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1
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Ponnam D, Arigari NK, Kalvagunta Venkata Naga SS, Jonnala KK, Singh S, Meena A, Misra P, Luqman S. Synthesis of non‐toxic anticancer active forskolin‐indole‐triazole conjugates along with their in silico succinate dehydrogenase inhibition studies. J Heterocycl Chem 2021. [DOI: 10.1002/jhet.4332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Devendar Ponnam
- Natural Product Chemistry Division CSIR‐Central Institute of Medicinal and Aromatic Plants, Research Centre Boduppal Hyderabad India
| | - Niranjana Kumar Arigari
- Natural Product Chemistry Division CSIR‐Central Institute of Medicinal and Aromatic Plants, Research Centre Boduppal Hyderabad India
| | | | - Kotesh Kumar Jonnala
- Natural Product Chemistry Division CSIR‐Central Institute of Medicinal and Aromatic Plants, Research Centre Boduppal Hyderabad India
| | - Shilpi Singh
- Molecular Bio‐Prospection Department CSIR‐Central Institute of Medicinal and Aromatic Plants Lucknow India
| | - Abha Meena
- Metabolic and Structural Biology Department CSIR‐Central Institute of Medicinal and Aromatic Plants Lucknow India
| | - Pallavi Misra
- Molecular Bio‐Prospection Department CSIR‐Central Institute of Medicinal and Aromatic Plants Lucknow India
| | - Suaib Luqman
- Molecular Bio‐Prospection Department CSIR‐Central Institute of Medicinal and Aromatic Plants Lucknow India
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Smith JN, Dawson DM, Christo KF, Jogasuria AP, Cameron MJ, Antczak MI, Ready JM, Gerson SL, Markowitz SD, Desai AB. 15-PGDH inhibition activates the splenic niche to promote hematopoietic regeneration. JCI Insight 2021; 6:143658. [PMID: 33600377 PMCID: PMC8026178 DOI: 10.1172/jci.insight.143658] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 02/17/2021] [Indexed: 01/08/2023] Open
Abstract
The splenic microenvironment regulates hematopoietic stem and progenitor cell (HSPC) function, particularly during demand-adapted hematopoiesis; however, practical strategies to enhance splenic support of transplanted HSPCs have proved elusive. We have previously demonstrated that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using the small molecule (+)SW033291 (PGDHi), increases BM prostaglandin E2 (PGE2) levels, expands HSPC numbers, and accelerates hematologic reconstitution after BM transplantation (BMT) in mice. Here we demonstrate that the splenic microenvironment, specifically 15-PGDH high-expressing macrophages, megakaryocytes (MKs), and mast cells (MCs), regulates steady-state hematopoiesis and potentiates recovery after BMT. Notably, PGDHi-induced neutrophil, platelet, and HSPC recovery were highly attenuated in splenectomized mice. PGDHi induced nonpathologic splenic extramedullary hematopoiesis at steady state, and pretransplant PGDHi enhanced the homing of transplanted cells to the spleen. 15-PGDH enzymatic activity localized specifically to macrophages, MK lineage cells, and MCs, identifying these cell types as likely coordinating the impact of PGDHi on splenic HSPCs. These findings suggest that 15-PGDH expression marks HSC niche cell types that regulate hematopoietic regeneration. Therefore, PGDHi provides a well-tolerated strategy to therapeutically target multiple HSC niches, promote hematopoietic regeneration, and improve clinical outcomes of BMT.
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Affiliation(s)
- Julianne Np Smith
- Department of Medicine and Case Comprehensive Cancer Center Case Western Reserve University, Cleveland, Ohio, USA
| | - Dawn M Dawson
- Department of Medicine and Case Comprehensive Cancer Center Case Western Reserve University, Cleveland, Ohio, USA
| | - Kelsey F Christo
- Department of Medicine and Case Comprehensive Cancer Center Case Western Reserve University, Cleveland, Ohio, USA
| | - Alvin P Jogasuria
- Department of Medicine and Case Comprehensive Cancer Center Case Western Reserve University, Cleveland, Ohio, USA
| | - Mark J Cameron
- Department of Medicine and Case Comprehensive Cancer Center Case Western Reserve University, Cleveland, Ohio, USA
| | - Monika I Antczak
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Joseph M Ready
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.,Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Stanton L Gerson
- Department of Medicine and Case Comprehensive Cancer Center Case Western Reserve University, Cleveland, Ohio, USA.,University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA
| | - Sanford D Markowitz
- Department of Medicine and Case Comprehensive Cancer Center Case Western Reserve University, Cleveland, Ohio, USA.,University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA
| | - Amar B Desai
- Department of Medicine and Case Comprehensive Cancer Center Case Western Reserve University, Cleveland, Ohio, USA
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Slco2a1 deficiency exacerbates experimental colitis via inflammasome activation in macrophages: a possible mechanism of chronic enteropathy associated with SLCO2A1 gene. Sci Rep 2020; 10:4883. [PMID: 32184453 PMCID: PMC7078201 DOI: 10.1038/s41598-020-61775-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 03/04/2020] [Indexed: 12/15/2022] Open
Abstract
Loss-of-function mutations in the solute carrier organic anion transporter family, member 2a1 gene (SLCO2A1), which encodes a prostaglandin (PG) transporter, have been identified as causes of chronic nonspecific multiple ulcers in the small intestine; however, the underlying mechanisms have not been revealed. We, therefore, evaluated the effects of systemic knockout of Slco2a1 (Slco2a1−/−) and conditional knockout in intestinal epithelial cells (Slco2a1ΔIEC) and macrophages (Slco2a1ΔMP) in mice with dextran sodium sulphate (DSS)-induced acute colitis. Slco2a−/− mice were more susceptible to DSS-induced colitis than wild-type (WT) mice, but did not spontaneously develop enteritis or colitis. The nucleotide-binding domain, leucine-rich repeats containing family, pyrin domain-containing-3 (NLRP3) inflammasome was more strongly upregulated in colon tissues of Slco2a−/− mice administered DSS and in macrophages isolated from Slco2a1−/− mice than in the WT counterparts. Slco2a1ΔMP, but not Slco2a1ΔIEC mice, were more susceptible to DSS-induced colitis than WT mice, partly phenocopying Slco2a−/− mice. Concentrations of PGE2 in colon tissues and macrophages from Slco2a1−/− mice were significantly higher than those of WT mice. Blockade of inflammasome activation suppressed the exacerbation of colitis. These results indicated that Slco2a1-deficiency increases the PGE2 concentration, resulting in NLRP3 inflammasome activation in macrophages, thus exacerbating intestinal inflammation.
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Zhang Y, Desai A, Yang SY, Bae KB, Antczak MI, Fink SP, Tiwari S, Willis JE, Williams NS, Dawson DM, Wald D, Chen WD, Wang Z, Kasturi L, Larusch GA, He L, Cominelli F, Di Martino L, Djuric Z, Milne GL, Chance M, Sanabria J, Dealwis C, Mikkola D, Naidoo J, Wei S, Tai HH, Gerson SL, Ready JM, Posner B, Willson JKV, Markowitz SD. TISSUE REGENERATION. Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration. Science 2015; 348:aaa2340. [PMID: 26068857 DOI: 10.1126/science.aaa2340] [Citation(s) in RCA: 200] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. Here, we show that inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs in mice. In a chemical screen, we identify a small-molecule inhibitor of 15-PGDH (SW033291) that increases prostaglandin PGE2 levels in bone marrow and other tissues. SW033291 accelerates hematopoietic recovery in mice receiving a bone marrow transplant. The same compound also promotes tissue regeneration in mouse models of colon and liver injury. Tissues from 15-PGDH knockout mice demonstrate similar increased regenerative capacity. Thus, 15-PGDH inhibition may be a valuable therapeutic strategy for tissue regeneration in diverse clinical contexts.
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Affiliation(s)
- Yongyou Zhang
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Amar Desai
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Sung Yeun Yang
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. Department of Gastroenterology, Haeundae Paik Hospital, Inje University, Busan 612896, South Korea
| | - Ki Beom Bae
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. Department of Surgery, Busan Paik Hospital, and Paik Institute of Clinical Research and Ocular Neovascular Research Center, Inje University, Busan, South Korea
| | - Monika I Antczak
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Stephen P Fink
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Shruti Tiwari
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. Case Medical Center, University Hospitals of Cleveland, Cleveland, OH 44106, USA
| | - Joseph E Willis
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. Case Medical Center, University Hospitals of Cleveland, Cleveland, OH 44106, USA
| | - Noelle S Williams
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Dawn M Dawson
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - David Wald
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. Case Medical Center, University Hospitals of Cleveland, Cleveland, OH 44106, USA
| | - Wei-Dong Chen
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Zhenghe Wang
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Lakshmi Kasturi
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Gretchen A Larusch
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Lucy He
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Fabio Cominelli
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. Case Medical Center, University Hospitals of Cleveland, Cleveland, OH 44106, USA
| | - Luca Di Martino
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Zora Djuric
- Department of Family Medicine, University of Michigan, Ann Arbor MI 48109, USA
| | - Ginger L Milne
- Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA
| | - Mark Chance
- Proteomics Center, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Juan Sanabria
- Department of Surgery, Case Western Reserve University, Cleveland, OH 44106, USA. Case Medical Center, University Hospitals of Cleveland, Cleveland, OH 44106, USA
| | - Chris Dealwis
- Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Debra Mikkola
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Jacinth Naidoo
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Shuguang Wei
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Hsin-Hsiung Tai
- College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA
| | - Stanton L Gerson
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. Case Medical Center, University Hospitals of Cleveland, Cleveland, OH 44106, USA.
| | - Joseph M Ready
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
| | - Bruce Posner
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
| | - James K V Willson
- Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
| | - Sanford D Markowitz
- Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. Case Medical Center, University Hospitals of Cleveland, Cleveland, OH 44106, USA.
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Dai L, King DW, Perera DS, Lubowski DZ, Burcher E, Liu L. Inverse expression of prostaglandin E2-related enzymes highlights differences between diverticulitis and inflammatory bowel disease. Dig Dis Sci 2015; 60:1236-46. [PMID: 25666316 DOI: 10.1007/s10620-014-3478-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 11/30/2014] [Indexed: 12/30/2022]
Abstract
BACKGROUND Prostaglandin E2 (PGE2) is the dominant prostaglandin in the colon and is associated with colonic inflammation. PGE2 levels are regulated not only by cyclooxygenases (COX-1 and COX-2) but also by 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the major PGE2-degrading enzyme. Information about the involvement of 15-PGDH in colonic inflammation is sparse. AIM We thus aimed to determine the gene expression and immunoreactivity (IR) of COX-1, COX-2, and 15-PGDH in colonic mucosa from patients with diverse inflammatory disorders: ulcerative colitis (UC), Crohn's disease (CD), and acute diverticular disease (DD). METHODS RNA from human colonic mucosa was extracted and assessed for gene expression by real-time PCR. Intact colon sections were processed for immunohistochemistry with immunostaining of the mucosal areas quantified using ImageJ. RESULTS In colonic mucosa of both UC and CD, COX-2 mRNA and COX-2-IR were significantly increased, whereas 15-PGDH mRNA and 15-PGDH-IR were significantly reduced. In macroscopically undamaged acute DD mucosa, the opposite findings were seen: for both gene expression and immunoreactivity, there was a significant downregulation of COX-2 and upregulation of 15-PGDH. COX-1 mRNA and COX-1-IR remained unchanged in all diseases. CONCLUSIONS Our study for the first time demonstrated differential expression of the PGE2-related enzymes COX-2 and 15-PGDH in colonic mucosa from UC, CD, and acute DD. The reduction of 15-PGDH in IBD provides an additional mechanism for PGE2 increase in IBD. With respect to DD, alterations of PGE2-related enzymes suggest that a low PGE2 level may precede the onset of inflammation, thus providing new insight into the pathogenesis of DD.
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Affiliation(s)
- Liying Dai
- Department of Pharmacology, School of Medical Sciences, UNSW Australia, Sydney, NSW, 2052, Australia
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He N, Zheng H, Li P, Zhao Y, Zhang W, Song F, Chen K. miR-485-5p binding site SNP rs8752 in HPGD gene is associated with breast cancer risk. PLoS One 2014; 9:e102093. [PMID: 25003827 PMCID: PMC4087002 DOI: 10.1371/journal.pone.0102093] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Accepted: 06/13/2014] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Single nucleotide polymorphisms (SNPs) that reside in microRNA target sites may play an important role in breast cancer development and progression. To reveal the association between microRNA target site SNPs and breast cancer risk, we performed a large case-control study in China. METHODS We performed a two-stage case-control study including 2744 breast cancer cases and 3125 controls. In Stage I, we genotyped 192 SNPs within microRNA binding sites identified from the "Patrocles" database using custom Illumina GoldenGate VeraCode assays on the Illumina BeadXpress platform. In Stage II, genotyping was performed on SNPs potentially associated with breast cancer risk using the TaqMan platform in an independent replication set. RESULTS In stage I, 15 SNPs were identified to be significantly associated with breast cancer risk (P<0.05). In stage II, one SNP rs8752 was replicated at P<0.05. This SNP is located in the 3' untranslated region (UTR) of the 15-hydroxyprostaglandin dehydrogenase (HPGD) gene at 4q34-35, a miR-485-5p binding site. Compared with the GG genotype, the combined GA+AA genotypes has a significantly higher risk of breast cancer (OR = 1.18; 95% CI: 1.06-1.31, P = 0.002). Specifically, this SNP was associated with estrogen receptor (ER) positive breast cancer (P = 0.0007), but not with ER negative breast cancer (P = 0.23), though p for heterogeneity not significant. CONCLUSION Through a systematic case-control study of microRNA binding site SNPs, we identified a new breast cancer risk variant rs8752 in HPGD in Chinese women. Further studies are warranted to investigate the underling mechanism for this association.
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Affiliation(s)
- Na He
- Department of Epidemiology and Biostatistics, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, P. R. China
| | - Hong Zheng
- Department of Epidemiology and Biostatistics, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, P. R. China
| | - Pei Li
- Department of Epidemiology and Biostatistics, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, P. R. China
| | - Yanrui Zhao
- Department of Epidemiology and Biostatistics, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, P. R. China
| | - Wei Zhang
- Department of Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Fengju Song
- Department of Epidemiology and Biostatistics, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, P. R. China
- * E-mail:
| | - Kexin Chen
- Department of Epidemiology and Biostatistics, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, P. R. China
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15-PGDH/15-KETE plays a role in hypoxia-induced pulmonary vascular remodeling through ERK1/2-dependent PAR-2 pathway. Cell Signal 2014; 26:1476-88. [DOI: 10.1016/j.cellsig.2014.03.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2013] [Revised: 02/20/2014] [Accepted: 03/10/2014] [Indexed: 11/19/2022]
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Abstract
The PGE2 pathway is important in inflammation-driven diseases and specific targeting of the inducible mPGES-1 is warranted due to the cardiovascular problems associated with the long-term use of COX-2 inhibitors. This review focuses on patents issued on methods of measuring mPGES-1 activity, on drugs targeting mPGES-1 and on other modulators of free extracellular PGE2 concentration. Perspectives and conclusions regarding the status of these drugs are also presented. Importantly, no selective inhibitors targeting mPGES-1 have been identified and, despite the high number of published patents, none of these drugs have yet made it to clinical trials.
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9
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Kang JH, Kang SH, Seo SH, Shin JH, An MS, Ha TK, Bae KB, Kim TH, Choi CS, Oh SH, Kang MS, Kim KH. Relationship between 15-hydroxyprostaglandin dehydrogenase and gastric adenocarcinoma. Ann Surg Treat Res 2014; 86:302-8. [PMID: 24949321 PMCID: PMC4062450 DOI: 10.4174/astr.2014.86.6.302] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Revised: 01/14/2014] [Accepted: 02/12/2014] [Indexed: 01/29/2023] Open
Abstract
Purpose Prostaglandin E2 (PGE2) is a contributory carcinogen in gastric adenocarcinoma. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) catabolizes PGE2 by oxidizing its 15(s)-hydroxy group. The aim of this study was to investigate the expression of 15-PGDH in gastric adenocarcinoma tissue and the relationship between 15-PGDH expression and clinicopathologic features of gastric adenocarcinoma. Methods Ninety-nine patients who underwent surgical resection for gastric adenocarcinoma between January 2007 and December 2007 were enrolled and evaluated retrospectively. Results In 62 patients (62.6%), 15-PGDH expression was lower in gastric adenocarcinoma tissue than in nonneoplastic tissue. Regarding the relationship between 15-PGDH expression and clinicopathological features, 15-PGDH expression was significantly lower in tissues with poor differentiation (P = 0.002), advanced T stage (P = 0.0319), a higher number of lymph node metastases (P = 0.045), lymphatic invasion (P = 0.031), and vascular invasion (P = 0.036). Conclusion 15-PGDH expression was associated with a subset of clinicopathologic features such as differentiation grade, T stage, lymphatic invasion, and vascular invasion.
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Affiliation(s)
- Jae Hyun Kang
- Department of Surgery, Inje University College of Medicine, Busan, Korea
| | - Sang Hyun Kang
- Department of Surgery, Inje University College of Medicine, Busan, Korea
| | - Sang Hyuk Seo
- Department of Surgery, Inje University College of Medicine, Busan, Korea
| | - Jae Ho Shin
- Department of Surgery, Inje University College of Medicine, Busan, Korea
| | - Min Sung An
- Department of Surgery, Inje University College of Medicine, Busan, Korea
| | - Tae Kwun Ha
- Department of Surgery, Inje University College of Medicine, Busan, Korea
| | - Ki Beom Bae
- Department of Surgery, Inje University College of Medicine, Busan, Korea
| | - Tae Hyun Kim
- Department of Surgery, Inje University College of Medicine, Busan, Korea
| | - Chang Soo Choi
- Department of Surgery, Inje University College of Medicine, Busan, Korea
| | - Sang Hoon Oh
- Department of Surgery, Inje University College of Medicine, Busan, Korea
| | - Mi Seon Kang
- Department of Surgery, Inje University College of Medicine, Busan, Korea
| | - Kwang Hee Kim
- Department of Surgery, Inje University College of Medicine, Busan, Korea
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Castro-Sánchez L, Agra N, Llorente Izquierdo C, Motiño O, Casado M, Boscá L, Martín-Sanz P. Regulation of 15-hydroxyprostaglandin dehydrogenase expression in hepatocellular carcinoma. Int J Biochem Cell Biol 2013; 45:2501-2511. [PMID: 23954207 DOI: 10.1016/j.biocel.2013.08.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Revised: 07/12/2013] [Accepted: 08/07/2013] [Indexed: 02/07/2023]
Abstract
Cyclooxygenase-2 (COX-2), a rate limiting step in arachidonic acid cascade, plays a key role in the biosynthesis of prostaglandin E2 (PGE2) upon inflammatory stimuli, growth factors, hormones and other cellular stresses. Overproduction of PGE2 stimulates proliferation of various cancer cells, confers resistance to apoptosis and favors metastasis and angiogenesis. The steady-state level of PGE2 is maintained by interplay between the biosynthetic pathway including COX and PGE2 synthases and the catabolic pathways involving nicotinamide adenine dinucleotide (NAD(+))-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). 15-PGDH is a crucial enzyme responsible for the biological inactivation of PGE2. Adult hepatocytes fail to induce COX-2 expression regardless of the pro-inflammatory factors used. COX-2 is induced in hepatocytes after partial hepatectomy (PH), in animal models of cirrhosis, in human hepatoma cell lines, in human HCC and after HBV and HCV infection. However, no data are available regarding 15-PGDH expression in HCC. Our results show that 15-PGDH is downregulated in human hepatoma cells with a high COX-2 expression, in chemical and genetic murine models of HCC and in human HCC biopsies. Moreover, 15-PGDH expression is suppressed by EGF (epidermal growth factor) and HGF (hepatocyte growth factor) mainly involving PI3K (phosphatidylinositol-3-kinase), ERK (extracellular signal-regulated kinase) and p38MAPK (mitogen-activated protein kinase) activation. Conversely, ectopic expression of 15-PGDH induces apoptosis in hepatoma cells and decreases the growth of hepatoma cells in nude mice whereas the silencing of 15-PGDH increases the tumor formation. These data suggest a potential therapeutic application of 15-PGDH in HCC.
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MESH Headings
- Adult
- Animals
- Apoptosis/drug effects
- Apoptosis/genetics
- Biopsy
- Carcinoma, Hepatocellular/enzymology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Cell Survival/drug effects
- Cell Survival/genetics
- Cyclooxygenase 2/metabolism
- Disease Models, Animal
- Down-Regulation/drug effects
- Down-Regulation/genetics
- Epidermal Growth Factor/pharmacology
- ErbB Receptors/metabolism
- Gene Expression Regulation, Enzymologic/drug effects
- Gene Expression Regulation, Neoplastic/drug effects
- Hepatocyte Growth Factor/pharmacology
- Humans
- Hydroxyprostaglandin Dehydrogenases/metabolism
- Intramolecular Oxidoreductases/metabolism
- Liver Neoplasms/enzymology
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- MAP Kinase Signaling System/drug effects
- MAP Kinase Signaling System/genetics
- Mice
- Mice, Inbred C57BL
- Phosphatidylinositol 3-Kinases/metabolism
- Prostaglandin-E Synthases
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
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Affiliation(s)
- Luis Castro-Sánchez
- Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Arturo Duperier, 4, 28029 Madrid, Spain
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Gheorghe KR, Sadique S, Leclerc P, Idborg H, Wobst I, Catrina AI, Jakobsson PJ, Korotkova M. Limited effect of anti-rheumatic treatment on 15-prostaglandin dehydrogenase in rheumatoid arthritis synovial tissue. Arthritis Res Ther 2012; 14:R121. [PMID: 22616846 PMCID: PMC3446502 DOI: 10.1186/ar3851] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2012] [Revised: 04/20/2012] [Accepted: 05/22/2012] [Indexed: 01/22/2023] Open
Abstract
Introduction Rheumatoid arthritis (RA) is a chronic inflammatory disease in which prostaglandin E2 (PGE2) displays an important pathogenic role. The enzymes involved in its synthesis are highly expressed in the inflamed synovium, while little is known about 15- prostaglandin dehydrogenase (15-PGDH) that metabolizes PGE2. Here we aimed to evaluate the localization of 15-PGDH in the synovial tissue of healthy individuals or patients with inflammatory arthritis and determine the influence of common RA therapy on its expression. Methods Synovial tissue specimens from healthy individuals, psoriatic arthritis, ostheoarthritis and RA patients were immunohistochemically stained to describe the expression pattern of 15-PGDH. In addition, the degree of enzyme staining was evaluated by computer analysis on stained synovial biopsies from two groups of RA patients, before and after RA specific treatment with either intra-articular glucocorticoids or oral methotrexate therapy. Prostaglandins derived from the cyclooxygenase (COX) pathway were determined by liquid-chromatography mass spectrometry in supernatants from interleukin (IL) 1β-activated fibroblast-like synoviocytes (FLS) treated with methotrexate. Results 15-PGDH was present in healthy and inflamed synovial tissue, mainly in lining macrophages, fibroblasts and vessels. Intra-articular glucocorticoids showed a trend towards reduced 15-PGDH expression in RA synovium (p = 0.08) while methotrexate treatment left the PGE2 pathway unaltered both in biopsies ex vivo and in cultured FLS. Conclusions Early methotrexate therapy has little influence on the expression of 15-PGDH and on any of the PGE2 synthesizing enzymes or COX-derived metabolites. Thus therapeutic strategies involving blocking induced PGE2 synthesis may find a rationale in additionally reducing local inflammatory mediators.
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Affiliation(s)
- Karina Roxana Gheorghe
- Department of Medicine, Rheumatology Unit, Karolinska Institute/Karolinska University Hospital Solna, Stockholm, 171 76 Sweden
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Lou LH, Jing DD, Lai YX, Lu YY, Li JK, Wu K. 15-PGDH is reduced and induces apoptosis and cell cycle arrest in gastric carcinoma. World J Gastroenterol 2012; 18:1028-37. [PMID: 22416177 PMCID: PMC3296976 DOI: 10.3748/wjg.v18.i10.1028] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2011] [Revised: 01/16/2012] [Accepted: 02/08/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in human gastric cancer and it’s mechanism in apoptosis and cell cycle arrest.
METHODS: Expression of 15-PGDH mRNA and protein was examined by immunohistochemistry, immunocytochemistry, reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting in tissue from human gastric cancer, gastric precancerous state (gastric polyps and atrophic gastritis), normal stomach, and gastric cancer cell lines. The relationship between gastric cancer, gastric precancerous state and 15-PGDH expression was determined. The association between expression of 15-PGDH and various clinicopathological parameters in gastric cancer was evaluated. Human gastric cancer cell line SGC-7901 was transfected with 15-PGDH expression plasmids. The effect of 15-PGDH on the cell cycle was examined by flow cytometry. The effect of 15-PGDH on apoptosis was examined by transmission electron microscopy, flow cytometry and transferase mediated nick end labeling (TUNEL) assay. Expression of cell cycle (p21, p27, p16 and p53) and apoptosis (Survivin, BCL-2, BCL-XL, BAK and BAX) genes was analyzed by RT-PCR.
RESULTS: Expression of 15-PGDH mRNA and protein in human gastric cancer tissues was significantly lower than in normal gastric tissues (P < 0.01). Expression in human gastric cancer cell lines MKN-28 and MKN-45 was reduced, and absent in SGC-7901 cells (P < 0.05). Reduction of 15-PGDH expression was also found in precancerous tissues, such as gastric polyps and atrophic gastritis (P < 0.01). There was a significant difference in expression of 15-PGDH among various gastric cancer pathological types (P < 0.05), with or without distant metastasis (P < 0.05) and different TNM stage (P < 0.01). Flow cytometry demonstrated a significant increase in apoptotic cells in SGC-7901 cells transfected with pcDNA3/15-PGDH plasmid for 24 h and 48 h (P < 0.01), and an increased fraction of sub-G1 phase after transfection (P < 0.05). TUNEL assay showed an increased apoptotic index in cells overexpressing 15-PGDH (P < 0.01). After transfection, expression of proapoptotic genes, such as BAK (P < 0.05), BAX and p53 (P < 0.01), was increased. Expression of antiapoptotic genes was decreased, such as Survivin, BCL-2 and BCL-XL (P < 0.01). Expression of cyclin-dependent kinase inhibitors p21 and p16 (P < 0.01) was significantly upregulated in cells overexpressing 15-PGDH.
CONCLUSION: Reduction of 15-PGDH is associated with carcinogenesis and development of gastric carcinoma. 15-PGDH induces apoptosis and cell cycle arrest in SGC-7901 cells.
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Na HK, Park JM, Lee HG, Lee HN, Myung SJ, Surh YJ. 15-Hydroxyprostaglandin dehydrogenase as a novel molecular target for cancer chemoprevention and therapy. Biochem Pharmacol 2011; 82:1352-60. [PMID: 21856294 DOI: 10.1016/j.bcp.2011.08.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2011] [Revised: 08/03/2011] [Accepted: 08/04/2011] [Indexed: 12/27/2022]
Abstract
Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in arachidonic acid cascade, plays a key role in the biosynthesis of prostaglandin E(2) (PGE(2)) upon inflammatory insults. Overproduction of PGE(2) stimulates proliferation of various cancer cells, confers resistance to apoptosis of cancerous or transformed cells, and accelerates metastasis and angiogenesis. Excess PGE(2) undergoes metabolic inactivation which is catalyzed by NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). In this context, 15-PGDH has been speculated as a physiological antagonist of COX-2 and a tumor suppressor. Thus, overexpression of 15-PGDH has been known to protect against experimentally induced carcinogenesis and renders the cancerous or transformed cells susceptible to apoptosis by counteracting oncogenic action of PGE(2). In contrast, silence of 15-PGDH is observed in some cancer cells, which is associated with epigenetic modification, such as DNA methylation and histone deacetylation, in the promoter region of 15-PGDH. A variety of compounds capable of inducing the expression of 15-PGDH have been reported, which include the histone deacetylase inhibitors, nonsteroidal anti-inflammatory drugs, and peroxisome proliferator-activated receptor-gamma agonists. Therefore, 15-PGDH may be considered as a novel molecular target for cancer chemoprevention and therapy. This review highlights the role of 15-PGDH in carcinogenesis and its regulation.
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Affiliation(s)
- Hye-Kyung Na
- Department of Food and Nutrition, College of Human Ecology, Sungshin Women's University, 147 Mia-dong, Kangbuk-gu, Seoul 142-100, South Korea
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Michelet JF, Colombe L, Gautier B, Gaillard O, Benech F, Pereira R, Boulle C, Dalko-Csiba M, Rozot R, Neuwels M, Bernard BA. Expression of NAD+dependent 15-hydroxyprostaglandin dehydrogenase and protection of prostaglandins in human hair follicle. Exp Dermatol 2008; 17:821-8. [DOI: 10.1111/j.1600-0625.2008.00706.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Krishnan AV, Moreno J, Nonn L, Malloy P, Swami S, Peng L, Peehl DM, Feldman D. Novel pathways that contribute to the anti-proliferative and chemopreventive activities of calcitriol in prostate cancer. J Steroid Biochem Mol Biol 2007; 103:694-702. [PMID: 17229571 DOI: 10.1016/j.jsbmb.2006.12.051] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2006] [Indexed: 12/20/2022]
Abstract
Calcitriol, the hormonally active form of Vitamin D, inhibits the growth and development of many cancers through multiple mechanisms. Our recent research supports the contributory role of several new and diverse pathways that add to the mechanisms already established as playing a role in the actions of calcitriol to inhibit the development and progression of prostate cancer (PCa). Calcitriol increases the expression of insulin-like growth factor binding protein-3 (IGFBP-3), which plays a critical role in the inhibition of PCa cell growth by increasing the expression of the cell cycle inhibitor p21. Calcitriol inhibits the prostaglandin (PG) pathway by three actions: (i) the inhibition of the expression of cyclooxygenase-2 (COX-2), the enzyme that synthesizes PGs, (ii) the induction of the expression of 15-prostaglandin dehydrogenase (15-PGDH), the enzyme that inactivates PGs and (iii) decreasing the expression of EP and FP PG receptors that are essential for PG signaling. Since PGs have been shown to promote carcinogenesis and progression of multiple cancers, the inhibition of the PG pathway may add to the ability of calcitriol to prevent and inhibit PCa development and growth. The combination of calcitriol and non-steroidal anti-inflammatory drugs (NSAIDs) result in a synergistic inhibition of PCa cell growth and offers a potential therapeutic strategy. Mitogen activated protein kinase phosphatase 5 (MKP5) is a member of a family of phosphatases that are negative regulators of MAP kinases. Calcitriol induces MKP5 expression in prostate cells leading to the selective dephosphorylation and inactivation of the stress-activated kinase p38. Since p38 activation is pro-carcinogenic and is a mediator of inflammation, this calcitriol action, especially coupled with the inhibition of the PG pathway, contributes to the chemopreventive activity of calcitriol in PCa. Mullerian Inhibiting Substance (MIS) has been evaluated for its inhibitory effects in cancers of the reproductive tissues and is in development as an anti-cancer drug. Calcitriol induces MIS expression in prostate cells revealing yet another mechanism contributing to the anti-cancer activity of calcitriol in PCa. Thus, we conclude that calcitriol regulates myriad pathways that contribute to the potential chemopreventive and therapeutic utility of calcitriol in PCa.
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Affiliation(s)
- Aruna V Krishnan
- Department of Medicine, Division of Endocrinology, Stanford University School of Medicine, Stanford, CA 94305, USA
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Swami S, Krishnan AV, Moreno J, Bhattacharyya RB, Peehl DM, Feldman D. Calcitriol and genistein actions to inhibit the prostaglandin pathway: potential combination therapy to treat prostate cancer. J Nutr 2007; 137:205S-210S. [PMID: 17182827 DOI: 10.1093/jn/137.1.205s] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
We present an overview of the prostaglandin (PG) pathway as a novel target for the treatment of prostate cancer (PCa) using a combination of calcitriol and genistein, both of which have known antiproliferative properties. Calcitriol inhibits the PG pathway in PCa cells in 3 separate ways: by decreasing cyclooxygenase-2 (COX-2) expression, stimulating 15-hydroxyprostaglandin dehydrogenase (15-PGDH) expression, and decreasing EP (PGE2) and FP (PGF(2alpha)) receptors. These actions of calcitriol result in reduced levels of biologically active PGE2, leading ultimately to growth inhibition of the PCa cells. We also demonstrate the advantages of using calcitriol in combination with genistein for the treatment of PCa. Genistein, a major component of soy, is a potent inhibitor of the activity of CYP24, the enzyme that initiates the degradation of calcitriol. This leads to increased half-life of bioactive calcitriol, thereby enhancing all of calcitriol's actions including those on the PG pathway. In addition to inhibiting CYP24 enzyme activity, genistein has its own independent actions on the PG pathway in PCa cells. Like calcitriol it inhibits COX-2 expression and activity, leading to decreased synthesis of PGE2. It also inhibits the EP and FP receptors, thereby reducing the biological function of PGE2. Thus, the combination of calcitriol and genistein acts additively to inhibit the PG pathway. Both calcitriol and genistein are relatively safe and have little toxicity associated with their intake. We postulate that the combination of calcitriol and genistein is an attractive therapeutic option for the treatment of PCa.
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Affiliation(s)
- Srilatha Swami
- Department of Medicine, Division of Endocrinology, Stanford University School of Medicine, Stanford, CA 94305, USA
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Tong M, Ding Y, Tai HH. Histone deacetylase inhibitors and transforming growth factor-beta induce 15-hydroxyprostaglandin dehydrogenase expression in human lung adenocarcinoma cells. Biochem Pharmacol 2006; 72:701-9. [PMID: 16844092 DOI: 10.1016/j.bcp.2006.06.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2006] [Revised: 06/01/2006] [Accepted: 06/07/2006] [Indexed: 12/27/2022]
Abstract
Histone deacetylase (HDAC) inhibitors have been actively exploited as potential anticancer agents. To identify gene targets of HDAC inhibitors, we found that HDAC inhibitors such as sodium butyrate, scriptaid, apicidin and oxamflatin induced the expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a potential cyclooxygenase-2 (COX-2) antagonist and tumor suppressor, in a time and concentration dependent manner in A549 and H1435 lung adenocarcinoma cells. Detailed analyses indicated that HDAC inhibitors activated the 15-PGDH promoter-luciferase reporter construct in transfected A549 cells. A representative HDAC inhibitor, scriptaid, and its negative structural analog control, nullscript, were further evaluated at the chromatin level. Scriptaid but not nullscript induced a significant accumulation of acetylated histones H3 and H4 which were associated with the 15-PGDH promoter as determined by chromatin immunoprecipitation assay. Transforming growth factor-beta1 (TGF-beta1) also induced the expression of 15-PGDH in a time and concentration dependent manner in A549 and H1435 cells. Induction of 15-PGDH expression by TGF-beta1 was synergistically stimulated by the addition of Wnt3A which was inactive by itself. However, combination of TGF-beta and an HDAC inhibitor, scriptaid, only resulted in an additive effect. Together, our results indicate that 15-PGDH is one of the target genes that HDAC inhibitors and TGF-beta may induce to exhibit tumor suppressive effects.
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Affiliation(s)
- Min Tong
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA
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Handayani R, Rice L, Cui Y, Medrano TA, Samedi VG, Baker HV, Szabo NJ, Shiverick KT. Soy isoflavones alter expression of genes associated with cancer progression, including interleukin-8, in androgen-independent PC-3 human prostate cancer cells. J Nutr 2006; 136:75-82. [PMID: 16365062 DOI: 10.1093/jn/136.1.75] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
High consumption of soy isoflavones in Asian diets has been correlated with a lower incidence of clinically important cases of prostate cancer. The chemopreventive properties of these diets may result from an interaction of several types of isoflavones, including genistein and daidzein. The present study investigated the effects of a soy isoflavone concentrate (ISF) on growth and gene expression profiles of PC-3 human prostate cancer cells. Trypan blue exclusion and [3H]-thymidine incorporation assays showed that ISF decreased cell viability and caused a dose-dependent inhibition of DNA synthesis, respectively, with 50% inhibition (IC50) of DNA synthesis at 52 mg/L (P = 0.05). The glucoside conjugates of genistein and daidzein in ISF were converted to bioactive free aglycones in cell culture in association with the inhibition of DNA synthesis. Flow cytometry and Western immunoblot analyses showed that ISF at 200 mg/L caused an accumulation of cells in the G2/M phase of the cell cycle (P < 0.05) and decreased cyclin A by 20% (P < 0.05), respectively. The effect of ISF on the gene expression profile of PC-3 cells was analyzed using Affymetrix oligonucleotide DNA microarrays that interrogate approximately 17,000 human genes. Of the 75 genes altered by ISF, 28 were upregulated and 47 were downregulated (P < 0.05). Further analysis showed that IL-8, matrix metalloproteinase 13, inhibin beta A, follistatin, and fibronectin mRNA levels were significantly reduced, whereas the expression of p21(CIP1), a major cell cycle inhibitory protein, was increased. The effects of ISF on the expression of IL-8 and p21(CIP1) mRNA and protein were validated at high and low ISF concentrations. Our data show that ISF inhibits the growth of PC-3 cells through modulation of cell cycle progression and the expression of genes involved in cell cycle regulation, metastasis, and angiogenesis.
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Affiliation(s)
- Renita Handayani
- Department of Pharmacology, College of Medicine, Univerisity of Florida, USA
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Moreno J, Krishnan AV, Swami S, Nonn L, Peehl DM, Feldman D. Regulation of prostaglandin metabolism by calcitriol attenuates growth stimulation in prostate cancer cells. Cancer Res 2005; 65:7917-25. [PMID: 16140963 DOI: 10.1158/0008-5472.can-05-1435] [Citation(s) in RCA: 155] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Calcitriol exhibits antiproliferative and pro-differentiation effects in prostate cancer. Our goal is to further define the mechanisms underlying these actions. We studied established human prostate cancer cell lines and primary prostatic epithelial cells and showed that calcitriol regulated the expression of genes involved in the metabolism of prostaglandins (PGs), known stimulators of prostate cell growth. Calcitriol significantly repressed the mRNA and protein expression of prostaglandin endoperoxide synthase/cyclooxygenase-2 (COX-2), the key PG synthesis enzyme. Calcitriol also up-regulated the expression of 15-hydroxyprostaglandin dehydrogenase, the enzyme initiating PG catabolism. This dual action was associated with decreased prostaglandin E2 secretion into the conditioned media of prostate cancer cells exposed to calcitriol. Calcitriol also repressed the mRNA expression of the PG receptors EP2 and FP, providing a potential additional mechanism of suppression of the biological activity of PGs. Calcitriol treatment attenuated PG-mediated functional responses, including the stimulation of prostate cancer cell growth. The combination of calcitriol with nonsteroidal anti-inflammatory drugs (NSAIDs) synergistically acted to achieve significant prostate cancer cell growth inhibition at approximately 2 to 10 times lower concentrations of the drugs than when used alone. In conclusion, the regulation of PG metabolism and biological actions constitutes a novel pathway of calcitriol action that may contribute to its antiproliferative effects in prostate cells. We propose that a combination of calcitriol and nonselective NSAIDs might be a useful chemopreventive and/or therapeutic strategy in men with prostate cancer, as it would allow the use of lower concentrations of both drugs, thereby reducing their toxic side effects.
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MESH Headings
- Anti-Inflammatory Agents, Non-Steroidal/pharmacology
- Calcitriol/pharmacology
- Cell Growth Processes/drug effects
- Cyclooxygenase 2
- Dinoprostone/biosynthesis
- Drug Synergism
- Gene Expression Regulation, Neoplastic/drug effects
- Genes, fos
- Humans
- Hydroxyprostaglandin Dehydrogenases/biosynthesis
- Hydroxyprostaglandin Dehydrogenases/genetics
- Hydroxyprostaglandin Dehydrogenases/metabolism
- Male
- Membrane Proteins
- Neoplasms, Hormone-Dependent/drug therapy
- Neoplasms, Hormone-Dependent/metabolism
- Neoplasms, Hormone-Dependent/pathology
- Prostaglandin-Endoperoxide Synthases/biosynthesis
- Prostaglandin-Endoperoxide Synthases/genetics
- Prostaglandin-Endoperoxide Synthases/metabolism
- Prostaglandins/biosynthesis
- Prostatic Neoplasms/drug therapy
- Prostatic Neoplasms/genetics
- Prostatic Neoplasms/metabolism
- Prostatic Neoplasms/pathology
- RNA, Messenger/biosynthesis
- RNA, Messenger/genetics
- Receptors, Prostaglandin/biosynthesis
- Receptors, Prostaglandin/metabolism
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Affiliation(s)
- Jacqueline Moreno
- Department of Medicine, Stanford University School of Medicine, Stanford, California 94305-5103, USA
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Backlund MG, Mann JR, Holla VR, Buchanan FG, Tai HH, Musiek ES, Milne GL, Katkuri S, DuBois RN. 15-Hydroxyprostaglandin dehydrogenase is down-regulated in colorectal cancer. J Biol Chem 2004; 280:3217-23. [PMID: 15542609 PMCID: PMC1847633 DOI: 10.1074/jbc.m411221200] [Citation(s) in RCA: 229] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Prostaglandin E2 (PGE2) can stimulate tumor progression by modulating several proneoplastic pathways, including proliferation, angiogenesis, cell migration, invasion, and apoptosis. Although steady-state tissue levels of PGE2 stem from relative rates of biosynthesis and breakdown, most reports examining PGE2 have focused solely on the cyclooxygenase-dependent formation of this bioactive lipid. Enzymatic degradation of PGE2 involves the NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). The present study examined a range of normal tissues in the human and mouse and found high levels of 15-PGDH in the large intestine. By contrast, the expression of 15-PGDH is decreased in several colorectal carcinoma cell lines and in other human malignancies such as breast and lung carcinomas. Consistent with these findings, we observe diminished 15-Pgdh expression in ApcMin+/- mouse adenomas. Enzymatic activity of 15-PGDH correlates with expression levels and the genetic disruption of 15-Pgdh completely blocks production of the urinary PGE2 metabolite. Finally, 15-PGDH expression and activity are significantly down-regulated in human colorectal carcinomas relative to matched normal tissue. In summary, these results suggest a novel tumor suppressive role for 15-PGDH due to loss of expression during colorectal tumor progression.
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Affiliation(s)
- Michael G Backlund
- Department of Medicine, Cell and Developmental Biology, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232-6838, USA
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