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Zebene ED, Lombardi R, Pucci B, Medhin HT, Seife E, Di Gennaro E, Budillon A, Woldemichael GB. Proteomic Analysis of Biomarkers Predicting Treatment Response in Patients with Head and Neck Cancers. Int J Mol Sci 2024; 25:12513. [PMID: 39684225 DOI: 10.3390/ijms252312513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 11/18/2024] [Accepted: 11/19/2024] [Indexed: 12/18/2024] Open
Abstract
Head and neck cancers (HNCs) are the sixth most commonly diagnosed cancer and the eighth leading cause of cancer-related mortality worldwide, with squamous cell carcinoma being the most prevalent type. The global incidence of HNCs is steadily increasing, projected to rise by approximately 30% per year by 2030, a trend observed in both developed and undeveloped countries. This study involved serum proteomic profiling to identify predictive clinical biomarkers in cancer patients undergoing chemoradiotherapy (CRT). Fifteen HNC patients at Tikur Anbessa Specialized Hospital, Radiotherapy (RT) center in Addis Ababa were enrolled. Serum samples were collected before and after RT, and patients were classified as responders (R) or non-responders (NR). Protein concentrations in the serum were determined using the Bradford assay, followed by nano-HPLC-MS/MS for protein profiling. Progenesis QI for proteomics identified 55 differentially expressed proteins (DEPs) between R and NR, with a significance of p < 0.05 and a fold-change (FC) ≥ 1.5. The top five-up-regulated proteins included MAD1L1, PSMC2, TRIM29, C5, and SERPING1, while the top five-down-regulated proteins were RYR1, HEY2, HIF1A, TF, and CNN3. Notably, about 16.4% of the DEPs were involved in cellular responses to DNA damage from cancer treatments, encompassing proteins related to deoxyribonucleic acid (DNA) damage sensing, checkpoint activation, DNA repair, and apoptosis/cell cycle regulation. The analysis of the relative abundance of ten proteins with high confidence scores identified three DEPs: ADIPOQ, HEY2, and FUT10 as potential predictive biomarkers for treatment response. This study highlighted the identification of three potential predictive biomarkers-ADIPOQ, HEY2, and FUT10-through serum proteomic profiling in HNC patients undergoing RT, emphasizing their significance in predicting treatment response.
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Affiliation(s)
- Emeshaw Damtew Zebene
- Nuclear Medicine Unit, Department of Internal Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa 9086, Ethiopia
- Department of Microbial Cellular and Molecular Biology, College of Natural and Computational Sciences, Addis Ababa University, Addis Ababa 9086, Ethiopia
| | - Rita Lombardi
- Experimental Animal Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
| | - Biagio Pucci
- Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
| | - Hagos Tesfay Medhin
- Nuclear Medicine Unit, Department of Internal Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa 9086, Ethiopia
| | - Edom Seife
- Radiotherapy Center, College of Health Sciences, Addis Ababa University, Addis Ababa 9086, Ethiopia
| | - Elena Di Gennaro
- Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
| | - Alfredo Budillon
- Scientific Directorate, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
| | - Gurja Belay Woldemichael
- Department of Microbial Cellular and Molecular Biology, College of Natural and Computational Sciences, Addis Ababa University, Addis Ababa 9086, Ethiopia
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Meng YW, Liu JY. Pathological and pharmacological functions of the metabolites of polyunsaturated fatty acids mediated by cyclooxygenases, lipoxygenases, and cytochrome P450s in cancers. Pharmacol Ther 2024; 256:108612. [PMID: 38369063 DOI: 10.1016/j.pharmthera.2024.108612] [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: 10/30/2023] [Revised: 01/19/2024] [Accepted: 02/05/2024] [Indexed: 02/20/2024]
Abstract
Oxylipins have garnered increasing attention because they were consistently shown to play pathological and/or pharmacological roles in the development of multiple cancers. Oxylipins are the metabolites of polyunsaturated fatty acids via both enzymatic and nonenzymatic pathways. The enzymes mediating the metabolism of PUFAs include but not limited to lipoxygenases (LOXs), cyclooxygenases (COXs), and cytochrome P450s (CYPs) pathways, as well as the down-stream enzymes. Here, we systematically summarized the pleiotropic effects of oxylipins in different cancers through pathological and pharmacological aspects, with specific reference to the enzyme-mediated oxylipins. We discussed the specific roles of oxylipins on cancer onset, growth, invasion, and metastasis, as well as the expression changes in the associated metabolic enzymes and the associated underlying mechanisms. In addition, we also discussed the clinical application and potential of oxylipins and related metabolic enzymes as the targets for cancer prevention and treatment. We found the specific function of most oxylipins in cancers, especially the underlying mechanisms and clinic applications, deserves and needs further investigation. We believe that research on oxylipins will provide not only more therapeutic targets for various cancers but also dietary guidance for both cancer patients and healthy humans.
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Affiliation(s)
- Yi-Wen Meng
- CNTTI of the Institute of Life Sciences & Department of Anesthesia of the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Chongqing 400016, China
| | - Jun-Yan Liu
- CNTTI of the Institute of Life Sciences & Department of Anesthesia of the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Chongqing 400016, China; College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
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Al-saraireh YM, Alshammari FOFO, Abu-azzam OH, Al-dalain SM, Al-sarayra YM, Haddad M, Makeen H, Al-Qtaitat A, Almermesh M, Al-sarayreh SA. Targeting Cytochrome P450 Enzymes in Ovarian Cancers: New Approaches to Tumor-Selective Intervention. Biomedicines 2023; 11:2898. [PMID: 38001897 PMCID: PMC10669316 DOI: 10.3390/biomedicines11112898] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/14/2023] [Accepted: 10/19/2023] [Indexed: 11/26/2023] Open
Abstract
Over the past decade, there have been significant developments in treatment for ovarian cancer, yet the lack of targeted therapy with few side effects still represents a major issue. The cytochrome P450 (CYP) enzyme family plays a vital role in the tumorigenesis process and metabolism of drugs and has a negative impact on therapy outcomes. Gaining more insight into CYP expression is crucial to understanding the pathophysiology of ovarian cancer since many isoforms are essential to the metabolism of xenobiotics and steroid hormones, which drive the disease's development. To the best of our knowledge, no review articles have documented the intratumoral expression of CYPs and their implications in ovarian cancer. Therefore, the purpose of this review is to provide a clear understanding of differential CYP expression in ovarian cancer and its implications for the prognosis of ovarian cancer patients, together with the effects of CYP polymorphisms on chemotherapy metabolism. Finally, we discuss opportunities to exploit metabolic CYP expression for the development of novel therapeutic methods to treat ovarian cancer.
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Affiliation(s)
- Yousef M. Al-saraireh
- Department of Pharmacology, Faculty of Medicine, Mutah University, P.O. Box 7, Al-Karak 61710, Jordan;
| | - Fatemah O. F. O. Alshammari
- Department of Medical Lab Technology, Faculty of Health Sciences, The Public Authority for Applied Education and Training, Shuwaikh 15432, Kuwait;
| | - Omar H. Abu-azzam
- Department of Obstetrics and Gynecology, Faculty of Medicine, Mutah University, P.O. Box 7, Al-Karak 61710, Jordan;
| | - Sa’ed M. Al-dalain
- Department of Pharmacology, Faculty of Medicine, Mutah University, P.O. Box 7, Al-Karak 61710, Jordan;
| | - Yahya M. Al-sarayra
- Al-Karak Governmental Hospital, Ministry of Health, P.O. Box 86, Al-Karak 11118, Jordan;
| | - Mansour Haddad
- Faculty of Pharmacy, Yarmouk University, Irbid 21163, Jordan;
| | - Hafiz Makeen
- Department of Clinical Pharmacy, College of Pharmacy, Jazan University, Jazan P.O. Box 114, Saudi Arabia;
| | - Aiman Al-Qtaitat
- Department of Anatomy and Histology, Faculty of Medicine, Mutah University, P.O. Box 7, Al-Karak 61710, Jordan;
- Faculty of Dentistry, Zarqa University, Zarqa 13110, Jordan
| | - Mohammad Almermesh
- Department of Pharmacology, College of Pharmacy, University of Hail, Hail 2440, Saudi Arabia;
| | - Sameeh A. Al-sarayreh
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Mutah University, P.O. Box 7, Al-Karak 61710, Jordan;
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Al-saraireh YM, Alshammari FOFO, Satari AO, Al-mahdy YS, Almuhaisen GH, Abu-azzam OH, Uwais AN, Abufraijeh SM, Al-Kharabsheh AM, Al-dalain SM, Al-Qtaitat A, Al-Tarawneh F, Al Shuneigat JM, Al-Sarayreh SA. Cytochrome 4Z1 Expression Connotes Unfavorable Prognosis in Ovarian Cancers. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58091263. [PMID: 36143940 PMCID: PMC9502355 DOI: 10.3390/medicina58091263] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/10/2022] [Accepted: 09/12/2022] [Indexed: 02/05/2023]
Abstract
Background and Objective: Ovarian cancer is a leading cause of death in females. Since its treatment is challenging and causes severe side effects, novel therapies are urgently needed. One of the potential enzymes implicated in the progression of cancers is Cytochrome 4Z1 (CYP4Z1). Its expression in ovarian cancer remains unknown. Therefore, the current study aims to assess CYP4Z1 expression in different subtypes of ovarian cancers. Materials and Methods: Immunohistochemistry was used to characterize CYP4Z1 expression in 192 cases of ovarian cancers along with eight normal ovarian tissues. The enzyme’s association with various clinicopathological characteristics and survival was determined. Results: CYP4Z1 was strongly expressed in 79% of ovarian cancers, compared to negative expression in normal ovarian samples. Importantly, significantly high CYP4Z1 expres-sion was determined in patients with advanced-stage cancer and a high depth of invasion (p < 0.05). Surprisingly, CYP4Z1 expression was significantly associated with a low patient survival rate. Univariate analysis revealed that patient survival was strongly associated with CYP4Z1 expression, tumor stage, depth of invasion, and lymph node metastasis (p < 0.05). Multivariate analysis showed that only CYP4Z1 expression was significantly associated with patient survival (p < 0.05). Conclusions: CYP4Z1 expression is correlated with shorter patient survival and has been identified as an independent indicator of a poor prognosis for ovarian cancer patients.
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Affiliation(s)
- Yousef M. Al-saraireh
- Department of Pharmacology, Faculty of Medicine, Mutah University, P.O. Box 7, Al-Karak 61710, Jordan
- Correspondence:
| | - Fatemah O. F. O. Alshammari
- Department of Medical Lab Technology, Faculty of Health Sciences, The Public Authority for Applied Education and Training, Shuwaikh 15432, Kuwait
| | - Anas O. Satari
- Faculty of Medicine, Mutah University, P.O. Box 7, Al-Karak 61710, Jordan
| | - Yanal S. Al-mahdy
- Faculty of Medicine, Mutah University, P.O. Box 7, Al-Karak 61710, Jordan
| | - Ghadeer H. Almuhaisen
- Department of Microbiology and Pathology, Faculty of Medicine, Mutah University, P.O. Box 7, Al-Karak 61710, Jordan
| | - Omar H. Abu-azzam
- Department of Obstetrics and Gynecology, Faculty of Medicine, Mutah University, P.O. Box 7, Al-Karak 61710, Jordan
| | - Ala N. Uwais
- Department of Obstetrics and Gynecology, Faculty of Medicine, Mutah University, P.O. Box 7, Al-Karak 61710, Jordan
| | - Seham M. Abufraijeh
- Department of Obstetrics and Gynecology, Faculty of Medicine, Mutah University, P.O. Box 7, Al-Karak 61710, Jordan
| | - Ahlam M. Al-Kharabsheh
- Department of Obstetrics and Gynecology, Faculty of Medicine, Mutah University, P.O. Box 7, Al-Karak 61710, Jordan
| | - Sa’ed M. Al-dalain
- Department of Pharmacology, Faculty of Medicine, Mutah University, P.O. Box 7, Al-Karak 61710, Jordan
| | - Aiman Al-Qtaitat
- Department of Anatomy and Histology, Faculty of Medicine, Mutah University, P.O. Box 7, Al-Karak 61710, Jordan
- Faculty of Dentistry, Zarqa University, Zarqa 13110, Jordan
| | - Fatima Al-Tarawneh
- Department of Allied Medical Sciences, Faculty of Al-Karak, Al-Balqa Applied University, P.O. Box 7, Al-Karak 61710, Jordan
| | - Jehad M. Al Shuneigat
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Mutah University, P.O. Box 7, Al-Karak 61710, Jordan
| | - Sameeh A. Al-Sarayreh
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Mutah University, P.O. Box 7, Al-Karak 61710, Jordan
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Ni L, Sun P, Ai M, Kong L, Xu R, Li J. Berberine inhibited the formation of metastasis by intervening the secondary homing of colorectal cancer cells in the blood circulation to the lung and liver through HEY2. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 104:154303. [PMID: 35802997 DOI: 10.1016/j.phymed.2022.154303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/17/2022] [Accepted: 06/26/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Metastasis is the leading cause of death in patients with colorectal cancer (CRC). The 5-year survival rate of CRC patients in whom the cancer has spread to distant sites is 13.5%. The most common sites of CRC metastasis are liver and lung. The principal therapies for CRC metastatic disease are surgery, but its benefits are limited. PURPOSE This study aimed to reveal the regulatory mechanism of berberine on secondary homing of CRC cells to form metastatic focus. This was more valuable than the previous direct study of the migration and metastasis characteristics of CRC cells. METHODS In this study, we used the functional enrichment analysis of differentially expressed genes after berberine treatment and investigated co-expression modules related with CRC metastasis by WGCNA. PPI and survival analyses of significant modules were also conducted. The biological functions of berberine in CRC lung and liver metastasis were investigated by a series of in vitro and in vivo experiments: MTT, colony formation and mouse tail vein injection. And we scanned through the entire extracellular domain of HEY2 protein for autodocking analysis with berberine. RESULTS We found the differentially expressed genes (DEGs) after berberine treatment were related with cancer progression and metastasis related pathways. Through WGCNA analysis, four cancer progression and metastasis related modules were detected. After PPI and survival analysis, we identified and validated HEY2 as a hub gene, high expression and poor survival at the metastatic stage. Functionally, berberine inhibited the survival, invasion and migration of CRC cells in vitro and in vivo. Mechanistically, berberine treatment down-regulated the expression of HEY2, metastasis related protein E-cadherin, β-catenin and Cyclin D1 during Mesenchymal epithelial transformation (MET). Berberine and HEY2 showed a significant interaction, and berberine binded to HEY2 protein at the residue HIS-99 interface with a hydrogen-bond distance of 1.9A. CONCLUSIONS We revealed that berberine could significantly inhibit the expression of hub gene HEY2 and metastasis related proteins E-cadherin and β-catenin and Cyclin D1 during MET in CRC lung and liver metastases. In total, HEY2 was a promising candidate biomarker for prognosis and molecular characteristics in CRC metastasis.
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Affiliation(s)
- Lulu Ni
- Department of Basic Medicine, Jiangnan University, Wuxi 214122, PR China
| | - Ping Sun
- Department of Pathology, The Affiliated Wuxi NO. 2 People's Hospital of Nanjing Medical University, Wuxi 214000,PR China
| | - Min Ai
- Laboratory Animal Center of Shanghai Jiao Tong University, Shanghai 200240, PR China
| | - Lingzhong Kong
- Department of Rehabilitation Acupuncture Medicine, Bozhou People's Hospital, Bozhou, Anhui 236800, PR China
| | - Rongrong Xu
- Department of Pathology, The Affiliated Wuxi NO. 2 People's Hospital of Nanjing Medical University, Wuxi 214000,PR China
| | - Jiangan Li
- Department of Emergency, The Affiliated Wuxi NO. 2 People's Hospital of Nanjing Medical University, No. 68 Zhongshan Road, Wuxi 214000, PR China.
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Khayeka-Wandabwa C, Ma X, Jia Y, Bureik M. Monitoring of autoantibodies against CYP4Z1 in patients with colon, ovarian, or prostate cancer. Immunobiology 2022; 227:152174. [PMID: 34999392 DOI: 10.1016/j.imbio.2021.152174] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 12/27/2021] [Accepted: 12/30/2021] [Indexed: 12/09/2022]
Abstract
We have previously monitored the detection of autoantibodies (aAbs) directed against CYP4Z1 in the sera of breast and lung cancer patients. In the present study, the occurence of anti-CYP4Z1 aAbs in patients suffering from colon (n = 100), ovarian (n = 72), or prostate (n = 85) cancer was examined. Determination of aAbs was done using our previously established ELISA method. On average, the levels of anti-CYP4Z1 aAbs detected in sera from all cancer patients were not significantly higher than controls. No correlations were found with respect to gender or tumor stage. However, a subgroup of colon cancer patients with increased anti-CYP4Z1 aAb titers exhibited positive fecal occult blood test (FOBT) results and higher levels of both carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA). These results do not suggest that anti-CYP4Z1 aAbs have value as an independent biomarker for the detection of either colon, ovarian, or prostate cancer. However, they might be useful in combination with other biomarkers for the identification of a subset of colon cancers. Investigations involving a more powered sample size of this subgroup are needed to support this notion.
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Affiliation(s)
| | - Xiaoshuang Ma
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - Yingjie Jia
- Dept. of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Matthias Bureik
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
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Al-Saraireh YM, Alshammari FOFO, Youssef AMM, Al-Sarayreh S, Almuhaisen GH, Alnawaiseh N, Al-Shuneigat JM, Alrawashdeh HM. Cytochrome 4Z1 Expression is Associated with Poor Prognosis in Colon Cancer Patients. Onco Targets Ther 2021; 14:5249-5260. [PMID: 34803385 PMCID: PMC8595061 DOI: 10.2147/ott.s332037] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 10/29/2021] [Indexed: 12/30/2022] Open
Abstract
Purpose Colon cancer is a leading cause of mortality worldwide. It has a relatively poor prognosis; therefore, new therapies are needed. One of the tumour-related enzymes that has gained considerable interest is CYP4Z1. This enzyme has been expressed in many tumours and has been hypothesized as a potential biomarker or target for novel anticancer therapies. Patients and Methods CYP4Z1 overexpression was immunohistochemically examined in a large panel of colon tissue types including normal, benign, primary and metastatic ones, and the enzyme’s relation to histopathological features and patient survival was evaluated. Results A high CYP4Z1 expression was observed in benign, primary and metastatic colon tissues compared to a weak or lack of expression in normal tissues. Importantly, there was a significant differential in CYP4Z1 expression where it was stronger in metastatic, primary and benign, respectively (p < 0.05). A significantly high rate of CYP4Z1 expression was found in high histological grades and late stages of the disease, where its expression was more evident in patients with metastasis in the lymph nodes (p < 0.05). Interestingly, CYP4Z1 expression was identified an independent prognostic predictor of poor overall survival of colon cancer patients (p = 0.003). Conclusion CYP4Z1 was distinctly overexpressed in benign, primary and metastatic colon tissues compared to corresponding normal tissues. This differential in CYP4Z1 expression across different types of colon tissues strongly supports CYP4Z1 as potential biomarker and target for novel anticancer therapy development.
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Affiliation(s)
- Yousef M Al-Saraireh
- Department of Pharmacology, Faculty of Medicine, Mutah University, Al-Karak, Jordan
| | - Fatemah O F O Alshammari
- Department of Medical Laboratory Technology, Faculty of Health Sciences, The Public Authority for Applied Education and Training, Shuwaikh, Kuwait
| | - Ahmed M M Youssef
- Department of Pharmacology, Faculty of Pharmacy, Mutah University, Al-Karak, Jordan
| | - Sameeh Al-Sarayreh
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Mutah University, Al-Karak, Jordan
| | - Ghadeer H Almuhaisen
- Department of Microbiology and Pathology, Faculty of Medicine, Mutah University, Al- Karak, Jordan
| | - Nedal Alnawaiseh
- Department of Public Health, Faculty of Medicine, Mutah University, Al-Karak, Jordan
| | - Jehad M Al-Shuneigat
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Mutah University, Al-Karak, Jordan
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Al-Saraireh YM, Alshammari FOFO, Youssef AMM, Al-Tarawneh F, Al-Sarayreh S, Almuhaisen GH, Satari AO, Al-Shuneigat J, Alrawashdeh HM. Cytochrome 4Z1 Expression is Associated with Unfavorable Survival in Triple-Negative Breast Cancers. BREAST CANCER-TARGETS AND THERAPY 2021; 13:565-574. [PMID: 34675653 PMCID: PMC8502010 DOI: 10.2147/bctt.s329770] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/24/2021] [Indexed: 12/26/2022]
Abstract
Purpose Triple-negative breast cancer (TNBC) is characterized by high mortality rate, and its clinical management is difficult and complex. Therefore, there is a need for extensive efforts aimed at accelerating the discovery of novel therapies for TNBC. CYP4Z1 has been implicated in the development of breast cancer. The current study aimed at characterizing the expression of CYP4Z1 on TNBC. Materials and Methods Using immunohistochemistry, CYP4Z1 expression was evaluated on 122 TNBC samples, four samples of breast cancers expressing ER, PR, and HER-2, and four samples of normal breast tissues. The association between the enzyme and various histopathological features and survival of patients were determined. Results CYP4Z1 was strongly expressed in 83.3% of various histopathological subtypes of TNBC, when compared to negative expression in normal breast tissues. Interestingly, there were marked variations in CYP4Z1 expression with respect to histopathology subtype, histological grade, histological stage and tumor diameter. There was a high incidence of CYP4Z1 expression in patients with advanced grades, late stages and larger tumor sizes. Importantly, CYP4Z1 expression was correlated with the survival of TNBC patients, but it was an independent determinant of the poor prognosis of TNBC (p< 0.05). Conclusion CYP4ZI may be a potential biomarker or target for evolving new CYP4Z1-targeted treatments.
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Affiliation(s)
- Yousef M Al-Saraireh
- Department of Pharmacology, Faculty of Medicine, Mutah University, Al-Karak, Jordan
| | - Fatemah O F O Alshammari
- Department of Medical Laboratory Technology, Faculty of Health Sciences, The Public Authority for Applied Education and Training, Shuwaikh, Kuwait
| | - Ahmed M M Youssef
- Department of Pharmacology, Faculty of Pharmacy, Mutah University, Al-Karak, Jordan
| | - Fatima Al-Tarawneh
- Department of Allied Medical Sciences, Faculty of Al-Karak, Al-Balqa Applied University, Al-Karak, Jordan
| | - Sameeh Al-Sarayreh
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Mutah University, Al-Karak, Jordan
| | - Ghadeer H Almuhaisen
- Department of Microbiology and Pathology, Faculty of Medicine, Mutah University, Al-Karak, Jordan
| | - Anas O Satari
- Faculty of Medicine, Mutah University, Al-Karak, Jordan
| | - Jehad Al-Shuneigat
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Mutah University, Al-Karak, Jordan
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Cytochrome 4Z1 Expression Is Correlated with Poor Prognosis in Patients with Cervical Cancer. ACTA ACUST UNITED AC 2021; 28:3573-3584. [PMID: 34590601 PMCID: PMC8482276 DOI: 10.3390/curroncol28050306] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/01/2021] [Accepted: 09/11/2021] [Indexed: 12/24/2022]
Abstract
Background: cervical cancer is one of the most common malignancies in women worldwide and its management remains challenging and complex. As Cytochrome4Z1 (CYP4Z1) is overexpressed in many tumours, its expression in cervical cancer is unknown. Therefore, the present study aimed to evaluate CYP4Z1 expression in cervical cancers. Methods: CYP4Z1 expression was immunohistochemically assessed in 100 cases of cervical cancers along with ten normal cervix tissues, and the enzyme’s relationship to several clinicopathological features and survival was explored. Results: CYP4Z1 was strongly expressed in 55% of cervical cancer patients. Normal cervix samples were negative for CYP4Z1 expression. Importantly, this expression was significantly found in patients with the late stage of the disease, lymph node metastasis, and high tumour invasion (p < 0.05). Interestingly, CYP4Z1 expression was significantly correlated with shorter survival times of cervical cancer patients. Univariate analysis showed that CYP4Z1 expression, tumour stage, lymph node metastasis, and tumour invasion were significantly correlated with patient survival (p < 0.05). The multivariate analysis revealed that only CYP4Z1 expression and tumour stage were significantly correlated with patient survival (p < 0.05). Conclusions: CYP4Z1 expression is associated with cervical cancer patients’ survival and may serve as an independent predictor of poor prognosis in cervical cancer patients.
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Cheng W, Cao J, Xia Y, Lei X, Wu L, Shi L. A DNA methylation profile of long non-coding RNAs can predict OS in prostate cancer. Bioengineered 2021; 12:3252-3262. [PMID: 34238128 PMCID: PMC8806446 DOI: 10.1080/21655979.2021.1945991] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Prostate cancer (PCa) is the most common male reproductive tract malignant tumor, accurate evaluation of PCa characterization and prognostic prediction at diagnosis are vital for the effective administration of the disease, especially at the molecular level. In this study, 48 CpG sites with differential methylation associated with overall survival (OS) were screened out between PCa and normal adjacent tissues. 16 CpG sites were selected by the least absolute shrinkage and selection operator (LASSO) and the risk score formula for methylated-based classifier was established. For 16-lncRNAs-CpG-classifier, the area under the curve (AUC) were 0.890, 0.917, and 0.932 at 3 years, 5 years and 7 years, respectively. Kaplan–Meier curves indicated that patients with high-risk scores had worse OS than those with low-risk scores. Prognostic methylation model of lncRNAs was identified from the whole genome in patients with PCa. This novel finding provides a novel insight for screening biomarkers of a prognosis for PCa.
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Affiliation(s)
- Wei Cheng
- Department of Neurology, Suizhou Hospital, Hubei University of Medicine, Suizhou, China
| | - Jie Cao
- Department of Tanslational Medicine Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yong Xia
- Department of Clinical Medical Laboratory, Peking University Shenzhen Hospital, Shenzhen, China
| | - Xin Lei
- Department of Tanslational Medicine Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lili Wu
- Department of Clinical Transfusion, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Liang Shi
- Department of Tanslational Medicine Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Laboratory Medicine, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
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11
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Al-Saraireh YM, Alshammari FOFO, Youssef AMM, Al-Sarayreh S, Almuhaisen GH, Alnawaiseh N, Al Shuneigat JM, Alrawashdeh HM. Profiling of CYP4Z1 and CYP1B1 expression in bladder cancers. Sci Rep 2021; 11:5581. [PMID: 33692504 PMCID: PMC7946900 DOI: 10.1038/s41598-021-85188-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 02/24/2021] [Indexed: 12/24/2022] Open
Abstract
Bladder cancer is the tenth most common cancer worldwide, where its burden remains a challenge and needs new novel therapies. Several reports indicate expression of CYP4Z1 and CYP1B1 in many tumours. Their expressions are associated with a poor prognosis, and therefore proposed as promising biomarkers or targets for anticancer therapy. By using immunohistochemistry, expression of CYP4Z1 and CYP1B1 was evaluated in a panel of different types of bladder cancer, and the enzymes' relation to histopathological features were assessed. Results showed an increased expression of CYP4Z1 (54.3%) and CYP1B1 (76.9%) in the majority of bladder cancers compared to weak or lack of expression of both enzymes in normal tissues. CYP4Z1expression was significantly associated with tumour grade and stage where the expression was markedly increased in a high grade and advanced stage of the disease (p < 0.05). Additionally, CYP1B1 expression was also associated with TNM staging (p < 0.05) and its expression was increased in patients with lymph node metastasis. The expression profiles of CYP4Z1 and CYP1B1 suggest that both enzymes have the potential to be biomarkers or targets for novel anticancer therapy for bladder cancer. Nevertheless, further studies are needed to better delineate whether these enzymes are druggable targets.
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Affiliation(s)
- Yousef M Al-Saraireh
- Department of Pharmacology, Faculty of Medicine, Mutah University, P.O.Box 7, Karak, 61710, Jordan.
| | - Fatemah O F O Alshammari
- Department of Medical Lab Technology, Faculty of Health Sciences, The Public Authority for Applied Education and Training, P.O.Box 14281, 15432, Shuwaikh, Kuwait
| | - Ahmed M M Youssef
- Department of Pharmacology, Faculty of Pharmacy, Mutah University, P.O.Box 7, Karak, 61710, Jordan
| | - Sameeh Al-Sarayreh
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Mutah University, PO. Box 7, Karak, 61710, Jordan
| | - Ghadeer H Almuhaisen
- Department of Microbiology and Pathology, Faculty of Medicine, Mutah University, P.O. Box 7, Karak, 61710, Jordan
| | - Nedal Alnawaiseh
- Department of Public Health, Faculty of Medicine, Mutah University, P.O. Box 7, Karak, 61710, Jordan
| | - Jehad M Al Shuneigat
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Mutah University, PO. Box 7, Karak, 61710, Jordan
| | - Hamzeh M Alrawashdeh
- Department of Ophthalmology, Ibn Al Haytham Hospital, P.O.Box 410739, Amman, Jordan
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12
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Discovery of a novel potent cytochrome P450 CYP4Z1 inhibitor. Eur J Med Chem 2021; 215:113255. [PMID: 33611185 DOI: 10.1016/j.ejmech.2021.113255] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 01/27/2021] [Accepted: 01/29/2021] [Indexed: 02/08/2023]
Abstract
Human cytochrome P450 enzyme CYP4Z1 represents a promising target for the treatment of a multitude of malignancies including breast cancer. The most active known non-covalent inhibitor (1-benzylimidazole) only shows low micromolar affinity to CYP4Z1. We report a new, highly active inhibitor for CYP4Z1 showing confirmed binding in an enzymatic assay and an IC50 value of 63 ± 19 nM in stably transfected MCF-7 cells overexpressing CYP4Z1. The new inhibitor was identified by a systematically developed virtual screening protocol. Binding was rationalized using a carefully elaborated 3D pharmacophore hypothesis and thoroughly characterized using extensive molecular dynamics simulations and dynamic 3D pharmacophore (dynophore) analyses. This novel inhibitor represents a valuable pharmacological tool to accelerate characterization of the still understudied CYP4Z1 and might pave the way for a new treatment strategy in CYP4Z1-associated malignancies. The presented in silico model for predicting CYP4Z1 interaction provides novel mechanistic insights and revealed that the drug ozagrel interacts with CYP4Z1.
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13
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Sopyllo K, Erickson AM, Mirtti T. Grading Evolution and Contemporary Prognostic Biomarkers of Clinically Significant Prostate Cancer. Cancers (Basel) 2021; 13:cancers13040628. [PMID: 33562508 PMCID: PMC7914622 DOI: 10.3390/cancers13040628] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 01/26/2021] [Accepted: 01/28/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Prostate cancer treatment decisions are based on clinical stage and histological diagnosis, including Gleason grading assessed by a pathologist, in biopsies. Prior to staging and grading, serum or blood prostate-specific antigen (PSA) levels are measured and often trigger diagnostic examinations. However, PSA is best suited as a marker of cancer relapse after initial treatment. In this review, we first narratively describe the evolution of histological grading, the current status of Gleason pattern-based diagnostics and glance into future methodology of risk assessment by histological examination. In the second part, we systematically review the biomarkers that have been shown, independent from clinical characteristics, to correlate with clinically relevant end-points, i.e., occurrence of metastases, disease-specific mortality and overall survival after initial treatment of localized prostate cancer. Abstract Gleason grading remains the strongest prognostic parameter in localized prostate adenocarcinoma. We have here outlined the evolution and contemporary practices in pathological evaluation of prostate tissue samples for Gleason score and Grade group. The state of more observer-independent grading methods with the aid of artificial intelligence is also reviewed. Additionally, we conducted a systematic review of biomarkers that hold promise in adding independent prognostic or predictive value on top of clinical parameters, Grade group and PSA. We especially focused on hard end points during the follow-up, i.e., occurrence of metastasis, disease-specific mortality and overall mortality. In peripheral blood, biopsy-detected prostate cancer or in surgical specimens, we can conclude that there are more than sixty biomarkers that have been shown to have independent prognostic significance when adjusted to conventional risk assessment or grouping. Our search brought up some known putative markers and panels, as expected. Also, the synthesis in the systematic review indicated markers that ought to be further studied as part of prospective trials and in well characterized patient cohorts in order to increase the resolution of the current clinico-pathological prognostic factors.
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Affiliation(s)
- Konrad Sopyllo
- Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland;
| | - Andrew M. Erickson
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, UK;
| | - Tuomas Mirtti
- Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland;
- Department of Pathology, HUS Diagnostic Centre, Helsinki University Hospital, 00029 Helsinki, Finland
- Correspondence:
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14
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Al-Saraireh YM, Alboaisa NS, Alrawashdeh HM, Hamdan O, Al-Sarayreh S, Al-Shuneigat JM, Nofal MN. Screening of cytochrome 4Z1 expression in human non-neoplastic, pre-neoplastic and neoplastic tissues. Ecancermedicalscience 2020; 14:1114. [PMID: 33144882 PMCID: PMC7581338 DOI: 10.3332/ecancer.2020.1114] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Indexed: 12/14/2022] Open
Abstract
Background: Cytochromes P450 (CYPs) constitute an enzyme family involved in the oxidative metabolism of a wide variety of endogenous and exogenous compounds, including anti-cancer drugs and carcinogens. Unlike other human CYPs, CYP4Z1 is highly expressed in human breast carcinoma and is associated with poor prognosis. As a result, CYP4Z1 was hypothesised to be a potential biomarker or drug target for the discovery and development of promising anti-cancer therapies. Materials and methods: CYP4Z1 expression was immunohistochemically studied in a set of 100 different human tissues, including normal, benign, malignant and metastatic tissues, which originated from 27 anatomical sites. As a tumour model for CYP4Z1 expression, a panel of different breast cancers was evaluated for CYP4Z1 expression and its relation to histopathological features and prognostic immunohistochemical markers. Results: The immunohistochemical results revealed that CYP4Z1 was expressed in only one (4.3%) of the normal tissues from the mammary glands, while the expression of the enzyme was positive in 1 (11%), 12 (19%) and 2 (40%) of the benign, malignant and metastatic tissues, respectively. Interestingly, several tumour entities showed prominent expressions of CYP4Z1, including carcinomas of adrenal cortex, squamous cells of oesophagus, lung and cervix, as well as seminoma, astrocytoma, melanoma and lastly endometrial adenocarcinoma. In breast cancers, CYP4Z1 was expressed in 82% of the cases. Its expression was significantly associated with the pathology of tumour, histological grade and status of lymph node metastasis. Importantly, it was also significantly associated with the expressions of Her2, P53 and Ki-67. Conclusion: These findings greatly support future plans for the use of CYP4Z1 as a biomarker or target for anti-cancer drugs. However, large-scale validation studies are needed to better delineate the potential use of CYP4Z1 for therapeutic purposes.
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Affiliation(s)
- Yousef M Al-Saraireh
- Department of Pharmacology, Faculty of Medicine, University of Mutah, Karak 61710, Jordan
| | - Nafea S Alboaisa
- Department of Pathology, College of Medicine, University of Anbar, Baghdad 55431, 55 Ramadi
| | | | - Omar Hamdan
- Department of Pathology, College of Medicine, University of Mutah, Karak 61710, Jordan
| | - Sameeh Al-Sarayreh
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Mutah, Karak 61710, Jordan
| | - Jehad M Al-Shuneigat
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Mutah, Karak 61710, Jordan
| | - Mohammad N Nofal
- Department of General Surgery, Faculty of Medicine, University of Mutah, Karak 61710, Jordan
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15
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Glassman PM, Myerson JW, Ferguson LT, Kiseleva RY, Shuvaev VV, Brenner JS, Muzykantov VR. Targeting drug delivery in the vascular system: Focus on endothelium. Adv Drug Deliv Rev 2020; 157:96-117. [PMID: 32579890 PMCID: PMC7306214 DOI: 10.1016/j.addr.2020.06.013] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 06/12/2020] [Accepted: 06/13/2020] [Indexed: 12/16/2022]
Abstract
The bloodstream is the main transporting pathway for drug delivery systems (DDS) from the site of administration to the intended site of action. In many cases, components of the vascular system represent therapeutic targets. Endothelial cells, which line the luminal surface of the vasculature, play a tripartite role of the key target, barrier, or victim of nanomedicines in the bloodstream. Circulating DDS may accumulate in the vascular areas of interest and in off-target areas via mechanisms bypassing specific molecular recognition, but using ligands of specific vascular determinant molecules enables a degree of precision, efficacy, and specificity of delivery unattainable by non-affinity DDS. Three decades of research efforts have focused on specific vascular targeting, which have yielded a multitude of DDS, many of which are currently undergoing a translational phase of development for biomedical applications, including interventions in the cardiovascular, pulmonary, and central nervous systems, regulation of endothelial functions, host defense, and permeation of vascular barriers. We discuss the design of endothelial-targeted nanocarriers, factors underlying their interactions with cells and tissues, and describe examples of their investigational use in models of acute vascular inflammation with an eye on translational challenges.
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Affiliation(s)
- Patrick M Glassman
- Department of Systems Pharmacology and Translational Therapeutics, Center for Targeted Therapeutics and Translational Nanomedicine of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America.
| | - Jacob W Myerson
- Department of Systems Pharmacology and Translational Therapeutics, Center for Targeted Therapeutics and Translational Nanomedicine of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America
| | - Laura T Ferguson
- Department of Systems Pharmacology and Translational Therapeutics, Center for Targeted Therapeutics and Translational Nanomedicine of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America; Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America
| | - Raisa Y Kiseleva
- Department of Systems Pharmacology and Translational Therapeutics, Center for Targeted Therapeutics and Translational Nanomedicine of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America
| | - Vladimir V Shuvaev
- Department of Systems Pharmacology and Translational Therapeutics, Center for Targeted Therapeutics and Translational Nanomedicine of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America
| | - Jacob S Brenner
- Department of Systems Pharmacology and Translational Therapeutics, Center for Targeted Therapeutics and Translational Nanomedicine of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America; Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America
| | - Vladimir R Muzykantov
- Department of Systems Pharmacology and Translational Therapeutics, Center for Targeted Therapeutics and Translational Nanomedicine of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America.
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16
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Cárdenas S, Colombero C, Panelo L, Dakarapu R, Falck JR, Costas MA, Nowicki S. GPR75 receptor mediates 20-HETE-signaling and metastatic features of androgen-insensitive prostate cancer cells. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1865:158573. [PMID: 31760076 DOI: 10.1016/j.bbalip.2019.158573] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 10/22/2019] [Accepted: 11/05/2019] [Indexed: 02/07/2023]
Abstract
PURPOSE Recent studies have shown that 20-hydroxyeicosatetraenoic acid (20-HETE) is a key molecule in sustaining androgen-mediated prostate cancer cell survival. Thus, the aim of this study was to determine whether 20-HETE can affect the metastatic potential of androgen-insensitive prostate cancer cells, and the implication of the newly described 20-HETE receptor, GPR75, in mediating these effects. METHODS The expression of GPR75, protein phosphorylation, actin polymerization and protein distribution were assessed by western blot and/or fluorescence microscopy. Additionally, in vitro assays including epithelial-mesenchymal transition (EMT), metalloproteinase-2 (MMP-2) activity, scratch wound healing, transwell invasion and soft agar colony formation were used to evaluate the effects of 20-HETE agonists/antagonists or GPR75 gene silencing on the aggressive features of PC-3 cells. RESULTS 20-HETE (0.1 nM) promoted the acquisition of a mesenchymal phenotype by increasing EMT, the release of MMP-2, cell migration and invasion, actin stress fiber formation and anchorage-independent growth. Also, 20-HETE augmented the expression of HIC-5, the phosphorylation of EGFR, NF-κB, AKT and p-38 and the intracellular redistribution of p-AKT and PKCα. These effects were impaired by GPR75 antagonism and/or silencing. Accordingly, the inhibition of 20-HETE formation with N-hydroxy-N'-(4-n-butyl-2-methylphenyl) formamidine (HET0016) elicited the opposite effects. CONCLUSIONS The present results show for the first time the involvement of the 20-HETE-GPR75 receptor in the activation of intracellular signaling known to be stimulated in cell malignant transformations leading to the differentiation of PC-3 cells towards a more aggressive phenotype. Targeting the 20-HETE/GPR75 pathway is a promising and novel approach to interfere with prostate tumor cell malignant progression.
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Affiliation(s)
- Sofia Cárdenas
- Centro de Investigaciones Endocrinológicas "Dr. Cesar Bergada" (CEDIE) CONICET-FEI-División de Endocrinología, Hospital de Niños "Ricardo Gutierrez", Gallo 1330, C1425EFD Buenos Aires, Argentina
| | - Cecilia Colombero
- Centro de Investigaciones Endocrinológicas "Dr. Cesar Bergada" (CEDIE) CONICET-FEI-División de Endocrinología, Hospital de Niños "Ricardo Gutierrez", Gallo 1330, C1425EFD Buenos Aires, Argentina
| | - Laura Panelo
- Laboratorio de Biología Molecular y Apoptosis, Instituto de Investigaciones Médicas Alfredo Lanari, IDIM-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Combatientes de Malvinas 3150, C1427ARN Buenos Aires, Argentina
| | - Rambabu Dakarapu
- Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, United States of America
| | - John R Falck
- Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, United States of America
| | - Monica A Costas
- Laboratorio de Biología Molecular y Apoptosis, Instituto de Investigaciones Médicas Alfredo Lanari, IDIM-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Combatientes de Malvinas 3150, C1427ARN Buenos Aires, Argentina
| | - Susana Nowicki
- Centro de Investigaciones Endocrinológicas "Dr. Cesar Bergada" (CEDIE) CONICET-FEI-División de Endocrinología, Hospital de Niños "Ricardo Gutierrez", Gallo 1330, C1425EFD Buenos Aires, Argentina.
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17
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Xu Q, Lin D, Li X, Xiao R, Liu Z, Xiong W, Cai L, He F. Association between single nucleotide polymorphisms of NOTCH signaling pathway-related genes and the prognosis of NSCLC. Cancer Manag Res 2019; 11:6895-6905. [PMID: 31413635 PMCID: PMC6662170 DOI: 10.2147/cmar.s197747] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 06/12/2019] [Indexed: 12/12/2022] Open
Abstract
Objective In this study, we analyzed the association between genetic variants of genes in the NOTCH signaling pathway and the prognosis of non-small-cell lung cancer (NSCLC) in the Chinese population. We also explored the interaction between genetic and epidemiological factors for the test group. Methods We performed genotyping of 987 NSCLC patients. Then, we used Cox proportional hazard models to analyze the associations between single-nucleotide polymorphisms (SNPs) and the prognosis of NSCLC. We employed Stata software to test the heterogeneity of associations between subgroups, and we analyzed the additive and multiplicative interactions between SNPs and epidemiologic factors. Results This work revealed the important prognostic and predictive value of rs915894 in the NOTCH4 gene, which may be regarded as a promising prognosis biomarker of NSCLC. Cox regression analysis indicated that the C allele of rs915894 is associated with longer survival and decreased risk of death in NSCLC (codominant model: adjusted HR =0.83, 95% CI =0.70-0.99; dominant model: adjusted HR =0.83, 95% CI =0.71-0.98). Additional stepwise regression analysis suggested that this SNP is an independently favorable factor for the prognosis of NSCLC (dominant model: adjusted HR =0.85, 95% CI =0.72-0.99). This protective effect is more pronounced for patients who are not smokers, have a history of other lung diseases, or have a family history of cancer. We also detected statistically significant additive and multiplicative interactions between rs915894 and smoking, rs915894 and history of lung diseases, and rs915894 and family history of cancer, which all affect NSCLC survival. Conclusion This study demonstrated that rs915894 in NOTCH 4 may be a genetic marker for NSCLC prognosis in the Chinese population and that rs915894 may have an interactive relationship with epidemiologic factors.
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Affiliation(s)
- Qiuping Xu
- Medical Department, The Affiliated Hospital of Putian University, Putian, Fujian, People's Republic of China.,Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, Fujian, People's Republic of China
| | - Danhua Lin
- Medical Department, The Affiliated Hospital of Putian University, Putian, Fujian, People's Republic of China
| | - Xu Li
- Department of Thoracic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, People's Republic of China
| | - Rendong Xiao
- Department of Thoracic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, People's Republic of China
| | - Zhiqiang Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, People's Republic of China
| | - Weimin Xiong
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, Fujian, People's Republic of China
| | - Lin Cai
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, Fujian, People's Republic of China
| | - Fei He
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, Fujian, People's Republic of China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, People's Republic of China
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18
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Wu DC, Zhang MF, Su SG, Fang HY, Wang XH, He D, Xie YY, Liu XH. HEY2, a target of miR-137, indicates poor outcomes and promotes cell proliferation and migration in hepatocellular carcinoma. Oncotarget 2018; 7:38052-38063. [PMID: 27191260 PMCID: PMC5122371 DOI: 10.18632/oncotarget.9343] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 04/26/2016] [Indexed: 01/26/2023] Open
Abstract
HEY2, a bHLH transcription factor, has been implicated in the progression of human cancers. Here, we showed that HEY2 expression was markedly increased in HCC, compared with the adjacent nontumorous tissues. High HEY2 expression was closely correlated with tumor multiplicity, tumor differentiation and TNM stage. Kaplan-Meier analyses revealed that HEY2 expression was significantly associated with poor overall and disease-free survival in a training cohort of 361 patients with HCC. The prognostic implication of HEY2 was validated in another cohort of 169 HCC patients. Multivariate Cox regression model indicated HEY2 as an independent factor for overall survival in HCC (Hazard ratio = 1.645, 95% confident interval: 1.309-2.067, P<0.001). We also demonstrated that HEY2 expression was inhibited by miR-137. In clinical samples, HEY2 expression was reversely associated to miR-137 expression. Furthermore, overexpression of HEY2 increased cell viabilities, colony formation and cell migration, whereas knockdown of HEY2 resulted in the opposite phenotypes. Collectively, our data suggest HEY2 as a promising biomarker for unfavorable outcomes and a novel therapeutic target for the clinical management of HCC.
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Affiliation(s)
- Dan-Chun Wu
- Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Mei-Fang Zhang
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shu-Guang Su
- Department of Pathology, The Affiliated Hexian Memorial Hospital of Southern Medical University, Guangzhou, China
| | - Heng-Ying Fang
- Department of Nursing, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xue-Hua Wang
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Dan He
- Department of Pathology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yuan-Yuan Xie
- Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xu-Hui Liu
- Department of Emergency, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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McDonald MG, Ray S, Amorosi CJ, Sitko KA, Kowalski JP, Paco L, Nath A, Gallis B, Totah RA, Dunham MJ, Fowler DM, Rettie AE. Expression and Functional Characterization of Breast Cancer-Associated Cytochrome P450 4Z1 in Saccharomyces cerevisiae. Drug Metab Dispos 2017; 45:1364-1371. [PMID: 29018033 PMCID: PMC5697098 DOI: 10.1124/dmd.117.078188] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2017] [Accepted: 10/04/2017] [Indexed: 12/22/2022] Open
Abstract
CYP4Z1 is an "orphan" cytochrome P450 (P450) enzyme that has provoked interest because of its hypothesized role in breast cancer through formation of the signaling molecule 20-hydroxyeicosatetraenoic acid (20-HETE). We expressed human CYP4Z1 in Saccharomyces cerevisiae and evaluated its catalytic capabilities toward arachidonic and lauric acids (AA and LA). Specific and sensitive mass spectrometry assays enabled discrimination of the regioselectivity of hydroxylation of these two fatty acids. CYP4Z1 generated 7-, 8-, 9-, 10-, and 11-hydroxy LA, whereas the 12-hydroxy metabolite was not detected. HET0016, the prototypic CYP4 inhibitor, only weakly inhibited laurate metabolite formation (IC50 ∼15 μM). CYP4Z1 preferentially oxidized AA to the 14(S),15(R)-epoxide with high regioselectivity and stereoselectivity, a reaction that was also insensitive to HET0016, but neither 20-HETE nor 20-carboxy-AA were detectable metabolites. Docking of LA and AA into a CYP4Z1 homology model was consistent with this preference for internal fatty acid oxidation. Thus, human CYP4Z1 has an inhibitor profile and product regioselectivity distinct from most other CYP4 enzymes, consistent with CYP4Z1's lack of a covalently linked heme. These data suggest that, if CYP4Z1 modulates breast cancer progression, it does so by a mechanism other than direct production of 20-HETE.
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Affiliation(s)
- Matthew G McDonald
- Departments of Medicinal Chemistry (M.G.M., S.R., J.P.K., L.P., A.N., B.G., R.A.T., A.E.R.), Genome Sciences (K.A.S., C.J.A., M.J.D., D.M.F.), and Bioengineering (D.M.F.), University of Washington, Seattle, Washington
| | - Sutapa Ray
- Departments of Medicinal Chemistry (M.G.M., S.R., J.P.K., L.P., A.N., B.G., R.A.T., A.E.R.), Genome Sciences (K.A.S., C.J.A., M.J.D., D.M.F.), and Bioengineering (D.M.F.), University of Washington, Seattle, Washington
| | - Clara J Amorosi
- Departments of Medicinal Chemistry (M.G.M., S.R., J.P.K., L.P., A.N., B.G., R.A.T., A.E.R.), Genome Sciences (K.A.S., C.J.A., M.J.D., D.M.F.), and Bioengineering (D.M.F.), University of Washington, Seattle, Washington
| | - Katherine A Sitko
- Departments of Medicinal Chemistry (M.G.M., S.R., J.P.K., L.P., A.N., B.G., R.A.T., A.E.R.), Genome Sciences (K.A.S., C.J.A., M.J.D., D.M.F.), and Bioengineering (D.M.F.), University of Washington, Seattle, Washington
| | - John P Kowalski
- Departments of Medicinal Chemistry (M.G.M., S.R., J.P.K., L.P., A.N., B.G., R.A.T., A.E.R.), Genome Sciences (K.A.S., C.J.A., M.J.D., D.M.F.), and Bioengineering (D.M.F.), University of Washington, Seattle, Washington
| | - Lorela Paco
- Departments of Medicinal Chemistry (M.G.M., S.R., J.P.K., L.P., A.N., B.G., R.A.T., A.E.R.), Genome Sciences (K.A.S., C.J.A., M.J.D., D.M.F.), and Bioengineering (D.M.F.), University of Washington, Seattle, Washington
| | - Abhinav Nath
- Departments of Medicinal Chemistry (M.G.M., S.R., J.P.K., L.P., A.N., B.G., R.A.T., A.E.R.), Genome Sciences (K.A.S., C.J.A., M.J.D., D.M.F.), and Bioengineering (D.M.F.), University of Washington, Seattle, Washington
| | - Byron Gallis
- Departments of Medicinal Chemistry (M.G.M., S.R., J.P.K., L.P., A.N., B.G., R.A.T., A.E.R.), Genome Sciences (K.A.S., C.J.A., M.J.D., D.M.F.), and Bioengineering (D.M.F.), University of Washington, Seattle, Washington
| | - Rheem A Totah
- Departments of Medicinal Chemistry (M.G.M., S.R., J.P.K., L.P., A.N., B.G., R.A.T., A.E.R.), Genome Sciences (K.A.S., C.J.A., M.J.D., D.M.F.), and Bioengineering (D.M.F.), University of Washington, Seattle, Washington
| | - Maitreya J Dunham
- Departments of Medicinal Chemistry (M.G.M., S.R., J.P.K., L.P., A.N., B.G., R.A.T., A.E.R.), Genome Sciences (K.A.S., C.J.A., M.J.D., D.M.F.), and Bioengineering (D.M.F.), University of Washington, Seattle, Washington
| | - Douglas M Fowler
- Departments of Medicinal Chemistry (M.G.M., S.R., J.P.K., L.P., A.N., B.G., R.A.T., A.E.R.), Genome Sciences (K.A.S., C.J.A., M.J.D., D.M.F.), and Bioengineering (D.M.F.), University of Washington, Seattle, Washington
| | - Allan E Rettie
- Departments of Medicinal Chemistry (M.G.M., S.R., J.P.K., L.P., A.N., B.G., R.A.T., A.E.R.), Genome Sciences (K.A.S., C.J.A., M.J.D., D.M.F.), and Bioengineering (D.M.F.), University of Washington, Seattle, Washington
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20
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Efficient substrate screening and inhibitor testing of human CYP4Z1 using permeabilized recombinant fission yeast. Biochem Pharmacol 2017; 146:174-187. [PMID: 28951277 DOI: 10.1016/j.bcp.2017.09.011] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 09/21/2017] [Indexed: 01/09/2023]
Abstract
We have established a protocol for the preparation of permeabilized fission yeast cells (enzyme bags) that recombinantly express human cytochrome P450 enzymes (CYPs). A direct comparison of CYP3A4 activity gave an eightfold higher space-time yield for enzyme bag-catalyzed biotransformation as compared to whole-cell biotransformation, even though the total number of cells employed was lower by a factor of 150. Biotransformation of the luminogenic substrate Luciferin-H using CYP2C9-containing enzyme bags proceeded efficiently and stably for 24h. CYP4Z1 is of interest because it is strongly overexpressed both in breast cancer cells and in breast cancer metastases; however, current knowledge about its catalytic properties is very limited. Screening of CYP4Z1-containing enzyme bags with 15 luminogenic substrates enabled us to identify two new hydroxylations and eleven ether cleavage reactions that are catalyzed by CYP4Z1. By far the best substrate found in this study was Luciferin benzyl ether (Luciferin-BE). On the basis of the recently published crystal structure of CYP4B1 we created a new homology model of CYP4Z1 and performed molecular docking experiments, which indicate that all active substrates show a highly similar binding geometry compared to the endogenous substrates. The model predicts that Ser113, Ser222, Asn381, and Ser383 are key hydrogen bonding residues. We also identified five new inhibitors of CYP4Z1: miconazole, econazole, aminobenzotriazole, tolazoline, and 1-benzylimidazole respectively, with the last compound being the most potent giving an IC50 value of 180nM in our test system.
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Colombero C, Papademetrio D, Sacca P, Mormandi E, Alvarez E, Nowicki S. Role of 20-Hydroxyeicosatetraenoic Acid (20-HETE) in Androgen-Mediated Cell Viability in Prostate Cancer Cells. HORMONES & CANCER 2017; 8:243-256. [PMID: 28639228 PMCID: PMC10355871 DOI: 10.1007/s12672-017-0299-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2017] [Accepted: 06/05/2017] [Indexed: 01/18/2023]
Abstract
20-Hydroxyeicosatetraenoic acid (20-HETE) is generated intracellularly through the ω-hydroxylation of arachidonic acid by the cytochrome P450 (in humans, CYP4A11 and CYP4F2). 20-HETE induces mitogenic responses in different cancer cells. The aim of this study was to analyze how 20-HETE impacts cell survival, proliferation, and apoptosis in prostate cancer cells. Incubation of the human androgen-sensitive cells (LNCaP) with 1-10 μM HET0016 (a selective inhibitor of 20-HETE synthesis) reduced cell viability by 49*-64%* (*p < 0.05 vs. control). This was explained by a reduction in cell proliferation (vehicle, 46 ± 3%; 1 μM, 23 ± 3%*; 10 μM, 28 ± 3%*) and by an increase in apoptosis (vehicle, 2.1 ± 0%; 1 μM, 16 ± 4%*; 10 μM, 31 ± 3%*). Furthermore, the increase in LNCaP cell viability induced by dihydrotestosterone (DHT, 0.1 nM) was abrogated by 30*-42%* by 1-10 μM HET0016. Incubation with 20-HETE (5-1000 nM) increased LNCaP cell viability up to 50%*, together with a 70%* reduction in apoptosis. PC-3 (androgen-insensitive) cell viability was not affected by either HET0016 or 20-HETE. In LNCaP cells, HET0016 (10 μM) diminished the expression of androgen receptors (AR): messenger RNA (mRNA) (40%*) and protein (50%*). DHT (10 nM) augmented CYP4F2 protein expression (1.9-fold*) and 20-HETE levels (50%*). Oppositely, enzalutamide (AR antagonist) reduced CYP4F2 mRNA and protein expressions by 30 and 25%, respectively. Thus, intracellular availability of 20-HETE is necessary to sustain LNCaP cell viability. 20-HETE may act as a signaling molecule in the pathways involved in LNCaP cell viability upon stimulation of the AR. This effect may be partially attributed to its role on securing normal AR expression levels that in turn contribute to maintain intracellular levels of 20-HETE.
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Affiliation(s)
- Cecilia Colombero
- Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Fundación de Endocrinología Infantil, División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1360, C1425EFD, Buenos Aires, Argentina
| | - Daniela Papademetrio
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquimica - Instituto de Estudios de la Inmunidad Humoral Prof Ricardo Margni. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Junin 954, C1113AAD, Buenos Aires, Argentina
| | - Paula Sacca
- Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - Eduardo Mormandi
- Laboratorio de Endocrinología, División Endocrinología, Hospital Carlos G. Durand, Av. Díaz Vélez 5044, C1405DCS, Buenos Aires, Argentina
| | - Elida Alvarez
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquimica - Instituto de Estudios de la Inmunidad Humoral Prof Ricardo Margni. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Junin 954, C1113AAD, Buenos Aires, Argentina
| | - Susana Nowicki
- Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Fundación de Endocrinología Infantil, División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1360, C1425EFD, Buenos Aires, Argentina.
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22
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Zhou J, Yang W, Hu Y, Höti N, Liu Y, Shah P, Sun S, Clark D, Thomas S, Zhang H. Site-Specific Fucosylation Analysis Identifying Glycoproteins Associated with Aggressive Prostate Cancer Cell Lines Using Tandem Affinity Enrichments of Intact Glycopeptides Followed by Mass Spectrometry. Anal Chem 2017; 89:7623-7630. [PMID: 28627880 PMCID: PMC5599242 DOI: 10.1021/acs.analchem.7b01493] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Fucosylation (Fuc) of glycoproteins plays an important role in regulating protein function and has been associated with the development of several cancer types including prostate cancer (Pca). Therefore, the research of Fuc glycoproteins has attracted increasing attention recently in the analytical field. Herein, a strategy based on lectin affinity enrichments of intact glycopeptides followed by mass spectrometry has been established to evaluate the specificities of various Fuc-binding lectins for glycosite-specific Fuc analysis of nonaggressive (NAG) and aggressive (AG) Pca cell lines. The enrichment specificities of Fuc glycopeptides using lectins (LCA, PSA, AAL, LTL, UEA I, and AOL) and MAX extraction cartridges alone, or in tandem, were evaluated. Our results showed that the use of lectin enrichment significantly increased the ratio of fucosylated glycopeptides to total glycopeptides compared to MAX enrichment. Furthermore, tandem use of lectin followed by MAX increased the number of identifications of Fuc glycopeptides compared to using lectin enrichment alone. LCA, PSA, and AOL showed stronger binding capacity than AAL, LTL, and UEA I. Also, LCA and PSA bound specifically to core Fuc, whereas AOL, AAL, and UEA I showed binding to both core Fuc and branch Fuc. The optimized enrichment method with tandem enrichment of LCA followed by MAX (LCA-MAX) was then applied to examine the Fuc glycoproteomes in two NAG and two AG Pca cell lines. In total, 973 intact Fuc glycopeptides were identified and quantified from 252 Fuc proteins by using the tandem-mass-tags (TMT) labeling and nanoliquid chromatography-mass spectrometry (nanoLC-MS/MS) analysis. Further data analysis revealed that 51 Fuc glycopeptides were overexpressed more than 2-fold in AG cell lines compared to NAG cells. The analysis of protein core fucosylation has great potential for aiding our understanding of invasive activity of AG Pca and may lead to the development of diagnostic approaches for AG Pca.
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Affiliation(s)
- Jianliang Zhou
- Department of Pathology, Johns Hopkins University, Baltimore 21287, Maryland United States
- Department of Traditional Chinese Medicines, Zhejiang Institute for Food and Drug Control, Hangzhou 310052, China
| | - Weiming Yang
- Department of Pathology, Johns Hopkins University, Baltimore 21287, Maryland United States
| | - Yingwei Hu
- Department of Pathology, Johns Hopkins University, Baltimore 21287, Maryland United States
| | - Naseruddin Höti
- Department of Pathology, Johns Hopkins University, Baltimore 21287, Maryland United States
| | - Yang Liu
- Department of Pathology, Johns Hopkins University, Baltimore 21287, Maryland United States
| | - Punit Shah
- Department of Pathology, Johns Hopkins University, Baltimore 21287, Maryland United States
| | - Shisheng Sun
- Department of Pathology, Johns Hopkins University, Baltimore 21287, Maryland United States
| | - David Clark
- Department of Pathology, Johns Hopkins University, Baltimore 21287, Maryland United States
| | - Stefani Thomas
- Department of Pathology, Johns Hopkins University, Baltimore 21287, Maryland United States
| | - Hui Zhang
- Department of Pathology, Johns Hopkins University, Baltimore 21287, Maryland United States
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Green WJF, Ball G, Powe D. Does the molecular classification of breast cancer point the way for biomarker identification in prostate cancer? World J Clin Urol 2016; 5:80-89. [DOI: 10.5410/wjcu.v5.i2.80] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 06/27/2016] [Accepted: 07/13/2016] [Indexed: 02/06/2023] Open
Abstract
There is significant variation in clinical outcome between patients diagnosed with prostate cancer (CaP). Although useful, statistical nomograms and risk stratification tools alone do not always accurately predict an individual’s need for and response to treatment. The factors that determine this variation are not fully elucidated. In particular, cellular response to androgen ablation and subsequent paracrine/autocrine adaptation is poorly understood and despite best therapies, median survival in castrate resistant patients is only approximately 35 mo. We propose that one way of understanding this is to look for correlates in other comparable malignancies, such as breast cancer, where markers of at least 4 distinct gene clusters coding for 4 different phenotypic subtypes have been identified. These subtypes have been shown to demonstrate prognostic significance and successfully guide appropriate treatment regimens. In this paper we assess and review the evidence demonstrating parallels in the biology and treatment approach between breast and CaP, and consider the feasibility of patients with CaP being stratified into different molecular classes that could be used to complement prostate specific antigen and histological grading for clinical decision making. We show that there are significant correlations between the molecular classification of breast and CaP and explain how techniques used successfully to predict response to treatment in breast cancer can be applied to the prostate. Molecular phenotyping is possible in CaP and identification of distinct subtypes may allow personalised risk stratification way beyond that currently available.
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Zhao SG, Evans JR, Kothari V, Sun G, Larm A, Mondine V, Schaeffer EM, Ross AE, Klein EA, Den RB, Dicker AP, Karnes RJ, Erho N, Nguyen PL, Davicioni E, Feng FY. The Landscape of Prognostic Outlier Genes in High-Risk Prostate Cancer. Clin Cancer Res 2015; 22:1777-86. [DOI: 10.1158/1078-0432.ccr-15-1250] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Accepted: 11/03/2015] [Indexed: 11/16/2022]
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25
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Shuvaev VV, Brenner JS, Muzykantov VR. Targeted endothelial nanomedicine for common acute pathological conditions. J Control Release 2015; 219:576-595. [PMID: 26435455 DOI: 10.1016/j.jconrel.2015.09.055] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Revised: 09/24/2015] [Accepted: 09/25/2015] [Indexed: 12/16/2022]
Abstract
Endothelium, a thin monolayer of specialized cells lining the lumen of blood vessels is the key regulatory interface between blood and tissues. Endothelial abnormalities are implicated in many diseases, including common acute conditions with high morbidity and mortality lacking therapy, in part because drugs and drug carriers have no natural endothelial affinity. Precise endothelial drug delivery may improve management of these conditions. Using ligands of molecules exposed to the bloodstream on the endothelial surface enables design of diverse targeted endothelial nanomedicine agents. Target molecules and binding epitopes must be accessible to drug carriers, carriers must be free of harmful effects, and targeting should provide desirable sub-cellular addressing of the drug cargo. The roster of current candidate target molecules for endothelial nanomedicine includes peptidases and other enzymes, cell adhesion molecules and integrins, localized in different domains of the endothelial plasmalemma and differentially distributed throughout the vasculature. Endowing carriers with an affinity to specific endothelial epitopes enables an unprecedented level of precision of control of drug delivery: binding to selected endothelial cell phenotypes, cellular addressing and duration of therapeutic effects. Features of nanocarrier design such as choice of epitope and ligand control delivery and effect of targeted endothelial nanomedicine agents. Pathological factors modulate endothelial targeting and uptake of nanocarriers. Selection of optimal binding sites and design features of nanocarriers are key controllable factors that can be iteratively engineered based on their performance from in vitro to pre-clinical in vivo experimental models. Targeted endothelial nanomedicine agents provide antioxidant, anti-inflammatory and other therapeutic effects unattainable by non-targeted counterparts in animal models of common acute severe human disease conditions. The results of animal studies provide the basis for the challenging translation endothelial nanomedicine into the clinical domain.
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Affiliation(s)
- Vladimir V Shuvaev
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States; Center for Translational Targeted Therapeutics and Nanomedicine of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Jacob S Brenner
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States; Center for Translational Targeted Therapeutics and Nanomedicine of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Vladimir R Muzykantov
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States; Center for Translational Targeted Therapeutics and Nanomedicine of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
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26
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Morley S, Hager MH, Pollan SG, Knudsen B, Di Vizio D, Freeman MR. Trading in your spindles for blebs: the amoeboid tumor cell phenotype in prostate cancer. Asian J Androl 2015; 16:530-5. [PMID: 24589458 PMCID: PMC4104075 DOI: 10.4103/1008-682x.122877] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Affiliation(s)
| | | | | | | | - Dolores Di Vizio
- Division of Cancer Biology and Therapeutics, Departments of Surgery, Medicine and Biomedical Sciences, and The Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA; Urological Diseases Research Center, Boston Children's Hospital and Department of Surgery, Harvard Medical School, Boston, MA, USA
| | - Michael R Freeman
- Division of Cancer Biology and Therapeutics, Departments of Surgery, Medicine and Biomedical Sciences, and The Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA; Urological Diseases Research Center, Boston Children's Hospital; Department of Surgery, Harvard Medical School, Boston, MA and Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
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27
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Johnson AL, Edson KZ, Totah RA, Rettie AE. Cytochrome P450 ω-Hydroxylases in Inflammation and Cancer. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2015; 74:223-62. [PMID: 26233909 DOI: 10.1016/bs.apha.2015.05.002] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Cytochrome P450-dependent ω-hydroxylation is a prototypic metabolic reaction of CYP4 family members that is important for the elimination and bioactivation of not only therapeutic drugs, but also endogenous compounds, principally fatty acids. Eicosanoids, derived from arachidonic acid, are key substrates in the latter category. Human CYP4 enzymes, mainly CYP4A11, CYP4F2, and CYP4F3B, hydroxylate arachidonic acid at the omega position to form 20-HETE, which has important effects in tumor progression and on angiogenesis and blood pressure regulation in the vasculature and kidney. CYP4F3A in myeloid tissue catalyzes the ω-hydroxylation of leukotriene B4 to 20-hydroxy leukotriene B4, an inactivation process that is critical for the regulation of the inflammatory response. Here, we review the enzymology, tissue distribution, and substrate selectivity of human CYP4 ω-hydroxylases and their roles as catalysts for the formation and termination of the biological effects of key eicosanoid metabolites in inflammation and cancer progression.
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Affiliation(s)
- Amanda L Johnson
- Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington, USA
| | - Katheryne Z Edson
- Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington, USA; Amgen Inc., Thousand Oaks, California, USA
| | - Rheem A Totah
- Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington, USA
| | - Allan E Rettie
- Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington, USA.
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28
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Li QK, Chen L, Ao MH, Chiu JH, Zhang Z, Zhang H, Chan DW. Serum fucosylated prostate-specific antigen (PSA) improves the differentiation of aggressive from non-aggressive prostate cancers. Theranostics 2015; 5:267-76. [PMID: 25553114 PMCID: PMC4279190 DOI: 10.7150/thno.10349] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2014] [Accepted: 11/01/2014] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Clinically, it is still challenging to differentiate aggressive from non-aggressive prostate cancers (Pca) by non-invasive approaches. Our recent studies showed that overexpression of alpha (1-6) fucosyltransferase played an important role in Pca cells. In this study, we have investigated levels of glycoproteins and their fucosylated glycoforms in sera of Pca patients, as well as the potential utility of fucosylated glycoproteins in the identification of aggressive Pca. MATERIAL AND METHODS Serum samples from histomorphology-proven Pca cases were included. Prostate-specific antigen (PSA), tissue inhibitor of metallopeptidase 1 (TIMP1) and tissue plasminogen activator (tPA), and their fucosylated glycoforms were captured by Aleuria Aurantia Lectin (AAL), followed by the multiplex magnetic bead-based immunoassay. The level of fucosylated glycoproteins was correlated with patients' Gleason score of the tumor. RESULT Among three fucosylated glycoproteins, the fucosylated PSA was significantly increased and correlated with the tumor Gleason score (p<0.05). The ratio of fucosylated PSA showed a marked increase in aggressive tumors in comparison to non-aggressive tumors. ROC analysis also showed an improved predictive power of fucosylated PSA in the identification of aggressive Pca. CONCLUSIONS Our data demonstrated that fucosylated PSA has a better predictive power to differentiate aggressive tumors from non-aggressive tumors, than that of native PSA and two other glycoproteins. The fucosylated PSA has the potential to be used as a surrogate biomarker.
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Affiliation(s)
- Qing Kay Li
- Departments of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA
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29
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Whitaker HC, Shiong LL, Kay JD, Grönberg H, Warren AY, Seipel A, Wiklund F, Thomas B, Wiklund P, Miller JL, Menon S, Ramos-Montoya A, Vowler SL, Massie C, Egevad L, Neal DE. N-acetyl-L-aspartyl-L-glutamate peptidase-like 2 is overexpressed in cancer and promotes a pro-migratory and pro-metastatic phenotype. Oncogene 2014; 33:5274-87. [PMID: 24240687 DOI: 10.1038/onc.2013.464] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Revised: 08/27/2013] [Accepted: 09/16/2013] [Indexed: 02/02/2023]
Abstract
N-acetyl-L-aspartyl-L-glutamate peptidase-like 2 (NAALADL2) is a member of the glutamate carboxypeptidase II family, best characterized by prostate-specific membrane antigen (PSMA/NAALAD1). Using immunohistochemistry (IHC), we have shown overexpression of NAALADL2 in colon and prostate tumours when compared with benign tissue. In prostate cancer, NAALADL2 expression was associated with stage and Grade, as well as circulating mRNA levels of the NAALADL2 gene. Overexpression of NAALADL2 was shown to predict poor survival following radical prostatectomy. In contrast to PSMA/NAALAD1, NAALADL2 was localized at the basal cell surface where it promotes adhesion to extracellular matrix proteins. Using stable knockdown and overexpression cell lines, we have demonstrated NAALADL2-dependent changes in cell migration, invasion and colony-forming potential. Expression arrays of the knockdown and overexpression cell lines have identified nine genes that co-expressed with NAALADL2, which included membrane proteins and genes known to be androgen regulated, including the prostate cancer biomarkers AGR2 and SPON2. Androgen regulation was confirmed in a number of these genes, although NAALADL2 itself was not found to be androgen regulated. NAALADL2 was also found to regulate levels of Ser133 phosphorylated C-AMP-binding protein (CREB), a master regulator of a number of cellular processes involved in cancer development and progression. In combination, these data suggest that changes in expression of NAALADL2 can impact upon a number of pro-oncogenic pathways and processes, making it a useful biomarker for both diagnosis and prognosis.
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Affiliation(s)
- H C Whitaker
- 1] Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK [2] Cancer Research UK Biomarker Initiative, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - L L Shiong
- Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - J D Kay
- Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - H Grönberg
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
| | - A Y Warren
- 1] Department of Histopathology and ISH Core Facility, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK [2] Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - A Seipel
- Department of Pathology, Karolinska Institute, Stockholm, Sweden
| | - F Wiklund
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
| | - B Thomas
- Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - P Wiklund
- Department of Pathology, Karolinska Institute, Stockholm, Sweden
| | - J L Miller
- 1] Department of Histopathology and ISH Core Facility, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK [2] Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - S Menon
- Bioinformatics Core Facility, Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, UK
| | - A Ramos-Montoya
- Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - S L Vowler
- Bioinformatics Core Facility, Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, UK
| | - C Massie
- Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - L Egevad
- Department of Pathology, Karolinska Institute, Stockholm, Sweden
| | - D E Neal
- Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
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Abstract
Hey bHLH transcription factors are direct targets of canonical Notch signaling. The three mammalian Hey proteins are closely related to Hes proteins and they primarily repress target genes by either directly binding to core promoters or by inhibiting other transcriptional activators. Individual candidate gene approaches and systematic screens identified a number of Hey target genes, which often encode other transcription factors involved in various developmental processes. Here, we review data on interaction partners and target genes and conclude with a model for Hey target gene regulation. Furthermore, we discuss how expression of Hey proteins affects processes like cell fate decisions and differentiation, e.g., in cardiovascular, skeletal, and neural development or oncogenesis and how this relates to the observed developmental defects and phenotypes observed in various knockout mice.
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Affiliation(s)
- David Weber
- Developmental Biochemistry, Theodor-Boveri-Institute/Biocenter, Wuerzburg University, Wuerzburg, Germany
| | - Cornelia Wiese
- Developmental Biochemistry, Theodor-Boveri-Institute/Biocenter, Wuerzburg University, Wuerzburg, Germany
| | - Manfred Gessler
- Developmental Biochemistry, Theodor-Boveri-Institute/Biocenter, Wuerzburg University, Wuerzburg, Germany; Comprehensive Cancer Center Mainfranken, Wuerzburg University, Wuerzburg, Germany.
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A combination of paclitaxel and siRNA-mediated silencing of Stathmin inhibits growth and promotes apoptosis of nasopharyngeal carcinoma cells. Cell Oncol (Dordr) 2013; 37:53-67. [DOI: 10.1007/s13402-013-0163-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/18/2013] [Indexed: 12/30/2022] Open
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32
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Mistry SJ, Oh WK. New paradigms in microtubule-mediated endocrine signaling in prostate cancer. Mol Cancer Ther 2013; 12:555-66. [PMID: 23635655 DOI: 10.1158/1535-7163.mct-12-0871] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Metastatic prostate cancer has limited therapeutic options and has remained a major clinical challenge. Historically, prostate cancer has been widely recognized as a chemotherapy-resistant disease. However, clinical studies with anti-microtubule agents over the past decade have shown important efficacy in improving survival in patients with advanced disease. The favorable outcomes with microtubule-targeted agents have thus rekindled interest in such therapies for the clinical management of prostate cancer. Microtubules are dynamic polymers of tubulin molecules that play diverse roles within the cell. The dynamic property of microtubules is responsible for forming the bipolar mitotic apparatus, the mitotic spindle, that functions to precisely segregate the chromosomes during cell division. Thus, owing to the pivotal role that they play in the orchestration of mitotic events, microtubules provide excellent targets for anti-cancer therapy. Recent evidence also suggests that microtubules play a crucial role in the regulation of endocrine signaling pathways. Interestingly, microtubule-targeted agents such as taxanes not only inhibit cell division but also impair endocrine receptor signaling in prostate cancer. Herein, we provide an overview of the current status of microtubule-targeted therapies that are used in the treatment of prostate cancer and discuss novel mechanisms by which such therapies modulate endocrine signaling in prostate cancer. We also address the emerging roles of microtubule regulatory proteins in prostate carcinogenesis that could serve as attractive targets for prostate cancer therapy and might also serve as predictive biomarkers to identify patients who may benefit from endocrine and/or chemotherapy. This may have important implications in designing mechanism-based and targeted-therapeutic strategies for prostate cancer.
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Affiliation(s)
- Sucharita J Mistry
- Division of Hematology-Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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You HW, Jung SB, Jeon SH, Chang SG, Kim JI, Lim JW. Does the Presence of Hypoechoic Lesions on Transrectal Ultrasound Suggest a Poor Prognosis for Patients With Localized Prostate Cancer? Korean J Urol 2013; 54:11-4. [PMID: 23362441 PMCID: PMC3556546 DOI: 10.4111/kju.2013.54.1.11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Accepted: 10/17/2012] [Indexed: 11/18/2022] Open
Abstract
Purpose Materials and Methods Results Conclusions
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Affiliation(s)
- Hyun Wook You
- Department of Urology, Kyung Hee University School of Medicine, Seoul, Korea
| | - Sae Bin Jung
- Department of Urology, Kyung Hee University School of Medicine, Seoul, Korea
| | - Seung Hyun Jeon
- Department of Urology, Kyung Hee University School of Medicine, Seoul, Korea
| | - Sung-Goo Chang
- Department of Urology, Kyung Hee University School of Medicine, Seoul, Korea
| | - Jin Il Kim
- Department of Urology, Kyung Hee University School of Medicine, Seoul, Korea
| | - Ju Won Lim
- Department of Radiology, Kyung Hee University School of Medicine, Seoul, Korea
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