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Martín-García D, García-Aranda M, Redondo M. Therapeutic Potential of Clusterin Inhibition in Human Cancer. Cells 2024; 13:665. [PMID: 38667280 PMCID: PMC11049052 DOI: 10.3390/cells13080665] [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: 02/05/2024] [Revised: 03/11/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Clusterin (CLU) protein is involved in various pathophysiological processes including carcinogenesis and tumor progression. In recent years, the role of the secretory isoform has been demonstrated in tumor cells, where it inhibits apoptosis and favors the acquisition of resistance to conventional treatments used to treat cancer. To determine the possible therapeutic potential of inhibiting this protein, numerous studies have been carried out in this field. In this article, we present the existing knowledge to date on the inhibition of this protein in different types of cancer and analyze the importance it could have in the development of new therapies targeted against this disease.
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Affiliation(s)
- Desirée Martín-García
- Surgical Specialties, Biochemistry and Immunology Department, Faculty of Medicine, University of Málaga, 29010 Málaga, Spain;
- Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS), Instituto de Investigación Biomédica de Málaga (IBIMA), 29590 Málaga, Spain;
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina—IBIMA Plataforma BIONAND, 29590 Málaga, Spain
- Research and Innovation Unit, Hospital Costa del Sol, 29602 Marbella, Spain
| | - Marilina García-Aranda
- Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS), Instituto de Investigación Biomédica de Málaga (IBIMA), 29590 Málaga, Spain;
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina—IBIMA Plataforma BIONAND, 29590 Málaga, Spain
- Research and Innovation Unit, Hospital Costa del Sol, 29602 Marbella, Spain
| | - Maximino Redondo
- Surgical Specialties, Biochemistry and Immunology Department, Faculty of Medicine, University of Málaga, 29010 Málaga, Spain;
- Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS), Instituto de Investigación Biomédica de Málaga (IBIMA), 29590 Málaga, Spain;
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina—IBIMA Plataforma BIONAND, 29590 Málaga, Spain
- Research and Innovation Unit, Hospital Costa del Sol, 29602 Marbella, Spain
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Téllez T, Martin-García D, Redondo M, García-Aranda M. Clusterin Expression in Colorectal Carcinomas. Int J Mol Sci 2023; 24:14641. [PMID: 37834086 PMCID: PMC10572822 DOI: 10.3390/ijms241914641] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/25/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
Colorectal cancer is the third most diagnosed cancer, behind only breast and lung cancer. In terms of overall mortality, it ranks second due to, among other factors, problems with screening programs, which means that one of the factors that directly impacts survival and treatment success is early detection of the disease. Clusterin (CLU) is a molecular chaperone that has been linked to tumorigenesis, cancer progression and resistance to anticancer treatments, which has made it a promising drug target. However, it is still necessary to continue this line of research and to adjust the situations in which its use is more favorable. The aim of this paper is to review the current genetic knowledge on the role of CLU in tumorigenesis and cancer progression in general, and discuss its possible use as a therapeutic target in colorectal cancer.
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Affiliation(s)
- Teresa Téllez
- Surgical Specialties, Biochemistry and Immunology Department, Faculty of Medicine, University of Málaga, 29010 Malaga, Spain; (T.T.); (D.M.-G.)
- Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS), Instituto de Investigación Biomédica de Málaga (IBIMA), 29590 Malaga, Spain;
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina—IBIMA Plataforma BIONAND, 29590 Malaga, Spain
| | - Desirée Martin-García
- Surgical Specialties, Biochemistry and Immunology Department, Faculty of Medicine, University of Málaga, 29010 Malaga, Spain; (T.T.); (D.M.-G.)
- Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS), Instituto de Investigación Biomédica de Málaga (IBIMA), 29590 Malaga, Spain;
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina—IBIMA Plataforma BIONAND, 29590 Malaga, Spain
- Research and Innovation Unit, Hospital Costa del Sol, 29602 Marbella, Spain
| | - Maximino Redondo
- Surgical Specialties, Biochemistry and Immunology Department, Faculty of Medicine, University of Málaga, 29010 Malaga, Spain; (T.T.); (D.M.-G.)
- Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS), Instituto de Investigación Biomédica de Málaga (IBIMA), 29590 Malaga, Spain;
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina—IBIMA Plataforma BIONAND, 29590 Malaga, Spain
- Research and Innovation Unit, Hospital Costa del Sol, 29602 Marbella, Spain
| | - Marilina García-Aranda
- Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS), Instituto de Investigación Biomédica de Málaga (IBIMA), 29590 Malaga, Spain;
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina—IBIMA Plataforma BIONAND, 29590 Malaga, Spain
- Research and Innovation Unit, Hospital Costa del Sol, 29602 Marbella, Spain
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Gao G, Luan X. Diagnostic performance of clusterin in hepatocellular carcinoma: A meta-analysis. Int J Biol Markers 2022; 37:404-411. [PMID: 35645149 DOI: 10.1177/03936155221101206] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Introduction Clusterin (CLU) is a pleiotropic protein with numerous functions. It has recently attracted considerable attention owing to its association with cancer progression and metastasis. However, its role in hepatocellular carcinoma (HCC) has not been investigated. This meta-analysis is the first evaluation of the diagnostic performance of CLU in HCC. Methods Articles published in PubMed, EMBASE, Web of Science, Wanfang Data Knowledge Service Platform, and China Science and Technology Journal Database until January 2022 were searched. Studies that reported the usefulness of CLU for the differentiation of HCC and non-HCC (e.g., liver cirrhosis, chronic hepatitis, and other benign liver disease) patients were selected. Alpha-fetoprotein (AFP) was used as a positive control in this study. The sensitivity, specificity, diagnostic odds ratio (DOR), and area under the curve (AUC) were compared between CLU and AFP. Results Eight articles including 811 participants were included. The pooled sensitivity (95% confidence interval (CI)), specificity (95% CI), DOR (95% CI), and AUC (95% CI) were: 0.86 (0.78–0.91), 0.85 (0.75–0.91), 35 (13–94), and 0.92 (0.89–0.94) for CLU; 0.74 (0.67–0.81), 0.89 (0.79–0.94), 22 (8–61), and 0.87 (0.84–0.90) for AFP; 0.93 (0.88–0.96), 0.85 (0.68–0.94), 75 (21–262), and 0.95 (0.92–0.96) for CLU + AFP, respectively. Compared with AFP, CLU showed higher sensitivity, DOR, and AUC, as well as similar specificity. The combination of CLU and AFP resulted in higher sensitivity, DOR, and AUC. Conclusions Serum CLU is a better biomarker versus AFP for the diagnosis of HCC. The combination of CLU and AFP improved diagnostic performance.
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Affiliation(s)
- Ge Gao
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P.R. China
| | - Xuke Luan
- IBM Dalian Global Delivery Company Limited, Shanghai, P.R. China
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Souza MM, Coutinho-Camillo CM, de Paula FM, de Paula F, Bologna SB, Lourenço SV. Relevant proteins for the monitoring of engraftment phases after allogeneic hematopoietic stem cell transplantation. Clinics (Sao Paulo) 2022; 77:100134. [PMID: 36403426 PMCID: PMC9678684 DOI: 10.1016/j.clinsp.2022.100134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 10/10/2022] [Indexed: 11/18/2022] Open
Abstract
INTRODUCTION Hematopoietic Stem Cell Transplant (HSCT) has been successfully used as standard therapy for hematological disorders. After conditioning therapy, patients undergoing allogeneic HSCT, present three different phases of engraftment: early pre-engraftment, early post-engraftment, and late engraftment. Severe complications are associated with morbidity, mortality, and malignancies in these phases, which include effects on the oral cavity. OBJECTIVES The changes in the salivary composition after HSCT may contribute to identifying relevant proteins that could map differences among the phases of diseases, driven for personalized diagnostics and therapy. METHODS Unstimulated whole saliva was collected from patients submitted to HSCT. The samples were submitted to trypsin digestion for a Mass spectrometry analysis. MaxQuant processed the Data analysis, and the relevant expressed proteins were subjected to pathway and network analyses. RESULTS Differences were observed in the most identified proteins, specifically in proteins involved with the regulation of body fluid levels and the mucosal immune response. The heatmap showed a list of proteins exclusively expressed during the different phases of HSCT: HBB, KNG1, HSPA, FGB, APOA1, PFN1, PRTN3, TMSB4X, YWHAZ, CAP1, ACTN1, CLU and ALDOA. Bioinformatics analysis implicated pathways involved in protein processing in the endoplasmic reticulum, complement and coagulation cascades, apoptosis signaling, and cholesterol metabolism. CONCLUSION The compositional changes in saliva reflected the three phases of HSCT and demonstrated the usefulness of proteomics and computational approaches as a revolutionary field in diagnostic methods.
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Affiliation(s)
- Milena Monteiro Souza
- Department of Dermatology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil; Department of General Pathology, Faculdade de Odontologia da Universidade de São Paulo, São Paulo, SP, Brazil; International Research Center, A.C. Camargo Cancer Center, São Paulo, SP, Brazil
| | | | - Fabiana Martins de Paula
- Medical Research Laboratory, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
| | - Fernanda de Paula
- Department of General Pathology, Faculdade de Odontologia da Universidade de São Paulo, São Paulo, SP, Brazil
| | - Sheyla Batista Bologna
- Department of General Pathology, Faculdade de Odontologia da Universidade de São Paulo, São Paulo, SP, Brazil
| | - Silvia Vanessa Lourenço
- Department of General Pathology, Faculdade de Odontologia da Universidade de São Paulo, São Paulo, SP, Brazil; Medical Research Laboratory, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
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Beheshti Namdar A, Kabiri M, Mosanan Mozaffari H, Aminifar E, Mehrad-Majd H. Circulating Clusterin Levels and Cancer Risk: A Systematic Review and Meta-Analysis. Cancer Control 2022; 29:10732748211038437. [PMID: 35465749 PMCID: PMC9047800 DOI: 10.1177/10732748211038437] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Introduction The previous reports on clusterin (CLU) levels in various types of cancer
have been controversial and heterogeneous. The present meta-analysis has
aimed to evaluate the association between soluble CLU levels and the risk of
different human cancers based on observational studies. Methods A systematic literature review was conducted to determine the relevant
eligible studies in English language from health-related electronic
databases up to January 2021. Random effects models were used to calculate
the summary standard mean difference (SMD) with 95% confidence intervals
(CIs) to identify the correlation between CLU levels and cancer risk. The
meta-regression, sensitivity, Galbraith, and subgroup analyses were
performed to explore the source of between-study heterogeneity. Furthermore,
the funnel plot and Egger’s linear regression tests were carried out to
evaluate the risk of publication bias. Results According to 16 eligible articles, 3331 patients and 839 healthy controls
were included in our meta-analysis. Overall, the CLU levels were
significantly higher in various cancer cases compared to the healthy groups
(SMD = 1.50, 95% CI = 0.47–2.53). Moreover, subgroup analysis based on types
of cancer showed a significant correlation between CLU levels and the risk
of digestive system cancers (SMD = 1.54, 95% CI = 0.91–2.18,
P <0.001), especially in HCC (SMD = 1.89, 95% CI =
0.76–3.03, P = 0.001), and CRC (SMD = 1.63, 95% CI =
0.0–3.23, P = 0.048). Conclusion The present meta-analysis indicates a significant association of CLU levels
with the risk of digestive system cancers such as hepatocellular carcinoma
and colorectal cancer. Therefore, CLU can be monitored as a novel molecular
biomarker for the prognosis and diagnosis of various types of cancers
particularly in the digestive system.
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Affiliation(s)
- Ali Beheshti Namdar
- Department of Gastroenterology and Hepatology, Faculty of Medicine, 37552Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mona Kabiri
- School of Pharmacy, 37552Mashhad University of Medical Sciences, Mashhad, Iran.,Clinical Research Development Unit, Ghaem Hospital, 37552Mashhad University of Medical Sciences, Mashhad, Iran
| | - Homan Mosanan Mozaffari
- Department of Gastroenterology and Hepatology, Faculty of Medicine, 37552Mashhad University of Medical Sciences, Mashhad, Iran
| | - Elham Aminifar
- Student Research Committee, Islamic Azad University, Mashhad Branch, Mashhad, Iran
| | - Hassan Mehrad-Majd
- Cancer Molecular Pathology Research Center, 37552Mashhad University of Medical Sciences, Mashhad, Iran
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Praharaj PP, Patra S, Panigrahi DP, Patra SK, Bhutia SK. Clusterin as modulator of carcinogenesis: A potential avenue for targeted cancer therapy. Biochim Biophys Acta Rev Cancer 2020; 1875:188500. [PMID: 33385484 DOI: 10.1016/j.bbcan.2020.188500] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 12/14/2020] [Accepted: 12/24/2020] [Indexed: 12/30/2022]
Abstract
Clusterin (CLU) is an evolutionary conserved molecular chaperone present in different human tissues and fluids and established to be a significant cancer regulator. It controls several cancer-associated cellular events, including cancer cell proliferation, stemness, survival, metastasis, epithelial-mesenchymal transition, therapy resistance, and inhibition of programmed cell death to support cancer growth and recurrence. This multifunctional role of CLU makes it an ideal target for cancer control. More importantly, genetic and antisense-mediated (OGX-011) inhibition of CLU enhances the anticancer potential of different FDA-approved chemotherapeutic drugs at the clinical level, improving patient's survival. In this review, we have discussed the detailed mechanism of CLU-mediated modulation of different cancer-associated signaling pathways. We have also provided updated information on the current preclinical and clinical findings that drive trials in various cancer types for potential targeted cancer therapy.
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Affiliation(s)
- Prakash Priyadarshi Praharaj
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Srimanta Patra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Debasna Pritimanjari Panigrahi
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Samir Kumar Patra
- Epigenetics and Cancer Research Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Sujit Kumar Bhutia
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India.
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Merlotti A, Malizia AL, Michea P, Bonte PE, Goudot C, Carregal MS, Nuñez N, Sedlik C, Ceballos A, Soumelis V, Amigorena S, Geffner J, Piaggio E, Sabatte J. Aberrant fucosylation enables breast cancer clusterin to interact with dendritic cell-specific ICAM-grabbing non-integrin (DC-SIGN). Oncoimmunology 2019; 8:e1629257. [PMID: 31428526 PMCID: PMC6685524 DOI: 10.1080/2162402x.2019.1629257] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 05/30/2019] [Accepted: 06/01/2019] [Indexed: 01/26/2023] Open
Abstract
Clusterin is a glycoprotein able to mediate different physiological functions such as control of complement activation, promotion of unfolded protein clearance and modulation of cell survival. Clusterin is overexpressed in many types of cancers and a large body of evidence suggests that it promotes carcinogenesis and tumor progression. We have previously described a novel clusterin glycoform present in human semen, but not in serum, highly enriched in terminal fucose motifs. Here we show that human luminal breast cancer (LBC) clusterin also bears terminal fucosylated glycans, conferring clusterin the ability to interact with DC-SIGN, a C-type lectin receptor expressed by myeloid cells. This clusterin glycosylation pattern was absent or diminished in non-involved juxtatumoral tissue, suggesting that fucosylated clusterin might represent a cancer associated glycoform. We also found that DC-SIGN is expressed by luminal breast cancer intratumoral macrophages. Moreover, experiments performed in vitro using semen fucosylated clusterin and monocyte derived macrophages showed that the interaction of semen clusterin with DC-SIGN promoted a proangiogenic profile, characterized by a high production of VEGF, IL-8 and TNF-α. Our results reveal an unexpected complexity on the structure and function of secretory clusterin produced by tumors and suggest that fucosylated clusterin produced by luminal breast cancer cells might play a role in tumor progression by promoting the release of pro-angiogenic factors by intratumoral macrophages.
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Affiliation(s)
- Antonela Merlotti
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.,Institut Curie, PSL Research University, INSERM U932, Paris, France
| | - Alvaro López Malizia
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Paula Michea
- Institut Curie, PSL Research University, INSERM U932, Paris, France
| | | | - Christel Goudot
- Institut Curie, PSL Research University, INSERM U932, Paris, France
| | - María Sol Carregal
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Nicolás Nuñez
- Institut Curie, PSL Research University, INSERM U932, Paris, France
| | - Christine Sedlik
- Institut Curie, PSL Research University, INSERM U932, Paris, France
| | - Ana Ceballos
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Vassili Soumelis
- Institut Curie, PSL Research University, INSERM U932, Paris, France
| | | | - Jorge Geffner
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Eliane Piaggio
- Institut Curie, PSL Research University, INSERM U932, Paris, France
| | - Juan Sabatte
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
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Clusterin inhibition mediates sensitivity to chemotherapy and radiotherapy in human cancer. Anticancer Drugs 2017; 28:702-716. [PMID: 28471806 DOI: 10.1097/cad.0000000000000507] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Since its discovery in 1983, the protein clusterin (CLU) has been isolated from almost all human tissues and fluids and linked to the development of different physiopathological processes, including carcinogenesis and tumor progression. During the last few years, several studies have shown the cytoprotective role of secretory CLU in tumor cells, inhibiting their apoptosis and enhancing their resistance to conventional treatments including hormone depletion, chemotherapy, and radiotherapy. In an effort to determine the therapeutic potential that the inhibition of this protein could have on the development of new strategies for cancer treatment, numerous studies have been carried out in this field, with results, in most cases, satisfactory but sometimes contradictory. In this document, we summarize for the first time the current knowledge of the effects that CLU inhibition has on sensitizing tumor cells to conventional cancer treatments and discuss its importance in the development of new strategies against cancer.
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Nishikawa M, Miyake H, Gleave M, Fujisawa M. Effect of Targeting Clusterin Using OGX-011 on Antitumor Activity of Temsirolimus in a Human Renal Cell Carcinoma Model. Target Oncol 2017; 12:69-79. [PMID: 27526062 DOI: 10.1007/s11523-016-0448-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND It has not been well documented that the modulation of stress response mediates the efficacy of the mammalian target of rapamycin (mTOR) inhibitor in renal cell carcinoma (RCC). OBJECTIVE The objective of this study was to investigate whether the activity of the mTOR inhibitor temsirolimus against RCC could be enhanced by OGX-011, an antisense oligodeoxynucleotide (ODN) targeting the stress-activated chaperone clusterin. METHODS We investigated the efficacy of combined treatment with temsirolimus plus OGX-011 in a human RCC Caki-1 model focusing on the effects on apoptotic and autophagic pathways. RESULTS Although clusterin expression was increased by temsirolims, additional treatment of Caki-1 with OGX-011 significantly inhibited clusterin upregulation (p < 0.05). Combined treatment of temsirolimus and OGX-011 synergistically enhanced the sensitivity of Caki-1 to temsirolimus (p < 0.01), reducing the IC50 by approximately 50 %. Apoptotic changes were marked in Caki-1 following combined treatment with a sublethal dose of temsirolimus and OGX-011, accompanying the significant downregulation of Mcl-1 (p < 0.05), but not with either agent alone. Furthermore, this combined treatment markedly blocked the temsirolimus-induced activation of autophagy in Caki-1 (p < 0.01). In-vivo systemic administration of temsirolimus plus OGX-011 significantly inhibited the growth of Caki-1 tumors compared with that of temsirolimus plus control ODN (p < 0.05). CONCLUSIONS Silencing of clusterin using OGX-011 resulted in the further enhancement of proapoptotic activity as well as the marked attenuation of the autophagic pathway induced by temsirolimus in a human RCC model. Thus, the combined use of OGX-011 could be a promising strategy through the enhanced cytotoxic activity of temsirolimus against RCC.
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Affiliation(s)
- Masatomo Nishikawa
- Division of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Hideaki Miyake
- Department of Urology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan.
| | - Martin Gleave
- Vancouver Prostate Centre and University of British Columbia, Vancouver, British Columbia, V6H 3Z6, Canada
| | - Masato Fujisawa
- Division of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
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Wang X, Peng Y, Xie M, Gao Z, Yin L, Pu Y, Liu R. Identification of extracellular matrix protein 1 as a potential plasma biomarker of ESCC by proteomic analysis using iTRAQ and 2D-LC-MS/MS. Proteomics Clin Appl 2017; 11. [PMID: 28493612 DOI: 10.1002/prca.201600163] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Revised: 03/30/2017] [Accepted: 05/08/2017] [Indexed: 12/22/2022]
Abstract
PURPOSE This study was aimed to conduct a proteomics profiling analysis on plasma obtained from ESCC patients with the goal of identifying appropriate plasma protein biomarkers in the progression of ESCC. EXPERIMENTAL DESIGN Plasma from 28 ESCC patients and 28 healthy controls (HC) were analyzed by iTRAQ combined with 2D-LC-MS/MS. ProteinPilot software was used to identify the differentially expressed plasma proteins in ESCC compared to HC. Western blot was performed to verify the expression of selected proteins in 37 independent ESCC patients and 37 HC. Transwell and MTT assays were used to detect the biological function of ECM1 protein in vitro. RESULTS Nineteen (four upregulated and fifteen downregulated) proteins were identified as differentially expressed between ESCC and HC (p <0.05). Biological functions of these proteins are involved in cell adhesion, cell apoptosis and metabolic processes, visual perception and immune response. Of these, extracellular matrix 1 (ECM1) and lumican (LUM) were selected further confirmation by Western blot (p <0.05), which were consistent with the iTRAQ results. Furthermore, the migration ability of EC9706 cell line after overexpressing ECM1 was increased significantly (p <0.05). The proliferation ability of HUVEC cell was enhanced when treated with the culture supernatants of EC9706 overexpressed ECM1(p <0.05). CONCLUSION AND CLINICAL RELEVANCE This proteome analysis indicate that ECM1 is a potential novel plasma protein biomarker for the detection of primary ESCC and evaluation of neoplasms progression.
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Affiliation(s)
- Xianghu Wang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Yuan Peng
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Ming Xie
- North China Petroleum Bureau General Hospital, Renqiu, China
| | - Zhikui Gao
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Lihong Yin
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Yuepu Pu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Ran Liu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
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Edwards AY, Elgart A, Farrell C, Barnett-Griness O, Rabinovich-Guilatt L, Spiegelstein O. A population pharmacokinetic meta-analysis of custirsen, an antisense oligonucleotide, in oncology patients and healthy subjects. Br J Clin Pharmacol 2017; 83:1932-1943. [PMID: 28294391 DOI: 10.1111/bcp.13287] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 02/10/2017] [Accepted: 02/21/2017] [Indexed: 12/25/2022] Open
Abstract
AIMS Custirsen (OGX-011/TV-1011), a second-generation antisense oligonucleotide that reduces clusterin production, is under investigation with chemotherapy in prostate and lung cancer. This meta-analysis evaluated the population pharmacokinetics (PK) of custirsen in cancer patients and healthy subjects. METHODS The population PK analysis used custirsen plasma concentrations from five Phase 1 studies, one Phase 1/2 study, and one Phase 3 study in two stages. Cancer patients received multiple doses of custirsen (40-640 mg intravenously over 120 min) with chemotherapy; healthy subjects received single or multiple doses (320-640 mg). An interim population PK model was developed using a nonlinear mixed-effect approach incorporating data from four Phase 1 or 1/2 studies, followed by model refinement and inclusion of two Phase 1 and one Phase 3 studies. RESULTS The final model was developed with 5588 concentrations from 631 subjects with doses of 160-640 mg. Custirsen PK was adequately described by a three-compartment model with first-order elimination. For a representative 66-year-old individual with body weight 82 kg and serum creatinine level 0.933 mg dl-1 , the estimated typical (95% CI) parameter values were clearance (CL) = 2.36 (2.30-2.42) l h-1 , central volume of distribution (V1 ) = 6.08 (5.93-6.23) l, peripheral volume of distribution (V2 ) = 1.13 (1.01-1.25) l, volume of the second peripheral compartment (V3 ) = 15.8 (14.6-17.0) l, inter-compartmental clearance Q2 = 0.0755 (0.0689-0.0821) l h-1 , and Q3 = 0.0573 (0.0532-0.0614) l h-1 . Age, weight and serum creatinine were predictors of CL; age was a predictor of Q3 . CONCLUSION A population PK model for custirsen was successfully developed in cancer patients and healthy subjects, including covariates contributing to variability in custirsen PK.
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Affiliation(s)
| | - Anna Elgart
- Teva Pharmaceutical Industries Ltd., Netanya, Israel
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12
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eIF3f reduces tumor growth by directly interrupting clusterin with anti-apoptotic property in cancer cells. Oncotarget 2017; 7:18541-57. [PMID: 26988917 PMCID: PMC4951308 DOI: 10.18632/oncotarget.8105] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 02/05/2016] [Indexed: 01/07/2023] Open
Abstract
Clusterin is a secretory heterodimeric glycoprotein and the overexpression of secretory clusterin (sCLU) promotes cancer cell proliferation and reduces chemosensitivity. Therefore, sCLU might be an effective target for anticancer therapy. In the current study, we identified eIF3f as a novel CLU-interacting protein and demonstrated its novel function as a CLU inhibitor. The overexpression of eIF3f retarded cancer cell growth significantly and induced apoptosis. In addition, eIF3f interacted with the α-chain (1–227) of sCLU. This interaction blocked modification of psCLU, thereby decreasing the expression and secretion of α/β CLU. Consequently, the overexpression of eIF3f suppressed Akt and ERK signaling and subsequently depleted CLU expression. In addition, eIF3F stabilized p53, which increased the expression of p21 and Bax. Interestingly, the expression of Bax was increased without the activation of p53. eIF3f injected into a xenograft model of human cervical cancer in nude mice markedly inhibited tumor growth. The identification of this novel function of eIF3f as a sCLU inhibitor might open novel avenues for developing improved strategies for CLU-targeted anti-cancer therapies.
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Abstract
INTRODUCTION Clusterin (CLU) is a stress-activated, ATP-independent molecular chaperone, normally secreted from cells, that is up-regulated in Alzheimer disease and in many cancers. It plays important roles in protein homeostasis/proteostasis, inhibition of cell death pathways, and modulation of pro-survival signalling and transcriptional networks. Changes in the CLU gene locus are highly associated with Alzheimer disease, and many therapy-resistant cancers over-express CLU. The extensive post-translational processing and heterogeneous oligomerization of CLU have so far prevented any definitive structure determination. This in turn has meant that targeting CLU with small molecule inhibitors is challenging. Therefore, inhibiting CLU at the gene-expression level using siRNA or antisense is a valid approach to inhibit its function. Areas covered: This article reviews recent advances regarding the role of CLU in proteostasis, cellular trafficking, human diseases, and signalling pathways involved in oncogenesis. It addresses the rationale for CLU as a therapeutic target in cancer, and the current status of pre-clinical and clinical studies using CLU antisense inhibitor OGX011. Expert opinion: Discusses challenges facing the therapeutic targeting of CLU including rapid changes in the treatment landscape for prostate cancer with multiple new FDA approved drugs, selection of windows of intervention, and potential side effects when silencing CLU expression.
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Affiliation(s)
- Mark R Wilson
- a School of Biological Sciences , University of Wollongong , Wollongong , Australia
| | - Amina Zoubeidi
- b Department of Urologic Sciences, Vancouver Prostate Centre , University of British Columbia and Vancouver General Hospital , Vancouver , Canada
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14
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Current Status of Urinary Biomarkers for Detection and Surveillance of Bladder Cancer. Urol Clin North Am 2016; 43:47-62. [DOI: 10.1016/j.ucl.2015.08.005] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Mermelekas G, Vlahou A, Zoidakis J. SRM/MRM targeted proteomics as a tool for biomarker validation and absolute quantification in human urine. Expert Rev Mol Diagn 2015; 15:1441-54. [DOI: 10.1586/14737159.2015.1093937] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Muhammad LA, Saad F. The role of clusterin in prostate cancer: treatment resistance and potential as a therapeutic target. Expert Rev Anticancer Ther 2015; 15:1049-61. [DOI: 10.1586/14737140.2015.1064769] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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17
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Takeuchi A, Shiota M, Beraldi E, Thaper D, Takahara K, Ibuki N, Pollak M, Cox ME, Naito S, Gleave ME, Zoubeidi A. Insulin-like growth factor-I induces CLU expression through Twist1 to promote prostate cancer growth. Mol Cell Endocrinol 2014; 384:117-25. [PMID: 24491388 DOI: 10.1016/j.mce.2014.01.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2013] [Revised: 12/27/2013] [Accepted: 01/14/2014] [Indexed: 11/16/2022]
Abstract
Clusterin (CLU) is cytoprotective molecular chaperone that is highly expressed in castrate-resistant prostate cancer (CRPC). CRPC is also characterized by increased insulin-like growth factor (IGF)-I responsiveness which induces prostate cancer survival and CLU expression. However, how IGF-I induces CLU expression and whether CLU is required for IGF-mediated growth signaling remain unknown. Here we show that IGF-I induced CLU via STAT3-Twist1 signaling pathway. In response to IGF-I, STAT3 was phosphorylated, translocated to the nucleus and bound to the Twist1 promoter to activate Twist1 transcription. In turn, Twist1 bound to E-boxes on the CLU promoter and activated CLU transcription. Inversely, we demonstrated that knocking down Twist1 abrogated IGF-I induced CLU expression, indicating that Twist1 mediated IGF-I-induced CLU expression. When PTEN knockout mice were crossed with lit/lit mice, the resultant IGF-I deficiency suppressed Twist1 as well as CLU gene expression in mouse prostate glands. Moreover, both Twist1 and CLU knockdown suppressed prostate cancer growth accelerated by IGF-I, suggesting the relevance of this signaling not only in an in vitro, but also in an in vivo. Collectively, this study indicates that IGF-I induces CLU expression through sequential activation of STAT3 and Twist1, and suggests that this signaling cascade plays a critical role in prostate cancer pathogenesis.
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Affiliation(s)
- Ario Takeuchi
- The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Masaki Shiota
- The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Eliana Beraldi
- The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Daksh Thaper
- The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Kiyoshi Takahara
- The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Naokazu Ibuki
- The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Michael Pollak
- Department of Medicine and Oncology, McGill University, Montreal, Quebec, Canada
| | - Michael E Cox
- The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Seiji Naito
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Martin E Gleave
- The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Amina Zoubeidi
- The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
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Therapeutic applications of anti-sense mechanisms for the treatment of cancer. Mol Oncol 2013. [DOI: 10.1017/cbo9781139046947.085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
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Majidzadeh-A K, Gharechahi J. Plasma proteomics analysis of tamoxifen resistance in breast cancer. Med Oncol 2013; 30:753. [DOI: 10.1007/s12032-013-0753-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Accepted: 10/15/2013] [Indexed: 02/08/2023]
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Wang X, Luo L, Dong D, Yu Q, Zhao K. Clusterin plays an important role in clear renal cell cancer metastasis. Urol Int 2013; 92:95-103. [PMID: 24008723 DOI: 10.1159/000351923] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Accepted: 04/30/2013] [Indexed: 11/19/2022]
Abstract
OBJECTIVE Clusterin (CLU) is implicated in regulating clear renal cell carcinoma (CRCC) progression and metastasis, yet the mechanisms are not elucidated. In the present study, we explored the potential role of CLU in CRCC metastasis. METHODS Levels of CLU mRNA and CLU protein were measured by RT-PCR and immunohistochemistry analysis in 22 CRCC with metastasis and 22 without metastasis and 22 samples of normal kidney tissue. After CLU silencing and re-expression, the migration and invasion in vitro and in vivo of Caki-2 cells were determined by wound healing assay, transwell migration assay and pulmonary nodule assay, respectively. The expression of pERK1/2 and MMP-9 were detected by RT-PCR and Western blot assay. RESULTS We found a significant increase of CLU and CLU mRNA expression in CRCC, and the expression of CLU is strongly correlated in patients with metastatic disease. We discovered that CLU-rich Caki-2 cells displayed higher invasive ability which prompted us to investigate if CLU silencing could reduce the migration and invasion in Caki-2 cells. Compared with the vector-transfected cells, CLU knocked-down (CLUi) cells showed reduced migration and invasion in vitro, as well as decreased metastatic potential in experimental metastasis. Re-expression of CLU in CLUi cells restored the invasive phenotypes. We found that MMP-9 was downregulated in CLUi cells. We also discovered that levels of activated ERK1/2 correlated with the rich expression of CLU and MMP-9. CONCLUSION Our data suggest that CLU may regulate aggressive behavior of human CRCC cells through modulating ERK1/2 signaling and MMP-9 expression.
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Affiliation(s)
- Xinsheng Wang
- Department of Urology, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, PR China
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Biomarkers in bladder cancer: translational and clinical implications. Crit Rev Oncol Hematol 2013; 89:73-111. [PMID: 24029603 DOI: 10.1016/j.critrevonc.2013.08.008] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2013] [Revised: 07/23/2013] [Accepted: 08/13/2013] [Indexed: 01/15/2023] Open
Abstract
Bladder cancer is associated with high recurrence and mortality rates. These tumors show vast heterogeneity reflected by diverse morphologic manifestations and various molecular alterations associated with these disease phenotypes. Biomarkers that prospectively evaluate disease aggressiveness, progression risk, probability of recurrence and overall prognosis would improve patient care. Integration of molecular markers with conventional pathologic staging of bladder cancers may refine clinical decision making for the selection of adjuvant and salvage therapy. In the past decade, numerous bladder cancer biomarkers have been identified, including various tumor suppressor genes, oncogenes, growth factors, growth factor receptors, hormone receptors, proliferation and apoptosis markers, cell adhesion molecules, stromal factors, and oncoproteins. Recognition of two distinct pathways for urothelial carcinogenesis represents a major advance in the understanding and management of this disease. Nomograms for combining results from multiple biomarkers have been proposed to increase the accuracy of clinical predictions. The scope of this review is to summarize the major biomarker findings that may have translational and clinical implications.
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Abstract
Important inroads have been made in the understanding and treatment of metastatic prostate cancer in recent years. However, the need for agents targeting novel pathways remains ever present. One such area with promise is through apoptosis or programmed cell death. Many perturbations within the apoptotic process have been associated with treatment resistance and progression in castration-resistant prostate cancer; thus, therapeutic potential exists with agents that can restore an effective apoptotic response to cellular stressors. This article focuses on agents in clinical development targeting apoptosis through the intrinsic and extrinsic pathways. We review the current status of agents that intervene at the Bcl2 checkpoints, humanized antibodies to death receptors, agents that target the inhibitors of apoptosis proteins, mimetics of small mitochondria-derived activator of caspases, and antisense therapies targeting cytoprotective chaperones. Although single-agent activity has been demonstrated with some of these agents, the clinical development path forward will see them coupled with standard hormonal therapy and chemotherapy. OGX-011 (custirsen), which inhibits expression of the cytoprotective chaperone protein clusterin, is the most mature of these agents and is being tested in combination with chemotherapy in phase III clinical trials for castration-resistant prostate cancer, and results are eagerly awaited.
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Abstract
Over the last few years, five agents have demonstrated a survival benefit over a comparator treatment or placebo in the treatment of metastatic castration-resistant prostate cancer and have been approved by the US Food and Drug Administration: sipuleucel-T (a dendritic cell immunotherapy); cabazitaxel; abiraterone acetate and enzalutamide (both hormonal agents); and radium 223 (an alpha emitter). The development of these agents pivoted on whether patients had been treated with docetaxel, which remains the first-line chemotherapy of choice. To date, no combination of docetaxel and another active agent has demonstrated superiority to docetaxel alone despite numerous Phase III trials. Clusterin is a cytoprotective chaperone protein that is upregulated in response to various anticancer therapies. When overexpressed, clusterin interferes with apoptotic signaling, thereby promoting cell survival and conferring broad-spectrum resistance in cancer cell lines. Custirsen (OGX-011) is a second-generation 2'-methoxyethyl modified phosphorothioate antisense oligonucleotide that inhibits expression of clusterin. This review presents the preclinical and clinical data that provided the rationale for the combination of custirsen with chemotherapy in ongoing Phase III trials.
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Affiliation(s)
- Celestia S Higano
- Department of Medicine, University of Washington, and Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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Zielinski R, Chi KN. Custirsen (OGX-011): a second-generation antisense inhibitor of clusterin in development for the treatment of prostate cancer. Future Oncol 2013; 8:1239-51. [PMID: 23130925 DOI: 10.2217/fon.12.129] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Clusterin is a stress-induced cytoprotective chaperone that confers broad-spectrum treatment resistance and is overexpressed across a number of cancers. custirsen (OGX-011) is a promising novel second-generation antisense inhibitor of clusterin in clinical development. This article describes the mechanism of action and safety profile of OGX-011 and details the Phase I and II results in human solid organ malignancies. Two Phase III registration trials are currently under recruitment evaluating OGX-011 in combination with chemotherapy in patients with metastatic castration-resistant prostate cancer. These studies not only have the potential to significantly alter the standard of care in prostate cancer, but would also endorse a new class of targets and targeted therapy approach for cancer.
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Affiliation(s)
- Robert Zielinski
- Bristish Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia, V5Z 4E6, Canada
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FU YANXIA, LAI YINGRONG, WANG QIONGJUAN, LIU XINGYANG, HE WEIPENG, ZHANG HAIHONG, FAN CHUNYANG, YANG GUOFEN. Overexpression of clusterin promotes angiogenesis via the vascular endothelial growth factor in primary ovarian cancer. Mol Med Rep 2013; 7:1726-32. [DOI: 10.3892/mmr.2013.1436] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Accepted: 04/08/2013] [Indexed: 11/05/2022] Open
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Li J, Jia L, Zhao P, Jiang Y, Zhong S, Chen D. Stable knockdown of clusterin by vectorbased RNA interference in a human breast cancer cell line inhibits tumour cell invasion and metastasis. J Int Med Res 2012; 40:545-55. [PMID: 22613415 DOI: 10.1177/147323001204000216] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE Overexpression of the clusterin (CLU) gene occurs in breast cancer and is associated with lymph node metastasis. The present study explored the effect of CLU silencing on invasion and metastasis, and the relationship between CLU expression and the extracellular signal-regulated kinase (ERK) / matrix metalloproteinase-9 (MMP) signalling pathway in human breast cancer cells. METHODS A pcDNA3.1-based RNA interference approach was used to knockdown the CLU gene in MDA-231 cells (MDA-231-CLUi); control MDA-231 cells were transfected with an empty vector (MDA-231-Vec). Reverse transcription-polymerase chain reaction was used to assess CLU and MMP-9 mRNA levels, and Western blotting was used to analyse CLU, MMP-9 and ERK protein levels. Metastatic potential was evaluated using in vitro and in vivo models of invasion and metastasis. RESULTS Compared with MDA-231-Vec cells, the MDA-231-CLUi cells demonstrated reduced migration and invasion in vitro and decreased metastatic potential in vivo. Reintroduction and reexpression of the CLU gene into the MDA-231-CLUi cells restored the invasive phenotype. MMP-9 mRNA and protein levels were reduced in MDA-231-CLUi cells, and there was a correlation between activated ERK and CLU and MMP-9 protein levels. CONCLUSION CLU may regulate the aggressive behaviour of human breast cancer cells through modulation of ERK signalling and MMP9 expression.
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Affiliation(s)
- J Li
- Centre of Breast Disease, The Affiliated Hospital of QingDao University Medical College, QingDao University, QingDao, China
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Zoubeidi A, Gleave M. Small heat shock proteins in cancer therapy and prognosis. Int J Biochem Cell Biol 2012; 44:1646-56. [DOI: 10.1016/j.biocel.2012.04.010] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2012] [Revised: 02/27/2012] [Accepted: 04/11/2012] [Indexed: 01/05/2023]
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Ma X, Bai Y. IGF-1 activates the P13K/AKT signaling pathway via upregulation of secretory clusterin. Mol Med Rep 2012; 6:1433-7. [PMID: 23027041 DOI: 10.3892/mmr.2012.1110] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2012] [Accepted: 08/24/2012] [Indexed: 11/06/2022] Open
Abstract
Secretory clusterin (sCLU) is a type of stress-induced, pro-survival glycoprotein elevated in early-stage cancer. It enhances cancer cell survival and is associated with several types of cancer progression. In this study, we measured the PI3K/AKT signaling activity by determining the phosphorylation level of the AKT protein, namely pAKT. A549 human non-small cell lung carcinoma (NSCLC) cells were treated with insulin-like growth factor-1 (IGF-1) for various periods of time. The results showed that IGF-1 activated the PI3K/AKT signaling pathway in the A549 cells in a time-dependent manner. Western blot analysis was performed to determine the expression of sCLU protein in A549 cells treated with IGF-1. IGF-1 elevated the expression of sCLU. To determine whether sCLU is required for the IGF-1 activation of the PI3K/AKT signaling pathway, the A549 cells were treated with IGF-1 and sCLU antisense oligonuleotide (sCLU ASO). sCLU ASO blocked the IGF-1 activation of the PI3K/AKT signaling pathway. These results demonstrate that IGF-1 activates the P13K/AKT signaling pathway via the upregulation of sCLU. The present study implies that this pathway may uncover a new mechanism for cancer progression and reveal new targets for drug development in the treatment of NSCLC.
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Affiliation(s)
- Xiumei Ma
- Department of Radiation Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, P.R. China
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Lentivirus-mediated RNA interference of clusterin enhances the chemosensitivity of EJ bladder cancer cells to epirubicin in vitro. Mol Med Rep 2012; 6:1133-9. [DOI: 10.3892/mmr.2012.1017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2012] [Accepted: 06/18/2012] [Indexed: 11/05/2022] Open
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Clark GF, Grassi P, Pang PC, Panico M, Lafrenz D, Drobnis EZ, Baldwin MR, Morris HR, Haslam SM, Schedin-Weiss S, Sun W, Dell A. Tumor biomarker glycoproteins in the seminal plasma of healthy human males are endogenous ligands for DC-SIGN. Mol Cell Proteomics 2012; 11:M111.008730. [PMID: 21986992 PMCID: PMC3270097 DOI: 10.1074/mcp.m111.008730] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2011] [Revised: 09/06/2011] [Indexed: 01/15/2023] Open
Abstract
DC-SIGN is an immune C-type lectin that is expressed on both immature and mature dendritic cells associated with peripheral and lymphoid tissues in humans. It is a pattern recognition receptor that binds to several pathogens including HIV-1, Ebola virus, Mycobacterium tuberculosis, Candida albicans, Helicobacter pylori, and Schistosoma mansoni. Evidence is now mounting that DC-SIGN also recognizes endogenous glycoproteins, and that such interactions play a major role in maintaining immune homeostasis in humans and mice. Autoantigens (neoantigens) are produced for the first time in the human testes and other organs of the male urogenital tract under androgenic stimulus during puberty. Such antigens trigger autoimmune orchitis if the immune response is not tightly regulated within this system. Endogenous ligands for DC-SIGN could play a role in modulating such responses. Human seminal plasma glycoproteins express a high level of terminal Lewis(x) and Lewis(y) carbohydrate antigens. These epitopes react specifically with the lectin domains of DC-SIGN. However, because the expression of these sequences is necessary but not sufficient for interaction with DC-SIGN, this study was undertaken to determine if any seminal plasma glycoproteins are also endogenous ligands for DC-SIGN. Glycoproteins bearing terminal Lewis(x) and Lewis(y) sequences were initially isolated by lectin affinity chromatography. Protein sequencing established that three tumor biomarker glycoproteins (clusterin, galectin-3 binding glycoprotein, prostatic acid phosphatase) and protein C inhibitor were purified by using this affinity method. The binding of DC-SIGN to these seminal plasma glycoproteins was demonstrated in both Western blot and immunoprecipitation studies. These findings have confirmed that human seminal plasma contains endogenous glycoprotein ligands for DC-SIGN that could play a role in maintaining immune homeostasis both in the male urogenital tract and the vagina after coitus.
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Affiliation(s)
- Gary F. Clark
- From the ‡Division of Reproductive and Perinatal Research, Department of Obstetrics, Gynecology and Women's Health, University of Missouri, Columbia, Missouri 65211
| | - Paola Grassi
- §Division of Molecular Biosciences, Faculty of Natural Sciences, Imperial College London, SW7 2AZ, United Kingdom
| | - Poh-Choo Pang
- §Division of Molecular Biosciences, Faculty of Natural Sciences, Imperial College London, SW7 2AZ, United Kingdom
| | - Maria Panico
- §Division of Molecular Biosciences, Faculty of Natural Sciences, Imperial College London, SW7 2AZ, United Kingdom
| | - David Lafrenz
- From the ‡Division of Reproductive and Perinatal Research, Department of Obstetrics, Gynecology and Women's Health, University of Missouri, Columbia, Missouri 65211
| | - Erma Z. Drobnis
- ¶Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology and Women's Health, University of Missouri, Columbia, Missouri 65211
| | - Michael R. Baldwin
- ‖Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, Missouri 65211
| | - Howard R. Morris
- §Division of Molecular Biosciences, Faculty of Natural Sciences, Imperial College London, SW7 2AZ, United Kingdom
| | - Stuart M. Haslam
- §Division of Molecular Biosciences, Faculty of Natural Sciences, Imperial College London, SW7 2AZ, United Kingdom
| | - Sophia Schedin-Weiss
- **Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Wei Sun
- **Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Anne Dell
- §Division of Molecular Biosciences, Faculty of Natural Sciences, Imperial College London, SW7 2AZ, United Kingdom
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Expression of cell cycle-associated proteins in non-muscle-invasive bladder cancer: Correlation with intravesical recurrence following transurethral resection. Urol Oncol 2011; 29:495-501. [DOI: 10.1016/j.urolonc.2009.08.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2009] [Revised: 07/30/2009] [Accepted: 08/03/2009] [Indexed: 11/21/2022]
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Hassan MK, Watari H, Christenson L, Bettuzzi S, Sakuragi N. Intracellular clusterin negatively regulates ovarian chemoresistance: compromised expression sensitizes ovarian cancer cells to paclitaxel. Tumour Biol 2011; 32:1031-47. [PMID: 21761117 DOI: 10.1007/s13277-011-0207-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2011] [Accepted: 06/29/2011] [Indexed: 12/20/2022] Open
Abstract
Understanding the molecular events that lead to paclitaxel (TX) resistance is necessary to identify effective means to prevent chemoresistance. Previously, results from our lab revealed that secretory clusterin (CLU) form positively mediates TX response in ovarian cancer cells. Thus, we had interest to study the role of another non-secreted form (intracellular clusterin (i-CLU)) in chemo-response. Here, we provide evidences that i-CLU form localizes mainly in the nucleus and differentially expressed in the TX-responsive KF cells, versus TX-resistant, KF-TX, ovarian cancer cells and negatively regulate cellular chemo-response. I-CLU was cloned, by deleting the secretion-leading signaling peptide from full-length CLU cDNA, and transiently over-expressed in OVK-18 cells. Forced expression of truncated i-CLU was mainly detectable in the nuclei and significantly reduced cellular growth, accumulating cells in G1 phase which finally died through apoptosis. Importantly, compromised expression of i-CLU under an inducible promoter was tolerated and did not induce apoptosis but sensitized ovarian cancer cells to TX. We then demonstrated that this sensitization mechanism was cell cycle independent and relied on i-CLU/Ku70 binding probably due to controlling the free amount of Ku70 available for DNA repair in the nucleus. Results from CLU immunohistochemistry in ovarian tumor tissues verified the retardation of nuclear CLU staining in the recurrent tumor even though their primary counterparts showed nuclear CLU staining. Thus, the controversial data on CLU function in chemo-response/resistance may be explained by a shift in the pattern of CLU expression and intracellular localization as well when tumor acquires chemoresistance.
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Affiliation(s)
- Mohamed Kamel Hassan
- Department of Gynecology and Obstetrics, Graduate School of Medicine, Hokkaido University, Nishi Ku, Kita-15, Nishi-7, 060-8638, Sapporo, Japan.
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Chen Q, Wang Z, Zhang K, Liu X, Cao W, Zhang L, Zhang S, Yan B, Wang Y, Xia C. Clusterin confers gemcitabine resistance in pancreatic cancer. World J Surg Oncol 2011; 9:59. [PMID: 21609464 PMCID: PMC3120680 DOI: 10.1186/1477-7819-9-59] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2011] [Accepted: 05/24/2011] [Indexed: 12/19/2022] Open
Abstract
Objective To measure clusterin expression in pancreatic cancer tissues and cell lines and to evaluate whether clusterin confers resistance to gmcitabine in pancreatic cancer cells. Methods Immunohistochemistry for clusterin was performed on 50 primary pancreatic cancer tissues and 25 matched backgrounds, and clusterin expression in 5 pancreatic cancer cell lines was quantified by Western blot and PT-PCR. The correlation between clusterin expression level and gmcitabine IC50 in pancreatic cancer cell lines was evaluated. The effect of an antisense oligonucleotide (ASO) against clusterin(OGX-011) on gmcitabine resistance was evaluated by MTT assays. Xenograft model was used to demonstrate tumor growth. Results Pancreatic cancer tissues expressed significantly higher levels of clusterin than did normal pancreatic tissues (P < 0.01). Clusterin expression levels were correlated with gmcitabine resistance in pancreatic cancer cell lines, and OGX-011 significantly decreased BxPc-3 cells resistance to gmcitabine (P < 0.01). In vivo systemic administration of AS clusterin and gmcitabine significantly decreased the s.c. BxPC-3 tumor volume compared with mismatch control ODN plus gmcitabine. Conclusion Our finding that clusterin expression was significantly higher in pancreatic cancer than in normal pancreatic tissues suggests that clusterin may confer gmcitabine resistance in pancreatic cancer cells.
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Affiliation(s)
- Qingfeng Chen
- Affiliated Hospital of Medical College, QingDao University, RP China
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Li H, Li C, Wu H, Zhang T, Wang J, Wang S, Chang J. Identification of Apo-A1 as a biomarker for early diagnosis of bladder transitional cell carcinoma. Proteome Sci 2011; 9:21. [PMID: 21496341 PMCID: PMC3089778 DOI: 10.1186/1477-5956-9-21] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2010] [Accepted: 04/17/2011] [Indexed: 02/04/2023] Open
Abstract
Background Bladder transitional cell carcinoma (BTCC) is the fourth most frequent neoplasia in men, clinically characterized by high recurrent rates and poor prognosis. Availability of urinary tumor biomarkers represents a convenient alternative for early detection and disease surveillance because of its direct contact with the tumor and sample accessibility. Results We tested urine samples from healthy volunteers and patients with low malignant or aggressive BTCC to identify potential biomarkers for early detection of BTCC by two-dimensional electrophoresis (2-DE) coupled with mass spectrometry (MS) and bioinformatics analysis. We observed increased expression of five proteins, including fibrinogen (Fb), lactate dehydrogenase B (LDHB), apolipoprotein-A1 (Apo-A1), clusterin (CLU) and haptoglobin (Hp), which were increased in urine samples of patients with low malignant or aggressive bladder cancer. Further analysis of urine samples of aggressive BTCC showed significant increase in Apo-A1 expression compared to low malignant BTCC. Apo-A1 level was measured quantitatively using enzyme-linked immunosorbent assay (ELISA) and was suggested to provide diagnostic utility to distinguish patients with bladder cancer from controls at 18.22 ng/ml, and distinguish patients with low malignant BTCC from patients with aggressive BTCC in two-tie grading system at 29.86 ng/ml respectively. Further validation assay showed that Apo-A1 could be used as a biomarker to diagnosis BTCC with a sensitivity and specificity of 91.6% and 85.7% respectively, and classify BTCC in two-tie grading system with a sensitivity and specificity of 83.7% and 89.7% respectively. Conclusion Taken together, our findings suggest Apo-A1 could be a potential biomarker related with early diagnosis and classification in two-tie grading system for bladder cancer.
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Affiliation(s)
- Hongjie Li
- Department of Pathophysiology, HeBei United University, Tangshan, China
| | - Changying Li
- Research Laboratory for Tumor Immunity of Tianjin Urological Institute, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Huili Wu
- Tianjin Key Laboratory of Biomarkers for Occupational and Environmental Hazard of Chinese People's Armed Police Forces Medical College, Tianjin, China
| | - Ting Zhang
- Research Laboratory for Tumor Immunity of Tianjin Urological Institute, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Jin Wang
- Research Laboratory for Tumor Immunity of Tianjin Urological Institute, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Shixin Wang
- Tianjin Key Laboratory of Biomarkers for Occupational and Environmental Hazard of Chinese People's Armed Police Forces Medical College, Tianjin, China
| | - Jiwu Chang
- Research Laboratory for Tumor Immunity of Tianjin Urological Institute, Second Hospital of Tianjin Medical University, Tianjin, China
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Selevsek N, Matondo M, Sanchez Carbayo M, Aebersold R, Domon B. Systematic quantification of peptides/proteins in urine using selected reaction monitoring. Proteomics 2011; 11:1135-47. [PMID: 21360671 DOI: 10.1002/pmic.201000599] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2010] [Revised: 11/29/2010] [Accepted: 12/05/2010] [Indexed: 12/20/2022]
Abstract
The evaluation of biomarkers in bodily fluids necessitates the development of robust methods to quantify proteins in a complex background, using large sets of samples. The ability to multiplex numerous analytes in a single assay expedites the process. Liquid chromatography-mass spectrometry (LC-MS) analyses performed in selected reaction monitoring (SRM) in conjunction with stable isotope dilution MS present an effective way to detect and quantify biomarker candidates in bodily fluids. The strategy presented involves an initial qualification of predefined sets of proteins in urine. The technique was applied to detect and quantify peptides in urine samples as surrogates for a few endogenous proteins. Multiplexed assays were developed to analyze proteins associated with bladder cancer; a few exogenous proteins were added as internal standards. The sample preparation and the analytical protocols were optimized to ensure reproducibility, analytical precision, and quantification limits in the low nanogram per milliliter range. Analyses were performed using known amounts of isotopically labeled peptides. Systematic replication of the measurements indicated intra-assay and inter-assay variability, with CVs in the range of 10%. The differences measured for two targeted proteins were correlated with their level of expression in the corresponding tumors using immunohistochemistry.
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Affiliation(s)
- Nathalie Selevsek
- Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland
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Koupparis A, Casey R, Robinson M, Gleave ME. Novel targeted agents on the horizon for castration-resistant prostate cancer. Future Oncol 2010; 6:1883-95. [DOI: 10.2217/fon.10.145] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Androgen deprivation treatment in prostate cancer patients is well established; however, resistance to such treatment manifests itself by progression to castration-resistant prostate cancer (CRPC). Despite significant advances in treatment options for patients with CRPC, their prognosis remains poor. Resistance results from multiple processes that facilitate cancer cell growth and survival. Mechanisms underlying the shift to castrate resistance have been attributed to a complex interplay of clonal selection, reactivation of the androgen receptor axis despite castrate levels of serum testosterone, stress-induced prosurvival genes and cytoprotective chaperone networks and alternative mitogenic growth factor pathways. This article discusses several pathways involved in the development of CRPC, with a particular focus on those mechanisms that have led to the development of new targeted therapies.
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Affiliation(s)
- Anthony Koupparis
- The Vancouver Prostate Centre & Department of Urological Sciences, 2775 Laurel St., Vancouver, BC V6H 3Z6, Canada
| | - Rowan Casey
- The Vancouver Prostate Centre & Department of Urological Sciences, 2775 Laurel St., Vancouver, BC V6H 3Z6, Canada
| | - Michael Robinson
- The Vancouver Prostate Centre & Department of Urological Sciences, 2775 Laurel St., Vancouver, BC V6H 3Z6, Canada
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Ekici S, Eroğlu A, Doğan Ekici AI, Türkeri L. Clusterin immunoreactivity as a predictive factor for progression of non-muscle-invasive bladder carcinoma. Urol Int 2010; 86:31-5. [PMID: 21088377 DOI: 10.1159/000321692] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2010] [Accepted: 10/01/2010] [Indexed: 12/17/2022]
Abstract
INTRODUCTION There is a need for prognostic markers which can predict the subset of patients who will not respond sufficiently to conservative management in non-muscle-invasive bladder carcinoma. We analyzed the association of clusterin (CLU) with clinicopathological factors. MATERIALS AND METHODS Immunohistochemical CLU expression was investigated in paraffin-embedded archival tissues of initial transurethral resection specimens of 46 patients with non-muscle-invasive bladder carcinoma. The result was expressed as the proportion of the number of CLU-containing tumor cells to the total number of tumor cells detected in each slide and 'percent CLU expression' was calculated for each patient. RESULTS Of the 46 cases (35 male, 11 female), 18 were ≥ 65 years of age. CLU expression was significantly higher in male and elderly patients. Following the initial transurethral resection, 39 patients showed tumor recurrence, and progression was seen in 25 patients, of whom 17 progressed to muscle invasion during follow-up. Although there was no significant correlation between CLU expression and recurrence, significant correlation with overall progression and progression to muscle-invasive disease was observed in this cohort of patients (p = 0.001 and p = 0.014, respectively). Among the patients with progression to muscle invasion, 13 underwent radical cystectomy with pT2 tumor in 5 patients in the final pathology of surgical specimens and pT3 and higher in the remainder. CONCLUSIONS CLU immunoreactivity showed correlation with age, gender and progression, mainly progression to muscle invasion. Thus, CLU can be used as a molecular marker to predict the potential of progression to muscle-invasive disease in a particular tumor which in turn may prove useful in the decision-making process for early cystectomy without losing time with conservative management.
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Affiliation(s)
- Sinan Ekici
- Department of Urology, Maltepe University School of Medicine, Istanbul, Turkey.
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Behnsawy HM, Miyake H, Abdalla MA, Sayed MA, Ahmed AEFI, Fujisawa M. Expression of integrin proteins in non-muscle-invasive bladder cancer: significance of intravesical recurrence after transurethral resection. BJU Int 2010; 107:240-6. [DOI: 10.1111/j.1464-410x.2010.09534.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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Song ZM, Sun YL, Mao YS, Liu F, Zhou LP, Zhao XH. Clinical significance of clusterin expression in esophageal squamous cell carcinoma. Shijie Huaren Xiaohua Zazhi 2010; 18:1217-1221. [DOI: 10.11569/wcjd.v18.i12.1217] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of clusterin mRNA in esophageal squamous cell carcinoma (ESCC), measure preoperative and postoperative serum clusterin protein levels in ESCC patients, and evaluate their correlations with clinicopathological parameters in ESCC.
METHODS: The expression of full-length clusterin mRNA in ESCC tissue was detected by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). Serum clusterin level was measured by enzyme-linked immunosorbent assay (ELISA).
RESULTS: The expression of clusterin mRNA was significantly down-regulated in ESCC tissue compared with matched tumor-adjacent non-cancerous tissue. The median level of serum clusterin in postoperative ESCC patients was significantly higher than that in preoperative patients (25.71 mg/L vs 3.23 mg/L, P < 0.0001). The level of serum clusterin is correlated with tumor size, but not with age, gender, tumor differentiation, tumor grade, lymph node metastasis and biochemical parameters.
CONCLUSION: The expression of clusterin mRNA is down-regulated in ESCC. Serum clusterin level decreases in ESCC patients. Clusterin might be a potential tumor suppressor gene in ESCC. Dynamic measurement of serum clusterin level might aid to evaluate the progression of ESCC.
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Zoubeidi A, Chi K, Gleave M. Targeting the cytoprotective chaperone, clusterin, for treatment of advanced cancer. Clin Cancer Res 2010; 16:1088-93. [PMID: 20145158 PMCID: PMC2822877 DOI: 10.1158/1078-0432.ccr-09-2917] [Citation(s) in RCA: 104] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Many strategies used to kill cancer cells induce stress-responses that activate survival pathways to promote emergence of a treatment resistant phenotype. Secretory clusterin (sCLU) is a stress-activated cytoprotective chaperone up-regulated by many varied anticancer therapies to confer treatment resistance when overexpressed. sCLU levels are increased in several treatment recurrent cancers including castrate resistant prostate cancer, and therefore sCLU has become an attractive target in cancer therapy. sCLU is not druggable with small molecule inhibitors, therefore nucleotide-based strategies to inhibit sCLU at the RNA level are appealing. Preclinical studies have shown that antisense oligonucleotide (ASO) or siRNA knockdown of sCLU have preclinical activity in combination with hormone- and chemotherapy. Phase I and II clinical trial data indicate that the second generation ASO, custirsen (OGX-011), has biologic and clinical activity, suppressing sCLU expression in prostate cancer tissues by more than 90%. A randomized study comparing docetaxel-custirsen to docetaxel alone in men with castrate resistant prostate cancer reported improved survival by 7 months from 16.9 to 23.8 months. Strong preclinical and clinical proof-of-principle data provide rationale for further study of sCLU inhibitors in randomized phase III trials, which are planned to begin in 2010.
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Affiliation(s)
- Amina Zoubeidi
- Department of Urological Sciences, The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada
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Clusterin as a diagnostic and prognostic marker for transitional cell carcinoma of the bladder. Pathol Oncol Res 2009; 16:101-9. [PMID: 19757199 DOI: 10.1007/s12253-009-9196-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2009] [Accepted: 08/12/2009] [Indexed: 12/19/2022]
Abstract
We investigated the feasibility of profiling and measuring the concentration of clusterin in urine and serum for individuals with transitional cell carcinoma (TCC) of the bladder and comparing it with nontumor controls. In addition, we analyzed the correlation of expression of clusterin in specimens of TCC to various clinicopathologic parameters and prognosis of bladder cancer. Blood and urine samples were used from 68 patients with TCC of the bladder and from 61 patients with benign urological diseases. Enzyme-linked immunosorbent assays (ELISA) were performed for clusterin from serum and urine. Quantitation of clusterin mRNA was carried out in 68 bladder tumor specimens from radical cystectomy or transurethral resection and 26 normal bladder specimens from BPH patients by using RT-PCR method. Correlation for the expression of clusterin mRNA with clinicopathologic parameters was analyzed. Serum and urine clusterin was significantly higher in individuals with bladder cancer than control (p = 0.001). Sensitivity and specificity of serum and urine clusterin as a tumor marker for TCC of the bladder was found to be 80%, 91%, 87.1% and 96.7% respectively. Clusterin expression was significantly higher in TCC specimens than normal tissue specimens (P < 0.001). Expression of clusterin was significantly higher in patients with invasive TCC of the bladder than that in patients with superficial TCC and control (P < 0.001). Overexpression of clusterin mRNA was significantly associated with tumor recurrence and overall survival (p < 0.001). The recurrence-free survival time of patients with overexpression of clusterin was significantly shorter than that of patients with weak expression of clusterin (9.8 months vs. 35.2 months). Clusterin may be considered as a potential diagnostic and prognostic biomarker for bladder cancer using urine, serum and/or molecular biology techniques.
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Wei L, Xue T, Wang J, Chen B, Lei Y, Huang Y, Wang H, Xin X. Roles of clusterin in progression, chemoresistance and metastasis of human ovarian cancer. Int J Cancer 2009; 125:791-806. [DOI: 10.1002/ijc.24316] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Chayka O, Corvetta D, Dews M, Caccamo AE, Piotrowska I, Santilli G, Gibson S, Sebire NJ, Himoudi N, Hogarty MD, Anderson J, Bettuzzi S, Thomas-Tikhonenko A, Sala A. Clusterin, a haploinsufficient tumor suppressor gene in neuroblastomas. J Natl Cancer Inst 2009; 101:663-77. [PMID: 19401549 PMCID: PMC2720718 DOI: 10.1093/jnci/djp063] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2008] [Revised: 02/12/2009] [Accepted: 02/27/2009] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Clusterin expression in various types of human cancers may be higher or lower than in normal tissue, and clusterin may promote or inhibit apoptosis, cell motility, and inflammation. We investigated the role of clusterin in tumor development in mouse models of neuroblastoma. METHODS We assessed expression of microRNAs in the miR-17-92 cluster by real-time reverse transcription-polymerase chain reaction in MYCN-transfected SH-SY5Y and SH-EP cells and inhibited expression by transfection with microRNA antisense oligonucleotides. Tumor development was studied in mice (n = 66) that were heterozygous or homozygous for the MYCN transgene and/or for the clusterin gene; these mice were from a cross between MYCN-transgenic mice, which develop neuroblastoma, and clusterin-knockout mice. Tumor growth and metastasis were studied in immunodeficient mice that were injected with human neuroblastoma cells that had enhanced (by clusterin transfection, four mice per group) or reduced (by clusterin short hairpin RNA [shRNA] transfection, eight mice per group) clusterin expression. All statistical tests were two-sided. RESULTS Clusterin expression increased when expression of MYCN-induced miR-17-92 microRNA cluster in SH-SY5Y neuroblastoma cells was inhibited by transfection with antisense oligonucleotides compared with scrambled oligonucleotides. Statistically significantly more neuroblastoma-bearing MYCN-transgenic mice were found in groups with zero or one clusterin allele than in those with two clusterin alleles (eg, 12 tumor-bearing mice in the zero-allele group vs three in the two-allele group, n = 22 mice per group; relative risk for neuroblastoma development = 4.85, 95% confidence interval [CI] = 1.69 to 14.00; P = .005). Five weeks after injection, fewer clusterin-overexpressing LA-N-5 human neuroblastoma cells than control cells were found in mouse liver or bone marrow, but statistically significantly more clusterin shRNA-transfected HTLA230 cells (3.27%, with decreased clusterin expression) than control-transfected cells (1.53%) were found in the bone marrow (difference = 1.74%, 95% CI = 0.24% to 3.24%, P = .026). CONCLUSIONS We report, to our knowledge, the first genetic evidence that clusterin is a tumor and metastasis suppressor gene.
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Affiliation(s)
- Olesya Chayka
- Molecular Haematology and Cancer Biology Unit, UCL Institute of Child Health, 30 Guilford St, London WC1N 1EH, UK
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Rizzi F, Caccamo AE, Belloni L, Bettuzzi S. Clusterin is a short half-life, poly-ubiquitinated protein, which controls the fate of prostate cancer cells. J Cell Physiol 2009; 219:314-23. [PMID: 19137541 DOI: 10.1002/jcp.21671] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
The Clusterin (CLU) gene produces different forms of protein products, which vary in their biological properties and distribution within the cell. Both the extra- and intracellular CLU forms regulate cell proliferation and apoptosis. Dis-regulation of CLU expression occurs in many cancer types, including prostate cancer. The role that CLU plays in tumorigenesis is still unclear. We found that CLU over-expression inhibited cell proliferation and induced apoptosis in prostate cancer cells. Here we show that depletion of CLU affects the growth of PC-3 prostate cancer cells. Following siRNA targeting all CLU mRNA variants, all protein products quickly disappeared, inducing cell cycle progression and higher expression of specific proliferation markers (i.e., H3 mRNA, PCNA, and cyclins A, B1, and D) as detected by RT-qPCR and Western blot. Quite surprisingly, we also found that the turnover of CLU protein is very rapid and tightly regulated by ubiquitin-proteasome mediated degradation. Inhibition of protein synthesis by cycloheximide showed that CLU half-life is less than 2 h. CLU protein products were found poly-ubiquitinated by co-immuniprecipitation. Proteasome inhibition by MG132 caused stabilization and accumulation of all CLU protein products, including the nuclear form of CLU (nCLU), and committing cells to caspase-dependent death. In conclusion, proteasome inhibition may induce prostate cancer cell death through accumulation of nCLU, a potential tumor suppressor factor.
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Affiliation(s)
- Federica Rizzi
- Dipartimento di Medicina Sperimentale, Sezione di Biochimica, Biochimica Clinica e Biochimica dell'Esercizio Fisico, Parma, Italy
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Byrne JC, Downes MR, O'Donoghue N, O'Keane C, O'Neill A, Fan Y, Fitzpatrick JM, Dunn M, Watson RWG. 2D-DIGE as a strategy to identify serum markers for the progression of prostate cancer. J Proteome Res 2009; 8:942-57. [PMID: 19093873 DOI: 10.1021/pr800570s] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Prostate cancer is the most common solid organ malignancy affecting men in the United States and Western Europe. Currently, the main diagnostic tools used to look for evidence of prostate cancer include physical examination using digital rectal exam (DRE), serum concentrations of prostate specific antigen (PSA) and biopsy. However, due to the low specificity of PSA in differentiating prostate cancer from other benign conditions, many patients undergo overtreatment for their disease. There is an urgent need for additional markers to improve the diagnostic accuracy for early stages of prostate cancer. Proteomic analysis of serum has the potential to identify such markers. An initial discovery study has been completed using 12 serum samples from patients with different grades of prostate cancer (Gleason score 5 and 7) undergoing radical prostatectomy. Serum samples were subjected to immunoaffinity depletion and protein expression analysis using 2D-DIGE. Image analysis isolated 63 spots that displayed differential expression between the Gleason score 5 and 7 cohorts (p < 0.05), 13 of which were identified as statistically significant using two independent image analysis packages. Identification of differentially expressed spots was carried out using LC-MS/MS. Because of their functional relevance and potential significance with regards to prostate cancer progression, two of these proteins, pigment epithelium-derived factor (PEDF) and zinc-alpha2-glycoprotein (ZAG), have undergone extensive validation in serum and tissue samples from the original cohort and also from a larger independent cohort of patients. These results have indicated that PEDF is a more accurate predictor of early stage prostate cancer. We are confident that proteomics-based approaches have the potential to provide more insight into the underlying molecular mechanisms of the disease and also hold great promise for biomarker discovery in prostate cancer.
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Chandra P, Plaza JA, Zuo Z, Diwan AH, Koeppen H, Duvic M, Medeiros LJ, Prieto VG. Clusterin expression correlates with stage and presence of large cells in mycosis fungoides. Am J Clin Pathol 2009; 131:511-5. [PMID: 19289586 DOI: 10.1309/ajcph43zdvlsosnb] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Clusterin expression is common in systemic and cutaneous anaplastic large cell lymphoma (ALCL). Mycosis fungoides (MF) in large cell transformation can resemble ALCL. In this study, we immunohistochemically assessed for clusterin in 97 skin biopsy specimens, including 70 MF cases and 27 other cutaneous neoplasms including ALCL, peripheral T-cell lymphoma unspecified (PTCL), and lymphomatoid papulosis (LyP). Clusterin was positive in 36 (51%) of 70 cases of MF and correlated with clinical stage in 68 cases: 3 of 21 stage I, 11 of 20 stage II, and 23 of 27 stage III/IV. Clusterin expression also correlated with type of skin lesion (3/19 patch, 13/28 plaque, and 20/23 tumor/erythroderma) and number of large cells (6/30 small cell, 12/18 with increased large cells, and 18/22 with large cell transformation). Clusterin expression was not specific for MF as it also was positive in 3 of 3 cases of LyP, 2 of 2 systemic ALCL cases involving skin, 7 of 16 cutaneous ALCLs, and 1 of 6 PTCLs.
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Miyake H, Fujisawa M. Promise of antisense oligodeoxynucleotide-based therapy for bladder cancer. Expert Rev Anticancer Ther 2009; 8:1851-4. [PMID: 19046104 DOI: 10.1586/14737140.8.12.1851] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Clusterin interacts with Paclitaxel and confer Paclitaxel resistance in ovarian cancer. Neoplasia 2009; 10:964-72. [PMID: 18714397 DOI: 10.1593/neo.08604] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2008] [Revised: 06/17/2008] [Accepted: 06/20/2008] [Indexed: 01/17/2023] Open
Abstract
Optimal debulking followed by chemotherapy is the standard treatment of managing late-stage ovarian cancer, but chemoresistance is still a major problem. In this study, we compared expression profiles of primary tumor tissue from five long-term (>8 years) and five short-term (<2 years) ovarian cancer survivors and identified clusterin as one of the genes that were significantly up-regulated in short-term survivors. We then evaluated the prognostic significance of clusterin and its possible correlation with chemoresistance in ovarian cancer by immunohistostaining of clusterin in 62 tumor samples from patients with stage III, high-grade serous ovarian cancer. After adjusting for debulking status and age, Cox regression analyses showed that high levels of clusterin expression correlate with poor survival (hazard ratio, 1.07; 95% confidence interval, 1.002-1.443; P = .04). We also investigated clusterin in paclitaxel resistance by modulating the endogenous clusterin expression in ovarian cancer cells and treating the cells with purified clusterin. Results indicate that high-clusterin-expressing ovarian cancer cells are more resistant to paclitaxel. Moreover, exposing ovarian cancer cells to exogenous clusterin increases cells' resistance to paclitaxel. Finally, using size exclusion chromatography and fluorescently labeled paclitaxel, we demonstrated that clusterin binds to paclitaxel. In summary, our findings suggest that high levels of clusterin expression increase paclitaxel resistance in ovarian cancer cells by physically binding to paclitaxel, which may prevent paclitaxel from interacting with microtubules to induce apoptosis. Thus, clusterin is a potential therapeutic target for enhancing chemoresponsiveness in patients with a high-level clusterin expression.
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