CI 1.1--1.3). Twelve of 43 evaluable patients (28%) experienced at least one grade 4+ AE. Arm B: 39 evaluable patients yielded a 6-month survival rate of 41% (16/39, 95% CI 29.8% to 67.0%), median survival of 4.8 months (95% CI 2.4--7.4), median TTP of 2.4 months (95% CI 1.5--3.1), and confirmed RR of 10% (4 partial responses/0 complete responses, 95% CI 3% to 24%). Eleven of 43 evaluable patients (26%) experienced at least one grade 4+ AE. One patient had grade 5 hypotension. CONCLUSION The use of PS-341 alone or in combination with gemcitabine did not result in an overall survival and RR better than that expected for gemcitabine alone. Based on the lack of efficacy and the toxicity seen in our trial, there does not appear to be a role for PS-341 in pancreatic adenocarcinoma with either of the schedules used in this trial.
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Affiliation(s)
- S R Alberts
- Mayo Clinic and Mayo Foundation, Rochester, MN 55905.
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Pajonk F, van Ophoven A, McBride WH. Hyperthermia-induced proteasome inhibition and loss of androgen receptor expression in human prostate cancer cells. Cancer Res 2005; 65:4836-43. [PMID: 15930304 DOI: 10.1158/0008-5472.can-03-2749] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Prostate cancer is the second leading cause of death in men in western countries and is usually treated by surgery and/or radiotherapy. More recently, hyperthermia has been introduced into clinical trials investigating a possible effect in the first-line treatment of prostate cancer. However, the molecular mechanisms of hyperthermia are not completely understood. In this study, we investigated the effects of hyperthermia on proteasome function and its significance for signal transduction, cell death and androgen receptor (AR) expression in PC-3, LnCaP, and DU-145 human and TRAMP-C2 murine prostate cancer cells. Hyperthermia caused apoptosis and radiosensitization and decreased 26S proteasome activity in all three human cell lines to about 40% of untreated control cells. 20S proteasome activity was not affected by heat. Heat treatment inhibited constitutive and radiation-induced activation of nuclear factor kappaB caused by stabilization of IkappaB. Although stabilization of AR by proteasome inhibitors has been reported previously, AR protein levels in LnCaP cells decreased dramatically after heat. Our data suggest that inhibition of proteasome function and dependent signal transduction pathways might be a major molecular mechanisms of heat-induced apoptosis and radiosensitization. Hyperthermia abrogates AR expression in androgen-dependent cells and might thus promote malignant progression of prostate cancer.
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Affiliation(s)
- Frank Pajonk
- Department of Radiation Oncology, Experimental Division, David Geffen School of Medicine at UCLA, Los Angeles, California 90095-1714, USA.
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Pajonk F, van Ophoven A, Weissenberger C, McBride WH. The proteasome inhibitor MG-132 sensitizes PC-3 prostate cancer cells to ionizing radiation by a DNA-PK-independent mechanism. BMC Cancer 2005; 5:76. [PMID: 16001975 PMCID: PMC1177933 DOI: 10.1186/1471-2407-5-76] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2005] [Accepted: 07/07/2005] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND By modulating the expression levels of specific signal transduction molecules, the 26S proteasome plays a central role in determining cell cycle progression or arrest and cell survival or death in response to stress stimuli, including ionizing radiation. Inhibition of proteasome function by specific drugs results in cell cycle arrest, apoptosis and radiosensitization of many cancer cell lines. This study investigates whether there is also a concomitant increase in cellular radiosensitivity if proteasome inhibition occurs only transiently before radiation. Further, since proteasome inhibition has been shown to activate caspase-3, which is involved in apoptosis, and caspase-3 can cleave DNA-PKcs, which is involved in DNA-double strand repair, the hypothesis was tested that caspase-3 activation was essential for both apoptosis and radiosensitization following proteasome inhibition. METHODS Prostate carcinoma PC-3 cells were treated with the reversible proteasome inhibitor MG-132. Cell cycle distribution, apoptosis, caspase-3 activity, DNA-PKcs protein levels and DNA-PK activity were monitored. Radiosensitivity was assessed using a clonogenic assay. RESULTS Inhibition of proteasome function caused cell cycle arrest and apoptosis but this did not involve early activation of caspase-3. Short-time inhibition of proteasome function also caused radiosensitization but this did not involve a decrease in DNA-PKcs protein levels or DNA-PK activity. CONCLUSION We conclude that caspase-dependent cleavage of DNA-PKcs during apoptosis does not contribute to the radiosensitizing effects of MG-132.
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Affiliation(s)
- Frank Pajonk
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA90095-1714, USA
| | - Arndt van Ophoven
- Department of Urology, University Hospital Münster, Albert-Schweitzer-Straße 33, D-48149 Münster Germany
| | - Christian Weissenberger
- Department of Radiation Oncology, University Hospital Freiburg, Robert-Koch-Straße 3, D-79106 Freiburg, Germany
| | - William H McBride
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA90095-1714, USA
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Zhang WG, Yu JP, Wu QM, Tong Q, Li SB, Wang XH, Xie GJ. Inhibitory effect of ubiquitin-proteasome pathway on proliferation of esophageal carcinoma cells. World J Gastroenterol 2004; 10:2779-84. [PMID: 15334669 PMCID: PMC4572101 DOI: 10.3748/wjg.v10.i19.2779] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To investigate the inhibitory effect of ubiquitin-proteasome pathway (UPP) on proliferation of esophageal carcinoma cells.
METHODS: Esophageal carcinoma cell strain EC9706 was treated with MG-132 to inhibit its UPP specificity. Cell growth suppression was evaluated with 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. DNA synthesis was evaluated by 3H-thymidine (3H-TdR) incorporation. Morphologic changes of cells were observed under microscope. Activity of telomerase was examined by telomeric repeat amplification protocol (TRAP) of PCR-ELISA. Cell cycle and apoptosis were detected by flow cytometry (FCM). DNA fragment analysis was used to confirm the presence of apoptosis. Expression of p27kip1 was detected by immunocytochemical technique.
RESULTS: After exposed to MG-132, the growth and value of 3H-TdR incorporation of EC9706 cells were obviously inhibited. Cells became round, small and exfoliative under microscope. TRAP PCR-ELISA showed that light absorption of cells gradually decreased after exposed to 5 μmol/L of MG-132 for 24, 48, 72 and 96 h (P < 0.01). The percentage of cells at G0/G1 phase was increased and that at S and G2/M was decreased (P < 0.01). The rate of apoptotic cells treated with 5 μmol/L of MG-132 for 48 and 96 h was 31.7% and 66.4%, respectively. Agarose electrophoresis showed marked ladders. In addition, the positive signals of p27kip1 were located in cytoplasm and nuclei in MG-132 group in contrast to cytoplasm staining in control group.
CONCLUSION: MG-132 can obviously inhibit proliferation of EC9706 cells and induce apoptosis. The mechanisms include upregulation of p27kip1 expression, G1 arrest and depression of telomerase activity. The results indicate that inhibiting UPP is a novel strategy for esophageal carcinoma therapy.
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Affiliation(s)
- Wei-Guo Zhang
- Digestive Department, Taihe Hospital, Yunyang Medical College, Shiyan 442000, Hubei Province, China.
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29
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Zwergel T, Tahmatzopoulos A, Wullich B, Zwergel U, Stöckle M, Unteregger G. Proteasome inhibitors and their combination with antiandrogens: effects on apoptosis, cellular proliferation and viability of prostatic adenocarcinoma cell cultures. Prostate Cancer Prostatic Dis 2004; 7:138-43. [PMID: 15069423 DOI: 10.1038/sj.pcan.4500709] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The 26S proteasome is a ubiquitin-dependent proteolytic system that has been implicated in the regulation of cell cycle progression and apoptosis. We investigated the effects of the proteasome inhibitors MG115 and PSI alone or in combination with different concentrations of the antiandrogen hydroxyflutamide on the cellular proliferation, apoptosis and viability of 10 prostatic adenocarcinoma cell cultures. Treatment with both proteasome inhibitors resulted in apoptosis induction, whereas the combinations with hydroxyflutamide generally did not, with the exception of MG115 combined with 10(-7) M hydroxyflutamide. MG115 caused a significant decrease in cellular proliferation, as did the combinations of both proteasome inhibitors with hydroxyflutamide, whereas hydroxyflutamide alone was only effective at a concentration of 10(-5) M. Cellular viability was significantly reduced when both proteasome inhibitors were combined with 10(-5) M hydroxyflutamide. Although the results varied among different cell lines, we conclude that proteasome inhibitors are able to induce apoptosis and reduce cellular proliferation. They might prove effective as antineoplastic substances in prostatic adenocarcinoma alone or in combination with antiandrogens.
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Affiliation(s)
- T Zwergel
- Clinic and Department of Urology and Pediatric Urology, University of the Saarland, Germany.
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30
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Garg A, Aggarwal BB. Nuclear transcription factor-kappaB as a target for cancer drug development. Leukemia 2002; 16:1053-68. [PMID: 12040437 DOI: 10.1038/sj.leu.2402482] [Citation(s) in RCA: 352] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2001] [Accepted: 01/21/2002] [Indexed: 11/09/2022]
Abstract
Nuclear factor kappa B (NF-kappaB) is a family of inducible transcription factors found virtually ubiquitously in all cells. Since its discovery by Sen and Baltimore in 1986, much has been discovered about its mechanisms of activation, its target genes, and its function in a variety of human diseases including those related to inflammation, asthma, atherosclerosis, AIDS, septic shock, arthritis, and cancer. Due to its role in a wide variety of diseases, NF-kappaB has become one of the major targets for drug development. Here, we review our current knowledge of NF-kappaB, the possible mechanisms of its activation, its potential role in cancer, and various strategies being employed to target the NF-kappaB signaling pathway for cancer drug development.
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Affiliation(s)
- A Garg
- Cytokine Research Laboratory, Department of Bioimmunotherapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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31
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Affiliation(s)
- D L Mykles
- Department of Biology, Cell and Molecular Biology Program and Molecular, Cellular, and Integration Neurosciences Program, Colorado State University, Fort Collins, Colorado 80523, USA
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32
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Shah SA, Potter MW, Callery MP. Ubiquitin proteasome pathway: implications and advances in cancer therapy. Surg Oncol 2001; 10:43-52. [PMID: 11719028 DOI: 10.1016/s0960-7404(01)00018-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The degradation of most eukaryotic cells is controlled by the ubiquitin proteasome pathway. This pathway is responsible not only for the degradation of short and long-lived proteins but also tumor suppressors, transcription factors and cell cycle proteins. Altered degradation of these proteins is thought to promote cancer growth and spread. By contrast, inhibition of the proteasome would lead to cell cycle arrest and ultimately programmed cell death, or apoptosis. A structured review of the published literature examining the role of ubiquitin proteasome inhibition in cancer growth and regulation is provided. Advances in the development of proteasome inhibitors have allowed detailed investigation of this pathway in cancer growth. Relevant in vitro and in vivo studies of proteasome inhibition as pertains to cancer therapy are detailed. The ubiquitin proteasome pathway is critical in the degradation of proteins involved in cell cycle control and tumor growth. Proteasome inhibitors have been shown to arrest or retard cancer progression, by interfering with the ordered, temporal degradation of regulatory molecules. Clinical trials examining the agents have begun.
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Affiliation(s)
- S A Shah
- Department of Surgery, University of Massachusetts Medical Center, 55 Lake Avenue North, Worcester, MA 01655, USA
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Yoshimura S, Bondeson J, Brennan FM, Foxwell BM, Feldmann M. Role of NFkappaB in antigen presentation and development of regulatory T cells elucidated by treatment of dendritic cells with the proteasome inhibitor PSI. Eur J Immunol 2001; 31:1883-93. [PMID: 11433385 DOI: 10.1002/1521-4141(200106)31:6<1883::aid-immu1883>3.0.co;2-v] [Citation(s) in RCA: 89] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Dendritic cells (DC) are the most potent antigen-presenting cells for naive T cells, due to their high expression of MHC and costimulatory molecules, but relatively little is known about the biochemical pathways that regulate this function. We used the proteasome inhibitor N-benzyloxycarbonyl-Ile-Glu(O-tert-butyl)-Ala-leucinal (PSI) to demonstrate that DC antigen presentation is NFkappaB dependent. As PSI is not a specific inhibitor of NFkappaB, we reproduced this finding using a very specific approach, namely adenoviral gene transfer of IkappaBalpha, the naturally occurring inhibitor of NFkappaB. The mechanism for this inhibition of DC antigen presentation involves at least three aspects of antigen presenting function: down-regulation of HLA class II, down-regulation of CD86, and inhibition of the immunostimulatory cytokines IL-12 and TNF-alpha. In the light of the marked down-regulation of antigen-presentation cell function, it was of interest to investigate what effects exposure to PSI-treated DC might have on T cell function. It was found that immunological tolerance was induced, as challenge of T cells previously exposed to PSI-treated DC, with normal DC from the same donor did not restore their response, despite the presence of viable T cells. There were also changes in T cell surface markers, with down-regulation of CD3 and CD25 expression, and inhibition of the production of Th1 cytokines like IL-2 and IFN-gamma. These results demonstrates that NFkappaB is an effective target for blocking DC antigen presentation and inhibiting T cell-dependent immune responses, and this has implications for the development of therapeutic agents for use in multiple conditions, including transplantation, allergy and autoimmune diseases.
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Affiliation(s)
- S Yoshimura
- Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, London, GB
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Shah SA, Potter MW, McDade TP, Ricciardi R, Perugini RA, Elliott PJ, Adams J, Callery MP. 26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer. J Cell Biochem 2001; 82:110-22. [PMID: 11400168 DOI: 10.1002/jcb.1150] [Citation(s) in RCA: 173] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The 26S proteasome degrades proteins that regulate transcription factor activation, cell cycle progression, and apoptosis. In cancer, this may allow for uncontrolled cell division, promoting tumor growth, and spread. We examined whether selective inhibition of the 26S proteasome with PS-341, a dipeptide boronic acid analogue, would block proliferation and induce apoptosis in human pancreatic cancer. Proteasome inhibition significantly blocked mitogen (FCS) induced proliferation of BxPC3 human pancreatic cancer cells in vitro, while arresting cell cycle progression and inducing apoptosis by 24 h. Accumulation of p21(Cip1-Waf-1), a cyclin dependent kinase (CDK) inhibitor normally degraded by the 26S proteasome, occurred by 3 h and correlated with cell cycle arrest. When BxPC3 pancreatic cancer xenografts were established in athymic nu/nu mice, weekly administration of 1 mg/kg PS-341 significantly inhibited tumor growth. Both cellular apoptosis and p21(Cip1-Waf-1) protein levels were increased in PS-341 treated xenografts. Inhibition of tumor xenograft growth was greatest (89%) when PS-341 was combined with the tumoricidal agent CPT-11. Combined CPT-11/PS-341 therapy, but not single agent therapy, yielded highly apoptotic tumors, significantly inhibited tumor cell proliferation, and blocked NF-kappaB activation indicating this systemic therapy was effective at the cancer cell level. 26S proteasome inhibition may represent a new therapeutic approach against this highly resistant and lethal malignancy.
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Affiliation(s)
- S A Shah
- Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, USA
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36
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Abstract
This study demonstrates the ability of proteasome inhibitors (lactacystin, MG 115, MG 132) adenosine diphosphate to induce a time- and dose-dependent increase in poly-ADP-ribosylation (PAR) in the neural PC6 cell line, a subclone of PC12 cells. Elevated levels of PAR contribute to the toxicity associated with impaired proteasome activity, based on the ability of PAR inhibitors to ameliorate the toxicity associated with the application of lactacystin, MG 115, and MG 132. Proteasome inhibitors induced the accumulation of PAR and neuron death in primary hippocampal neuron cultures, which were both ameliorated by treatment with PAR inhibitors. Together, these data indicate a role for increased PAR in the toxicity associated with proteasome inhibition, and suggest that inhibitors of PAR may provide neuroprotection in conditions where proteasome inhibition occurs.
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Affiliation(s)
- J N Keller
- Sanders-Brown Center on Aging and Alzheimer's Disease Research Center, University of Kentucky Medical Center, Lexington, Kentucky
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