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1
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Son NN, Thanh VM, Huong NT. Synthesis of F127-GA@ZnO nanogel as a cisplatin drug delivery pH-sensitive system. RSC Adv 2024; 14:35005-35020. [PMID: 39497764 PMCID: PMC11533520 DOI: 10.1039/d4ra06514j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 10/26/2024] [Indexed: 11/07/2024] Open
Abstract
In this study, a novel drug delivery system based on zinc oxide nanoparticles (ZnO NPs) was developed for the enhanced delivery of cisplatin (CPT) to improve cancer treatment. The ZnO NPs were synthesized from guava leaf extract and then surface-functionalized with gallic acid (GA) to improve their biocompatibility and drug loading capacity. Pluronic F127, a biocompatible polymer, was then conjugated to the GA-modified ZnO NPs to further enhance their stability and cellular uptake. The resulting NPs were characterized by various techniques, including FT-IR, UV-Vis, SEM, TEM, 1H NMR, and DLS. The drug loading and release profiles of CPT from the NPs were investigated, showing high CPT loading capacity and pH-dependent release behavior. The in vitro cytotoxicity of the NPs was evaluated against various cancer cell lines, demonstrating enhanced cytotoxicity compared to free CPT. Overall, this study highlights the potential of GA and Pluronic-modified ZnO NPs as a promising drug delivery system for enhanced CPT delivery and improved cancer therapy.
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Affiliation(s)
- Nguyen Ngoc Son
- Institute of Chemistry and Materials 17 Hoang Sam, Cau Giay Hanoi Vietnam
| | - Vu Minh Thanh
- Institute of Chemistry and Materials 17 Hoang Sam, Cau Giay Hanoi Vietnam
| | - Nguyen Thi Huong
- Institute of Chemistry and Materials 17 Hoang Sam, Cau Giay Hanoi Vietnam
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2
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Lamenza FF, Upadhaya P, Roth P, Shrestha S, Jagadeesha S, Horn N, Pracha H, Oghumu S. Berries vs. Disease: Revenge of the Phytochemicals. Pharmaceuticals (Basel) 2024; 17:84. [PMID: 38256917 PMCID: PMC10818490 DOI: 10.3390/ph17010084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 01/03/2024] [Accepted: 01/05/2024] [Indexed: 01/24/2024] Open
Abstract
Secondary metabolites and phytochemicals in plant-based diets are known to possess properties that inhibit the development of several diseases including a variety of cancers of the aerodigestive tract. Berries are currently of high interest to researchers due to their high dietary source of phytochemicals. Black raspberries (BRB), Rubus occidentalis, are of special interest due to their rich and diverse composition of phytochemicals. In this review, we present the most up-to-date preclinical and clinical data involving berries and their phytochemicals in the chemoprevention of a variety of cancers and diseases. BRBs possess a variety of health benefits including anti-proliferative properties, anti-inflammatory activity, activation of pro-cell-death pathways, modulation of the immune response, microbiome modulation, reduction in oxidative stress, and many more. However, little has been done in both preclinical and clinical settings on the effects of BRB administration in combination with other cancer therapies currently available for patients. With the high potential for BRBs as chemopreventive agents, there is a need to investigate their potential in combination with other treatments to improve therapeutic efficacy.
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Affiliation(s)
- Felipe F. Lamenza
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (F.F.L.); (P.U.); (P.R.); (S.S.); (S.J.); (N.H.); (H.P.)
- Department of Microbiology, The Ohio State University, Columbus, OH 43210, USA
| | - Puja Upadhaya
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (F.F.L.); (P.U.); (P.R.); (S.S.); (S.J.); (N.H.); (H.P.)
| | - Peyton Roth
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (F.F.L.); (P.U.); (P.R.); (S.S.); (S.J.); (N.H.); (H.P.)
| | - Suvekshya Shrestha
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (F.F.L.); (P.U.); (P.R.); (S.S.); (S.J.); (N.H.); (H.P.)
- Department of Microbiology, The Ohio State University, Columbus, OH 43210, USA
| | - Sushmitha Jagadeesha
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (F.F.L.); (P.U.); (P.R.); (S.S.); (S.J.); (N.H.); (H.P.)
| | - Natalie Horn
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (F.F.L.); (P.U.); (P.R.); (S.S.); (S.J.); (N.H.); (H.P.)
| | - Hasan Pracha
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (F.F.L.); (P.U.); (P.R.); (S.S.); (S.J.); (N.H.); (H.P.)
| | - Steve Oghumu
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (F.F.L.); (P.U.); (P.R.); (S.S.); (S.J.); (N.H.); (H.P.)
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Korsten SGPJ, Vromans H, Garssen J, Willemsen LEM. Butyrate Protects Barrier Integrity and Suppresses Immune Activation in a Caco-2/PBMC Co-Culture Model While HDAC Inhibition Mimics Butyrate in Restoring Cytokine-Induced Barrier Disruption. Nutrients 2023; 15:2760. [PMID: 37375664 DOI: 10.3390/nu15122760] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 06/12/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Low-grade inflammation and barrier disruption are increasingly acknowledged for their association with non-communicable diseases (NCDs). Short chain fatty acids (SCFAs), especially butyrate, could be a potential treatment because of their combined anti-inflammatory and barrier- protective capacities, but more insight into their mechanism of action is needed. In the present study, non-activated, lipopolysaccharide-activated and αCD3/CD28-activated peripheral blood mononuclear cells (PBMCs) with and without intestinal epithelial cells (IEC) Caco-2 were used to study the effect of butyrate on barrier function, cytokine release and immune cell phenotype. A Caco-2 model was used to compare the capacities of butyrate, propionate and acetate and study their mechanism of action, while investigating the contribution of lipoxygenase (LOX), cyclooxygenase (COX) and histone deacetylase (HDAC) inhibition. Butyrate protected against inflammatory-induced barrier disruption while modulating inflammatory cytokine release by activated PBMCs (interleukin-1 beta↑, tumor necrosis factor alpha↓, interleukin-17a↓, interferon gamma↓, interleukin-10↓) and immune cell phenotype (regulatory T-cells↓, T helper 17 cells↓, T helper 1 cells↓) in the PBMC/Caco-2 co-culture model. Similar suppression of immune activation was shown in absence of IEC. Butyrate, propionate and acetate reduced inflammatory cytokine-induced IEC activation and, in particular, butyrate was capable of fully protecting against cytokine-induced epithelial permeability for a prolonged period. Different HDAC inhibitors could mimic this barrier-protective effect, showing HDAC might be involved in the mechanism of action of butyrate, whereas LOX and COX did not show involvement. These results show the importance of sufficient butyrate levels to maintain intestinal homeostasis.
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Affiliation(s)
- Sandra G P J Korsten
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
- Tiofarma B.V., 3261 ME Oud-Beijerland, The Netherlands
| | - Herman Vromans
- Tiofarma B.V., 3261 ME Oud-Beijerland, The Netherlands
- Division of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
- Danone/Nutricia Research B.V., 3584 CT Utrecht, The Netherlands
| | - Linette E M Willemsen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
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YPL-001 Shows Various Beneficial Effects against Cigarette Smoke Extract-Induced Emphysema Formation: Anti-Inflammatory, Anti-Oxidative, and Anti-Apoptotic Effects. Antioxidants (Basel) 2022; 12:antiox12010015. [PMID: 36670877 PMCID: PMC9855183 DOI: 10.3390/antiox12010015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 12/15/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
Inflammation, oxidative stress, and apoptosis are thought to be important causes of chronic obstructive pulmonary disease (COPD). We investigated the effect of YPL-001 (under phase 2a study, ClinicalTrials.gov identifier NCT02272634), a drug derived from Pseudolysimachion rotundum var. subintegrum, on cigarette smoke extract (CSE)-induced inflammation, the anti-oxidative pathway, and apoptosis in human lung epithelial cells and on CSE-induced emphysema in mice. YPL-001 suppressed CSE-induced expression of IL8 mRNA and protein. This was due to the reduction in NF-κB transcriptional activity by YPL-001, which resulted from the blockade of acetylation of the NF-κB subunit p65 (Lys310). Histone deacetylases (HDACs) prevent gene transcription by condensing the DNA structure and affecting NF-κB nuclear binding. YPL-001 alone increased HDAC2 activity and enhanced CSE-induced activation of HDAC2. YPL-001-induced suppression of NF-κB transcriptional activity might be caused by increased HDAC2 activity. YPL-001 increased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression via both degradation of its inhibitory protein, Kelch-like ECH-associated protein 1, and an increase in de novo protein synthesis. YPL-001 increased the DNA binding activity of Nrf2. Consequently, YPL-001 upregulated the expression of Nrf2-targeted anti-oxidant genes such as NAD(P)H quinone dehydrogenase 1 and heme oxygenase 1. Moreover, YPL-001 significantly suppressed CSE-induced apoptotic cell death. In vivo study showed that CSE-induced emphysematous changes, neutrophilic inflammation, protein leakage into bronchoalveolar space, and lung cell apoptosis in mice were suppressed by YPL-001 treatment. Taken together, these results suggest that YPL-001 is a good therapeutic candidate for the treatment of COPD by blocking inflammation and apoptosis and activating the anti-oxidative pathway.
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Inhibition of Class I Histone Deacetylase Activity Blocks the Induction of TNFAIP3 Both Directly and Indirectly via the Suppression of Endogenous TNF-α. Int J Mol Sci 2022; 23:ijms23179752. [PMID: 36077149 PMCID: PMC9456523 DOI: 10.3390/ijms23179752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/23/2022] [Accepted: 08/25/2022] [Indexed: 11/16/2022] Open
Abstract
Histone deacetylase inhibitors (HDIs) are promising drugs for the treatment of inflammatory diseases. However, their therapeutical exploitation is slowed down by severe adverse manifestations that can hardly be foreseen, mainly due to incomplete knowledge of how HDIs impact the delicate balance of inflammatory mediators. In this work, we characterized the effects of the HDI trichostatin A (TSA) on the expression of TNFAIP3, which is a crucial inhibitor of the classical NF-kB pathway and an LPS-induced negative feedback regulator. The accumulation of TNFAIP3 mRNA after LPS stimulation showed biphasic behavior, with one wave within the first hour of stimulation and a second wave several hours later, which were both reduced by TSA. By using inhibition and knockdown approaches, we identified two temporally and mechanistically distinct modes of action. The first wave of TNAIP3 accumulation was directly blunted by the histone deacetylase (HDAC) blockade. By contrast, the second wave was decreased mainly because of the lack of endogenous TNF-α induction, which, in turn, depended on the intact HDAC activity. In both cases, class I HDACs appeared to play a nonredundant role, with HDAC3 required, but not sufficient, for TNF-α and TNFAIP3 induction. In addition to TNFAIP3, TNF-α is known to induce many response genes that orchestrate the inflammatory cascade. Thus, suppression of TNF-α may represent a general mechanism through which HDIs regulate a selected set of target genes.
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Ashrafizadeh M, Zarrabi A, Mirzaei S, Hashemi F, Samarghandian S, Zabolian A, Hushmandi K, Ang HL, Sethi G, Kumar AP, Ahn KS, Nabavi N, Khan H, Makvandi P, Varma RS. Gallic acid for cancer therapy: Molecular mechanisms and boosting efficacy by nanoscopical delivery. Food Chem Toxicol 2021; 157:112576. [PMID: 34571052 DOI: 10.1016/j.fct.2021.112576] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 07/23/2021] [Accepted: 09/17/2021] [Indexed: 02/07/2023]
Abstract
Cancer is the second leading cause of death worldwide. Majority of recent research efforts in the field aim to address why cancer resistance to therapy develops and how to overcome or prevent it. In line with this, novel anti-cancer compounds are desperately needed for chemoresistant cancer cells. Phytochemicals, in view of their pharmacological activities and capacity to target various molecular pathways, are of great interest in the development of therapeutics against cancer. Plant-derived-natural products have poor bioavailability which restricts their anti-tumor activity. Gallic acid (GA) is a phenolic acid exclusively found in natural sources such as gallnut, sumac, tea leaves, and oak bark. In this review, we report on the most recent research related to anti-tumor activities of GA in various cancers with a focus on its underlying molecular mechanisms and cellular pathwaysthat that lead to apoptosis and migration of cancer cells. GA down-regulates the expression of molecular pathways involved in cancer progression such as PI3K/Akt. The co-administration of GA with chemotherapeutic agents shows improvements in suppressing cancer malignancy. Various nano-vehicles such as organic- and inorganic nano-materials have been developed for targeted delivery of GA at the tumor site. Here, we suggest that nano-vehicles improve GA bioavailability and its ability for tumor suppression.
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Affiliation(s)
- Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, 34956, Istanbul, Turkey; Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956, Istanbul, Turkey
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956, Istanbul, Turkey; Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Sariyer, Istanbul 34396, Turkey
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Farid Hashemi
- Phd student of pharmacology, Department of Comparative Biosciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Saeed Samarghandian
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Hui Li Ang
- Cancer Science Institute of Singapore and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Alan Prem Kumar
- Cancer Science Institute of Singapore and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore; NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea
| | - Noushin Nabavi
- Department of Urological Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H3Z6, Canada
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan, 23200, Pakistan.
| | - Pooyan Makvandi
- Centre for Materials Interfaces, Istituto Italiano di Tecnologia, viale Rinaldo Piaggio 34, 56025, Pontedera, Pisa, Italy.
| | - Rajender S Varma
- Regional Center of Advanced Technologies and Materials, Czech Advanced Technology and Research Institute, Palacky University, Šlechtitelů 27, 783 71, Olomouc, Czech Republic.
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Heregulin Drives Endocrine Resistance by Altering IL-8 Expression in ER-Positive Breast Cancer. Int J Mol Sci 2020; 21:ijms21207737. [PMID: 33086721 PMCID: PMC7589856 DOI: 10.3390/ijms21207737] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/14/2020] [Accepted: 10/16/2020] [Indexed: 02/04/2023] Open
Abstract
Sustained HER2/HER3 signaling due to the overproduction of the HER3 ligand heregulin (HRG) is proposed as a key contributor to endocrine resistance in estrogen receptor-positive (ER+) breast cancer. The molecular mechanisms linking HER2 transactivation by HRG-bound HER3 to the acquisition of a hormone-independent phenotype in ER+ breast cancer is, however, largely unknown. Here, we explored the possibility that autocrine HRG signaling drives cytokine-related endocrine resistance in ER+ breast cancer cells. We used human cytokine antibody arrays to semi-quantitatively measure the expression level of 60 cytokines and growth factors in the extracellular milieu of MCF-7 cells engineered to overexpress full-length HRGβ2 (MCF-7/HRG cells). Interleukin-8 (IL-8), a chemokine closely linked to ER inaction, emerged as one the most differentially expressed cytokines. Cytokine profiling using structural deletion mutants lacking both the N-terminus and the cytoplasmic-transmembrane region of HRGβ2-which is not secreted and cannot transactivate HER2-or lacking a nuclear localization signal at the N-terminus-which cannot localize at the nucleus but is actively secreted and transactivates HER2-revealed that the HRG-driven activation of IL-8 expression in ER+ cells required HRG secretion and transactivation of HER2 but not HRG nuclear localization. The functional blockade of IL-8 with a specific antibody inversely regulated ERα-driven transcriptional activation in endocrine-sensitive MCF-7 cells and endocrine-resistant MCF-7/HRG cells. Overall, these findings suggest that IL-8 participates in the HRG-driven endocrine resistance program in ER+/HER2- breast cancer and might illuminate a potential clinical setting for IL8- or CXCR1/2-neutralizing antibodies.
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Shi X, Gong L, Liu Y, Hou K, Fan Y, Li C, Wen T, Qu X, Che X. 4-phenylbutyric acid promotes migration of gastric cancer cells by histone deacetylase inhibition-mediated IL-8 upregulation. Epigenetics 2020; 15:632-645. [PMID: 31814524 PMCID: PMC7574398 DOI: 10.1080/15592294.2019.1700032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 11/15/2019] [Accepted: 11/22/2019] [Indexed: 12/31/2022] Open
Abstract
Histone acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). It is associated with gene transcription and expression. 4-Phenylbutyric acid (4-PBA), an HDAC inhibitor (HDACi), can inhibit cancer cell proliferation by increasing the level of histone acetylation. However, 4-PBA did not show any efficacy in clinical trials. In this study, we found that 4-PBA induced epithelial-mesenchymal transition (EMT) in gastric cancer cell lines MGC-803 and BGC-823 with ectopic E-cadherin expression. Based on the expression profile microarray, IL-8 was the most significantly up-regulated gene by 4-PBA, and was selected for further investigation. Knockdown of IL-8 partially prevented 4-PBA-induced-EMT by blocking the activation of the downstream Gab2-ERK pathway. Furthermore, CHIP assay confirmed that acetyl-H3 directly combined with the promoter region of IL-8 to promote its transcription. Therefore, the results of this study demonstrated that 4-PBA-mediated inhibition of HDAC activity could induce EMT in gastric cancer cells via acetyl-histone-mediated IL-8 upregulation, and the downstream Gab2/ERK activation. These data indicated the possible reason for the failure of 4-PBA in clinical trials.
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Affiliation(s)
- Xiaonan Shi
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Libao Gong
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Yunpeng Liu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Kezuo Hou
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Yibo Fan
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Ce Li
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Ti Wen
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Xiujuan Qu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Xiaofang Che
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
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Rasha F, Kahathuduwa C, Ramalingam L, Hernandez A, Moussa H, Moustaid-Moussa N. Combined Effects of Eicosapentaenoic Acid and Adipocyte Renin-Angiotensin System Inhibition on Breast Cancer Cell Inflammation and Migration. Cancers (Basel) 2020; 12:cancers12010220. [PMID: 31963198 PMCID: PMC7016836 DOI: 10.3390/cancers12010220] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 01/09/2020] [Accepted: 01/11/2020] [Indexed: 12/12/2022] Open
Abstract
Obesity is a major risk factor for breast cancer (BC). Obesity-related metabolic alterations such as inflammation and overactivation of the adipose renin–angiotensin system (RAS) may contribute to the progression of BC. Clinically used antihypertensive drugs such as angiotensin-converting enzyme inhibitors (ACE-I) and dietary bioactive components such as eicosapentaenoic acid (EPA) are known for their anti-inflammatory and adipose RAS blocking properties. However, whether EPA enhances the protective effects of ACE-I in lessening adipocyte inflammation on BC cells has not been studied. We hypothesized that combined EPA and ACE-I would attenuate BC cell inflammation and migration possibly via adipose RAS inhibition. To test our hypothesis, we examined the (i) direct effects of an ACE-I (captopril (CAP)) or EPA, individually and combined, on MCF-7 and MDA-MB-231 human BC cells, and the (ii) effects of conditioned medium (CM) from human adipocytes pretreated with the abovementioned agents on BC cells. We demonstrated that CM from adipocytes pretreated with EPA with or without captopril (but not direct treatments of BC cells) significantly reduced proinflammatory cytokines expression in both BC cell lines. Additionally, cell migration was reduced in MDA-MB-231 cells in response to both direct and CM-mediated CAP and/or EPA treatments. In summary, our study provides a significant insight into added benefits of combining anti-inflammatory EPA and antihypertensive ACE-I to attenuate the effects of adipocytes on breast cancer cell migration and inflammation.
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Affiliation(s)
- Fahmida Rasha
- Department of Nutritional Sciences, Texas Tech University, 1301 Akron Ave, Lubbock, TX 79409, USA
- Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA
| | - Chanaka Kahathuduwa
- Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA
- Department of Psychiatry, School of Medicine, Texas Tech University Health Science Center, Lubbock, TX 79430, USA
| | - Latha Ramalingam
- Department of Nutritional Sciences, Texas Tech University, 1301 Akron Ave, Lubbock, TX 79409, USA
- Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA
| | - Arelys Hernandez
- Department of Nutritional Sciences, Texas Tech University, 1301 Akron Ave, Lubbock, TX 79409, USA
| | - Hanna Moussa
- Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA
- Department of Mechanical Engineering, Texas Tech University, Lubbock, TX 79409, USA
| | - Naima Moustaid-Moussa
- Department of Nutritional Sciences, Texas Tech University, 1301 Akron Ave, Lubbock, TX 79409, USA
- Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA
- Correspondence: ; Tel.: +1-806-834-7946
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10
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Liu ZZ, Han ZD, Liang YK, Chen JX, Wan S, Zhuo YJ, Cai ZD, Deng YL, Lin ZY, Mo RJ, He HC, Zhong WD. TRIB1 induces macrophages to M2 phenotype by inhibiting IKB-zeta in prostate cancer. Cell Signal 2019; 59:152-162. [PMID: 30926388 DOI: 10.1016/j.cellsig.2019.03.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Revised: 03/18/2019] [Accepted: 03/19/2019] [Indexed: 11/27/2022]
Abstract
Immunotherapy has made great breakthroughs in the field of cancer. However, the immunotherapeutic effect of prostate cancer is unsatisfactory. We found that the expression of TRIB1 was significantly correlated with the infiltration of CD163+ macrophages in prostate cancer. This study focused on the effects of TRIB1 on macrophage polarization in the immune microenvironment of prostate cancer. RNA sequencing analysis demonstrated that TRIB1 has significant effects on the regulation of the nuclear factor (NF)-κB signaling pathway and downstream cytokines. Flow cytometry and enzyme-linked immunosorbent assay were used to examine THP-1 cells cultured in conditioned medium from prostate cancer cells overexpressing TRIB1 and showed that overexpression of TRIB1 promoted the secretion of CXCL2 and interleukin (IL)8 by PC3 cells, which increased the secretion of IL12 by THP-1 cells as well as the expression of CD163 on THP-1 cells. IKB-zeta, regulated by TRIB1, was expressed in PC3 cells but was barely detectable in DU145 cells. The reductions in CXCL2 and IL8 by the inhibition of TRIB1 were rescued by the deletion of IKB-zeta. Here we showed that TRIB1 promoted the secretion of cytokines from prostate cancer cells and induced the differentiation of monocytes/macrophages into M2 macrophages.
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Affiliation(s)
- Ze-Zhen Liu
- Department of Urology, Huadu District People's Hospital, Southern Medical University, Guangzhou 510800, China; Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China; Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Zhao-Dong Han
- Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China
| | - Ying-Ke Liang
- Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China
| | - Jun-Xu Chen
- Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China
| | - Song Wan
- Department of Urology, Huadu District People's Hospital, Southern Medical University, Guangzhou 510800, China
| | - Yang-Jia Zhuo
- Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China
| | - Zhi-Duan Cai
- Department of Urology, Huadu District People's Hospital, Southern Medical University, Guangzhou 510800, China; Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China
| | - Yu-Lin Deng
- Department of Urology, Huadu District People's Hospital, Southern Medical University, Guangzhou 510800, China; Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China
| | - Zhuo-Yuan Lin
- Department of Urology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510260, China
| | - Ru-Jun Mo
- Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China
| | - Hui-Chan He
- Urology Key Laboratory of Guangdong Province, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510230, China
| | - Wei-De Zhong
- Department of Urology, Huadu District People's Hospital, Southern Medical University, Guangzhou 510800, China; Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China; Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
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11
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Gatla HR, Muniraj N, Thevkar P, Yavvari S, Sukhavasi S, Makena MR. Regulation of Chemokines and Cytokines by Histone Deacetylases and an Update on Histone Decetylase Inhibitors in Human Diseases. Int J Mol Sci 2019; 20:E1110. [PMID: 30841513 PMCID: PMC6429312 DOI: 10.3390/ijms20051110] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 02/26/2019] [Accepted: 02/28/2019] [Indexed: 12/12/2022] Open
Abstract
Histone acetyltransferases (HATs) and histone deacetylases (HDACs) counteract with each other to regulate gene expression by altering chromatin structure. Aberrant HDAC activity was reported in many human diseases including wide range of cancers, viral infections, cardiovascular complications, auto-immune diseases and kidney diseases. HDAC inhibitors are small molecules designed to block the malignant activity of HDACs. Chemokines and cytokines control inflammation, immunological and other key biological processes and are shown to be involved in various malignancies. Various HDACs and HDAC inhibitors were reported to regulate chemokines and cytokines. Even though HDAC inhibitors have remarkable anti-tumor activity in hematological cancers, they are not effective in treating many diseases and many patients relapse after treatment. However, the role of HDACs and cytokines in regulating these diseases still remain unclear. Therefore, understanding exact mechanisms and effector functions of HDACs are urgently needed to selectively inhibit them and to establish better a platform to combat various malignancies. In this review, we address regulation of chemokines and cytokines by HDACs and HDAC inhibitors and update on HDAC inhibitors in human diseases.
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Affiliation(s)
- Himavanth Reddy Gatla
- Department of Pediatric Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
| | - Nethaji Muniraj
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
| | - Prashanth Thevkar
- Department of Microbiology, New York University, New York, NY 10016, USA.
| | - Siddhartha Yavvari
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
| | - Sahithi Sukhavasi
- Center for Distance Learning, GITAM University, Visakhapatnam, AP 530045, India.
| | - Monish Ram Makena
- Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
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12
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Liu YS, Hsu JW, Lin HY, Lai SW, Huang BR, Tsai CF, Lu DY. Bradykinin B1 receptor contributes to interleukin-8 production and glioblastoma migration through interaction of STAT3 and SP-1. Neuropharmacology 2019; 144:143-154. [PMID: 30366000 DOI: 10.1016/j.neuropharm.2018.10.033] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 10/20/2018] [Accepted: 10/22/2018] [Indexed: 01/05/2023]
Abstract
Glioblastoma (GBM), the most aggressive brain tumor, has a poor prognosis due to the ease of migration to surrounding healthy brain tissue. Recent studies have shown that bradykinin receptors are involved in the progression of various cancers. However, the molecular mechanism and pathological role of bradykinin receptors remains unclear. We observed the expressions of two major bradykinin receptors, B1R and B2R, in two different human GBM cell lines, U87 and GBM8901. Cytokine array analysis showed that bradykinin increases the production of interleukin (IL)-8 in GBM via B1R. Higher B1R levels correlate with IL-8 expression in U87 and GBM8901. We observed increased levels of phosphorylated STAT3 and SP-1 in the nucleus as well. Using chromatin immunoprecipitation assay, we found that STAT3 and SP-1 mediate IL-8 expression, which gets abrogated by the inhibition of FAK and STAT3. We further demonstrated that IL-8 expression and cell migration are also regulated by the SP-1. In addition, expression levels of STAT3 and SP-1 positively correlate with clinicopathological grades of gliomas. Interestingly, our results found that inhibition of HDAC increases IL-8 expression. Moreover, stimulation with bradykinin caused increases in acetylated SP-1 and p300 complex formation, which are abrogated by inhibition of FAK and STAT3. Meanwhile, knockdown of SP-1 and p300 decreased the augmentation of bradykinin-induced IL-8 expression. These results indicate that bradykinin-induced IL-8 expression is dependent on B1R which causes phosphorylated STAT3 and acetylated SP-1 to translocate to the nucleus, hence resulting in GBM migration.
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Affiliation(s)
- Yu-Shu Liu
- Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan; Department of Biotechnology, Asia University, Taichung, Taiwan
| | - Jhih-Wen Hsu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Hsiao-Yun Lin
- Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Sheng-Wei Lai
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
| | - Bor-Ren Huang
- Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; Department of Neurosurgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Cheng-Fang Tsai
- Department of Biotechnology, Asia University, Taichung, Taiwan
| | - Dah-Yuu Lu
- Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan; Department of Photonics and Communication Engineering, Asia University, Taichung, Taiwan.
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13
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Cheng M, Cai W, Huang W, Chen Y, Wu Z, Luo P, Yan W. Histone deacetylase 6 regulated expression of IL-8 is involved in the doxorubicin (Dox) resistance of osteosarcoma cells via modulating ABCB1 transcription. Eur J Pharmacol 2018; 840:1-8. [PMID: 30273544 DOI: 10.1016/j.ejphar.2018.09.032] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 09/13/2018] [Accepted: 09/27/2018] [Indexed: 12/16/2022]
Abstract
Emerging evidence shows that cytokines such as interleukins (ILs) are involved in the progression and chemoresistance of multiple tumors, including osteosarcoma (OS). Our present study established the doxorubicin (Dox) resistant human OS MG-63 and HOS cells and named them MG-63/Dox and HOS/Dox, respectively. The expression of IL-8, while not VEGFA, IL-32, or IL-34, was significantly increased in OS/Dox cells as compared with that in the parental cells. IL-8 neutralization antibody can significantly increase the Dox sensitivity of OS/Dox cells. Further, IL-8 can up regulate ABCB1, which encodes one important ATP-binding cassette (ABC) transporter /P-glycoprotein (P-gp). Mechanically, IL-8 increased the transcription of ABCB1 via up regulating its promoter activity, while had no effect on its protein or mRNA stability. Targeted inhibition of p65 can attenuate IL-8 induced transcription of ABCB1 in OS cells. Treatment OS cells with 5-aza-dC, the inhibitor of DNMT, had no effect on expression of IL-8. Expression of HDAC6 in MG-63/Dox and HOS/Dox cells was significantly greater than that in their parental cells. Knockdown of HDAC6 can suppress the expression of IL-8 in OS cells. Collectively, our data showed that HDAC6 mediated upregulation of IL-8 can regulate the Dox sensitivity of OS cells via transcriptionally regulating the expression of ABCB1. Targeted inhibition of IL-8 might be a potent potential approach for overcome the Dox resistance of OS cells and helpful for clinical therapy of OS patients.
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Affiliation(s)
- Mo Cheng
- Department of Musculoskeletal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Weiluo Cai
- Department of Musculoskeletal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Wending Huang
- Department of Musculoskeletal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Yong Chen
- Department of Musculoskeletal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Zhiqiang Wu
- Department of Musculoskeletal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Peng Luo
- Department of Musculoskeletal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Wangjun Yan
- Department of Musculoskeletal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
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14
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Kwon Y. Food-derived polyphenols inhibit the growth of ovarian cancer cells irrespective of their ability to induce antioxidant responses. Heliyon 2018; 4:e00753. [PMID: 30186979 PMCID: PMC6121158 DOI: 10.1016/j.heliyon.2018.e00753] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 07/16/2018] [Accepted: 08/22/2018] [Indexed: 11/12/2022] Open
Abstract
The use of plant polyphenols to prevent cancer has been studied extensively. However, recent findings regarding the cancer-promoting effects of some antioxidants have led to reservations regarding the therapeutic use of food-derived antioxidants including polyphenols. The aim of this study was to evaluate the therapeutic potential of food-derived polyphenols and their use and safety in cancer patients. The free-radical scavenging ability of sulforaphane and various food-derived polyphenols including curcumin, epigallocatechin gallate, epicatechin, pelargonidin, and resveratrol was compared with their growth inhibitory effect on ovarian cancer cells. Oxidative stress and/or antioxidant responses and anti-proliferative pathways were evaluated after administering sulforaphane and polyphenols at doses at which they have been shown to inhibit the growth of ovarian cancer cells. No correlation was observed between their ability to scavenge free radicals and their ability to inhibit the growth of ovarian cancer cells. With the exception of epigallocatechin gallate, all of the antioxidants that were tested at doses that inhibited cell growth significantly increased NAD(P)H quinone dehydrogenase I (NQO1) expression but induced cell cycle arrest and/or apoptotic signaling. Epigallocatechin gallate exhibited a higher free radical scavenging activity but did not induce NQO1 expression at either the mRNA or at the protein level. Treatment with polyphenols at physiological doses did not significantly alter the growth of ovarian cancer cells or NQO1 expression. Therefore, individual food-derived polyphenols appear to have different anti-cancer mechanisms. Their modes of action in relation to their chemical properties should be established, rather than collectively avoiding the use of these agents as antioxidants.
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Affiliation(s)
- Youngjoo Kwon
- Department of Food Science and Engineering, Ewha Womans University, Seoul, South Korea
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15
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Proteasome inhibition induces IKK-dependent interleukin-8 expression in triple negative breast cancer cells: Opportunity for combination therapy. PLoS One 2018; 13:e0201858. [PMID: 30089134 PMCID: PMC6082561 DOI: 10.1371/journal.pone.0201858] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 07/23/2018] [Indexed: 12/14/2022] Open
Abstract
Triple negative breast cancer (TNBC) cells express increased levels of the pro-inflammatory and pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8), which promotes their proliferation and migration. Because TNBC patients are unresponsive to current targeted therapies, new therapeutic strategies are urgently needed. While proteasome inhibition by bortezomib (BZ) or carfilzomib (CZ) has been effective in treating hematological malignancies, it has been less effective in solid tumors, including TNBC, but the mechanisms are incompletely understood. Here we report that proteasome inhibition significantly increases expression of IL-8, and its receptors CXCR1 and CXCR2, in TNBC cells. Suppression or neutralization of the BZ-induced IL-8 potentiates the BZ cytotoxic and anti-proliferative effect in TNBC cells. The IL-8 expression induced by proteasome inhibition in TNBC cells is mediated by IκB kinase (IKK), increased nuclear accumulation of p65 NFκB, and by IKK-dependent p65 recruitment to IL-8 promoter. Importantly, inhibition of IKK activity significantly decreases proliferation, migration, and invasion of BZ-treated TNBC cells. These data provide the first evidence demonstrating that proteasome inhibition increases the IL-8 signaling in TNBC cells, and suggesting that IKK inhibitors may increase effectiveness of proteasome inhibitors in treating TNBC.
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16
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Vancurova I, Uddin MM, Zou Y, Vancura A. Combination Therapies Targeting HDAC and IKK in Solid Tumors. Trends Pharmacol Sci 2017; 39:295-306. [PMID: 29233541 DOI: 10.1016/j.tips.2017.11.008] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 11/21/2017] [Accepted: 11/27/2017] [Indexed: 12/18/2022]
Abstract
The rationale for developing histone deacetylase (HDAC) inhibitors (HDACi) as anticancer agents was based on their ability to induce apoptosis and cell cycle arrest in cancer cells. However, while HDACi have been remarkably effective in the treatment of hematological malignancies, clinical studies with HDACi as single agents in solid cancers have been disappointing. Recent studies have shown that, in addition to inducing apoptosis in cancer cells, class I HDACi induce IκB kinase (IKK)-dependent expression of proinflammatory chemokines, such as interleukin-8 (IL8; CXCL8), resulting in the increased proliferation of tumor cells, and limiting the effectiveness of HDACi in solid tumors. Here, we discuss the mechanisms responsible for HDACi-induced CXCL8 expression, and opportunities for combination therapies targeting HDACs and IKK in solid tumors.
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Affiliation(s)
- Ivana Vancurova
- Department of Biological Sciences, St John's University, New York, NY 11439, USA.
| | - Mohammad M Uddin
- Department of Biological Sciences, St John's University, New York, NY 11439, USA
| | - Yue Zou
- Department of Biological Sciences, St John's University, New York, NY 11439, USA
| | - Ales Vancura
- Department of Biological Sciences, St John's University, New York, NY 11439, USA
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17
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Martins MB, Marcello MA, Batista FDA, Peres KC, Meneghetti M, Ward MAL, Etchebehere ECSDC, da Assumpção LVM, Ward LS. Serum interleukin measurement may help identify thyroid cancer patients with active disease. Clin Biochem 2017; 52:1-7. [PMID: 28987791 DOI: 10.1016/j.clinbiochem.2017.10.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 10/03/2017] [Accepted: 10/03/2017] [Indexed: 10/18/2022]
Abstract
BACKGROUND Investigate the clinical utility of serum interleukin dosages of IL-2, IL-2R, IL-4, IL-6, IL-6R, IL-8, IL-10 and IL-12 in the diagnosis and characterization of patients with DTC. In particular, verify ILs utility in the identification of individuals who are evolving disease-free or with the active disease. METHODS We evaluated 200 patients with malignant nodules (100 patients disease-free and 100 patients with recurrence/active disease); 60 benign nodules and 100 healthy controls, serum levels were assessed by ELISA. RESULTS All ILs, but not IL-4, differentiated these three groups. We observed that IL-2, 2R and 10 serum concentrations were associated with thyroglobulin levels. Serum IL-2 was able to differentiate patients with active disease from the disease-free with a sensitivity of 98%, specificity of 58%, positive predictive value (PPV) of 70% and negative predictive value (NPV) of 97% (p=0.0007). IL-6R levels differentiated patients with active disease from the disease-free patients with 56% sensitivity, 63% specificity, PPV of 60% and NPV of 59% (p<0.0001). IL-8 values also distinguished patients with active disease from the disease-free ones with sensitivity of 50%, specificity of 76%, PPV of 68% and NPV of 60% (p=0.0025); using IL-12, we obtained a sensitivity value of 73%, specificity of 66%, PPV of 68% and NPV of 71% (p<0.0001). Furthermore, interleukin levels showed association with some tumor characteristics of aggressiveness. CONCLUSION We suggest that the serum concentration of ILs may assist in the diagnosis and characterization of tumor malignancy helping identify patients with active disease who deserve closer medical attention.
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Affiliation(s)
- Mariana Bonjiorno Martins
- Laboratory of Cancer Molecular Genetics, Faculty of Medical Sciences (FCM), University of Campinas (Unicamp), 126, Tessalia Vieira de Camargo St., Campinas, SP, Brazil.
| | - Marjory Alana Marcello
- Laboratory of Cancer Molecular Genetics, Faculty of Medical Sciences (FCM), University of Campinas (Unicamp), 126, Tessalia Vieira de Camargo St., Campinas, SP, Brazil
| | - Fernando de Assis Batista
- Laboratory of Cancer Molecular Genetics, Faculty of Medical Sciences (FCM), University of Campinas (Unicamp), 126, Tessalia Vieira de Camargo St., Campinas, SP, Brazil
| | - Karina Colombera Peres
- Laboratory of Cancer Molecular Genetics, Faculty of Medical Sciences (FCM), University of Campinas (Unicamp), 126, Tessalia Vieira de Camargo St., Campinas, SP, Brazil
| | - Murilo Meneghetti
- Laboratory of Cancer Molecular Genetics, Faculty of Medical Sciences (FCM), University of Campinas (Unicamp), 126, Tessalia Vieira de Camargo St., Campinas, SP, Brazil
| | - Mirela Andrea Latham Ward
- Laboratory of Cancer Molecular Genetics, Faculty of Medical Sciences (FCM), University of Campinas (Unicamp), 126, Tessalia Vieira de Camargo St., Campinas, SP, Brazil
| | - Elba Cristina Sá de Camargo Etchebehere
- Division of Nuclear Medicine, Department of Radiology, Faculty of Medical Sciences (FCM), University of Campinas (Unicamp), 251, Vital Brazil St., Campinas, SP, Brazil
| | - Ligia Vera Montali da Assumpção
- Division of Endocrinology, Department of Medicine, Faculty of Medical Sciences (FCM), University of Campinas (Unicamp), 251, Vital Brazil St., Campinas, SP, Brazil
| | - Laura Sterian Ward
- Laboratory of Cancer Molecular Genetics, Faculty of Medical Sciences (FCM), University of Campinas (Unicamp), 126, Tessalia Vieira de Camargo St., Campinas, SP, Brazil
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18
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The Role of Interleukin-8 and Its Mechanism in Patients with Breast Cancer: Its Relation with Oxidative Stress and Estrogen Receptor. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2017. [DOI: 10.5812/ijcm.8791] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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19
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Wernly B, Gonçalves I, Kiss A, Paar V, Mösenlechner T, Leisch M, Santer D, Motloch LJ, Klein KU, Tretter EV, Kretzschmar D, Podesser B, Jung C, Hoppe UC, Lichtenauer M. Differences in Stem Cell Processing Lead to Distinct Secretomes Secretion-Implications for Differential Results of Previous Clinical Trials of Stem Cell Therapy for Myocardial Infarction. Biotechnol J 2017; 12. [PMID: 28731525 DOI: 10.1002/biot.201600732] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 06/28/2017] [Indexed: 01/04/2023]
Abstract
Stem cell therapy for acute myocardial infarction (AMI) seemed to be a promising therapy, however, large clinical trials brought differential outcome. It has been shown that paracrine effects of secretomes of stem cells rather than cell therapy might play a fundamental role. The present study seeks to compare cell processing protocols of clinical trials and investigate effects of differential cell culture conditions on chemokine secretion and functional effects. Different secretomes are compared regarding IL-8, VEGF, MCP-1, and TNF-alpha secretion. Secretome mediated effects are evaluated on endothelial cell (HUVEC) tube formation and migration. Cardioprotective signaling kinases in human cardiomyocytes are determined by Western immunoblotting. Cells processed according to the REPAIR-AMI protocol secrete significantly higher amounts of IL-8 (487.3 ± 1231.1 vs 9.1 ± 8.2 pg mL-1 ; p < 0.05). REAPIR-AMI supernatants lead to significantly pronounced tube formation and migration on HUVEC and enhance the phosphorylation of Akt, ERK, and CREB. Cell processing conditions have a major impact on the composition of the secretome. The REPAIR-AMI secretome significantly enhances proangiogenic chemokine secretion, angiogenesis, cell migration, and cardioprotective signaling pathways. These results might explain differential outcomes between clinical trials. Optimizing cell processing protocols with special regards to paracrine factors, might open a new therapeutic concept for improving patient outcome.
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Affiliation(s)
- Bernhard Wernly
- Internal Medicine II, Department of Cardiology, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Inês Gonçalves
- Ludwig Boltzmann Cluster for Cardiovascular Research, Department for Biomedical Research, Medical University Vienna, Vienna, Austria
| | - Attila Kiss
- Ludwig Boltzmann Cluster for Cardiovascular Research, Department for Biomedical Research, Medical University Vienna, Vienna, Austria
| | - Vera Paar
- Internal Medicine II, Department of Cardiology, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Tobias Mösenlechner
- Internal Medicine II, Department of Cardiology, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Michael Leisch
- Internal Medicine III, Department of Oncology, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - David Santer
- Ludwig Boltzmann Cluster for Cardiovascular Research, Department for Biomedical Research, Medical University Vienna, Vienna, Austria
| | - Lukas Jaroslaw Motloch
- Internal Medicine II, Department of Cardiology, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Klaus U Klein
- Department of Anesthesia, General Intensive Care and Pain Management, Medical University of Vienna, Vienna, Austria
| | - Eva V Tretter
- Department of Anesthesia, General Intensive Care and Pain Management, Medical University of Vienna, Vienna, Austria
| | - Daniel Kretzschmar
- Universitätsherzzentrum Thüringen, Clinic of Internal Medicine I, Department of Cardiology, Friedrich Schiller University Jena, Jena, Germany
| | - Bruno Podesser
- Ludwig Boltzmann Cluster for Cardiovascular Research, Department for Biomedical Research, Medical University Vienna, Vienna, Austria
| | - Christian Jung
- Division of Cardiology, Pulmonology, and Vascular Medicine University Duesseldorf, Medical Faculty, Duesseldorf, Germany
| | - Uta C Hoppe
- Internal Medicine II, Department of Cardiology, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Michael Lichtenauer
- Internal Medicine II, Department of Cardiology, Paracelsus Medical University Salzburg, Salzburg, Austria
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20
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Gatla HR, Zou Y, Uddin MM, Singha B, Bu P, Vancura A, Vancurova I. Histone Deacetylase (HDAC) Inhibition Induces IκB Kinase (IKK)-dependent Interleukin-8/CXCL8 Expression in Ovarian Cancer Cells. J Biol Chem 2017; 292:5043-5054. [PMID: 28167529 DOI: 10.1074/jbc.m116.771014] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Revised: 01/20/2017] [Indexed: 12/18/2022] Open
Abstract
Overexpression of the pro-angiogenic chemokine IL-8 (CXCL8) is associated with a poor prognosis in several solid tumors, including epithelial ovarian cancer (EOC). Even though histone deacetylase (HDAC) inhibition has shown remarkable antitumor activity in hematological malignancies, it has been less effective in solid tumors, including EOC. Here we report results that may explain the decreased efficiency of HDAC inhibition in EOC, based on our data demonstrating that HDAC inhibition specifically induces expression of IL-8/CXCL8 in SKOV3, CAOV3, and OVCAR3 cells. Suppression or neutralization of vorinostat-induced IL-8/CXCL8 potentiates the vorinostat inhibitory effect on cell viability and proliferation. The IL-8/CXCL8 expression induced by vorinostat in EOC cells is dependent on IκB kinase (IKK) activity and associated with a gene-specific recruitment of IKKβ and IKK-dependent recruitment of p65 NFκB to the IL-8/CXCL8 promoter. In addition, HDAC inhibition induces acetylation of p65 and histone H3 and their IL-8/CXCL8 promoter occupancy. In vivo results demonstrate that combining vorinostat and the IKK inhibitor Bay 117085 significantly reduces tumor growth in nude mice compared with control untreated mice or either drug alone. Mice in the combination group had the lowest IL-8/CXCL8 tumor levels and the lowest tumor expression of the murine neutrophil [7/4] antigen, indicating reduced neutrophil infiltration. Together, our results demonstrate that HDAC inhibition specifically induces IL-8/CXCL8 expression in EOC cells and that the mechanism involves IKK, suggesting that using IKK inhibitors may increase the effectiveness of HDAC inhibitors when treating ovarian cancer and other solid tumors characterized by increased IL-8/CXCL8 expression.
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Affiliation(s)
- Himavanth R Gatla
- From the Department of Biological Sciences, St. John's University, New York, New York 11439 and
| | - Yue Zou
- From the Department of Biological Sciences, St. John's University, New York, New York 11439 and
| | - Mohammad M Uddin
- From the Department of Biological Sciences, St. John's University, New York, New York 11439 and
| | | | - Pengli Bu
- From the Department of Biological Sciences, St. John's University, New York, New York 11439 and
| | - Ales Vancura
- From the Department of Biological Sciences, St. John's University, New York, New York 11439 and
| | - Ivana Vancurova
- From the Department of Biological Sciences, St. John's University, New York, New York 11439 and
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21
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Ebenezer DL, Fu P, Suryadevara V, Zhao Y, Natarajan V. Epigenetic regulation of pro-inflammatory cytokine secretion by sphingosine 1-phosphate (S1P) in acute lung injury: Role of S1P lyase. Adv Biol Regul 2017; 63:156-166. [PMID: 27720306 PMCID: PMC5292070 DOI: 10.1016/j.jbior.2016.09.007] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 09/20/2016] [Accepted: 09/25/2016] [Indexed: 11/25/2022]
Abstract
Cellular level of sphingosine-1-phosphate (S1P), the simplest bioactive sphingolipid, is tightly regulated by its synthesis catalyzed by sphingosine kinases (SphKs) 1 & 2 and degradation mediated by S1P phosphatases, lipid phosphate phosphatases, and S1P lyase. The pleotropic actions of S1P are attributed to its unique inside-out (extracellular) signaling via G-protein-coupled S1P1-5 receptors, and intracellular receptor independent signaling. Additionally, S1P generated in the nucleus by nuclear SphK2 modulates HDAC1/2 activity, regulates histone acetylation, and transcription of pro-inflammatory genes. Here, we present data on the role of S1P lyase mediated S1P signaling in regulating LPS-induced inflammation in lung endothelium. Blocking S1P lyase expression or activity attenuated LPS-induced histone acetylation and secretion of pro-inflammatory cytokines. Degradation of S1P by S1P lyase generates Δ2-hexadecenal and ethanolamine phosphate and the long-chain fatty aldehyde produced in the cytoplasmic compartment of the endothelial cell seems to modulate histone acetylation pattern, which is different from the nuclear SphK2/S1P signaling and inhibition of HDAC1/2. These in vitro studies suggest that S1P derived long-chain fatty aldehyde may be an epigenetic regulator of pro-inflammatory genes in sepsis-induced lung inflammation. Trapping fatty aldehydes and other short chain aldehydes such as 4-hydroxynonenal derived from S1P degradation and lipid peroxidation, respectively by cell permeable agents such as phloretin or other aldehyde trapping agents may be useful in treating sepsis-induced lung inflammation via modulation of histone acetylation. .
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Affiliation(s)
- David L Ebenezer
- Department of Biochemistry & Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA
| | - Panfeng Fu
- Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA
| | - Vidyani Suryadevara
- Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA
| | - Yutong Zhao
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Viswanathan Natarajan
- Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA; Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
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22
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Lima KG, Krause GC, Schuster AD, Catarina AV, Basso BS, De Mesquita FC, Pedrazza L, Marczak ES, Martha BA, Nunes FB, Chiela ECF, Jaeger N, Thomé MP, Haute GV, Dias HB, Donadio MVF, De Oliveira JR. Gallic acid reduces cell growth by induction of apoptosis and reduction of IL-8 in HepG2 cells. Biomed Pharmacother 2016; 84:1282-1290. [DOI: 10.1016/j.biopha.2016.10.048] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2016] [Revised: 10/05/2016] [Accepted: 10/17/2016] [Indexed: 11/15/2022] Open
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Losson H, Schnekenburger M, Dicato M, Diederich M. Natural Compound Histone Deacetylase Inhibitors (HDACi): Synergy with Inflammatory Signaling Pathway Modulators and Clinical Applications in Cancer. Molecules 2016; 21:molecules21111608. [PMID: 27886118 PMCID: PMC6274245 DOI: 10.3390/molecules21111608] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 11/03/2016] [Accepted: 11/03/2016] [Indexed: 12/20/2022] Open
Abstract
The remarkable complexity of cancer involving multiple mechanisms of action and specific organs led researchers Hanahan and Weinberg to distinguish biological capabilities acquired by cancer cells during the multistep development of human tumors to simplify its understanding. These characteristic hallmarks include the abilities to sustain proliferative signaling, evade growth suppressors, resist cell death, enable replicative immortality, induce angiogenesis, activate invasion and metastasis, avoid immune destruction, and deregulate cellular energetics. Furthermore, two important characteristics of tumor cells that facilitate the acquisition of emerging hallmarks are tumor-promoting inflammation and genome instability. To treat a multifactorial disease such as cancer, a combination treatment strategy seems to be the best approach. Here we focus on natural histone deacetylase inhibitors (HDACi), their clinical uses as well as synergies with modulators of the pro-inflammatory transcription factor signaling pathways.
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Affiliation(s)
- Hélène Losson
- Laboratoire de Biologie Moléculaire et Cellulaire du Cancer (LBMCC), Hôpital Kirchberg, 9 Rue Edward Steichen, Luxembourg L-2540, Luxembourg.
| | - Michael Schnekenburger
- Laboratoire de Biologie Moléculaire et Cellulaire du Cancer (LBMCC), Hôpital Kirchberg, 9 Rue Edward Steichen, Luxembourg L-2540, Luxembourg.
| | - Mario Dicato
- Laboratoire de Biologie Moléculaire et Cellulaire du Cancer (LBMCC), Hôpital Kirchberg, 9 Rue Edward Steichen, Luxembourg L-2540, Luxembourg.
| | - Marc Diederich
- Department of Pharmacy, College of Pharmacy, Seoul National University, Building 29 Room 223, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea.
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24
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Escobar P, Bouclier C, Serret J, Bièche I, Brigitte M, Caicedo A, Sanchez E, Vacher S, Vignais ML, Bourin P, Geneviève D, Molina F, Jorgensen C, Lazennec G. IL-1β produced by aggressive breast cancer cells is one of the factors that dictate their interactions with mesenchymal stem cells through chemokine production. Oncotarget 2016; 6:29034-47. [PMID: 26362269 PMCID: PMC4745709 DOI: 10.18632/oncotarget.4732] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Accepted: 07/22/2015] [Indexed: 12/26/2022] Open
Abstract
The aim of this work was to understand whether the nature of breast cancer cells could modify the nature of the dialog of mesenchymal stem cells (MSCs) with cancer cells. By treating MSCs with the conditioned medium of metastatic Estrogen-receptor (ER)-negative MDA-MB-231, or non-metastatic ER-positive MCF-7 breast cancer cells, we observed that a number of chemokines were produced at higher levels by MSCs treated with MDA-MB-231 conditioned medium (CM). MDA-MB-231 cells were able to induce NF-κB signaling in MSC cells. This was shown by the use of a NF-kB chemical inhibitor or an IκB dominant negative mutant, nuclear translocation of p65 and induction of NF-κB signature. Our results suggest that MDA-MB-231 cells exert their effects on MSCs through the secretion of IL-1β, that activates MSCs and induces the same chemokines as the MDA-MB-231CM. In addition, inhibition of IL-1β secretion in the MDA-MB-231 cells reduces the induced production of a panel of chemokines by MSCs, as well the motility of MDA-MB-231 cells. Our data suggest that aggressive breast cancer cells secrete IL-1β, which increases the production of chemokines by MSCs.
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Affiliation(s)
| | - Céline Bouclier
- CNRS, SYS2DIAG, Cap Delta, Montpellier, F-34184, France.,INSERM, U844, U1183, Montpellier, F-34091, France
| | | | - Ivan Bièche
- Institut Curie, Unité de Pharmacogénomique, Département de Génétique, Paris, 75248, France
| | | | | | | | - Sophie Vacher
- Institut Curie, Unité de Pharmacogénomique, Département de Génétique, Paris, 75248, France
| | | | - Philippe Bourin
- Univercell Biosolutions, Pierre Potier, Toulouse, F-31106, France.,CSA21, Toulouse, F-31100, France
| | | | - Franck Molina
- CNRS, SYS2DIAG, Cap Delta, Montpellier, F-34184, France
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25
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Increased expression of interleukin-8 is an independent indicator of poor prognosis in clear-cell renal cell carcinoma. Tumour Biol 2015; 37:4523-9. [DOI: 10.1007/s13277-015-4158-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 09/24/2015] [Indexed: 11/26/2022] Open
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26
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Choi SH, Kwon OJ, Park JY, Kim DY, Ahn SH, Kim SU, Ro SW, Kim KS, Park JH, Kim S, Yun CO, Han KH. Inhibition of tumour angiogenesis and growth by small hairpin HIF-1α and IL-8 in hepatocellular carcinoma. Liver Int 2014; 34:632-642. [PMID: 24321089 DOI: 10.1111/liv.12375] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Accepted: 10/27/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Hypoxia-inducible factor-1α (HIF-1α), a key transcription factor in the cellular response to hypoxia, and interleukin 8 (IL-8), a key mediator of angiogenesis, are important in cancerous tumour growth. In this study, we evaluated the effects of HIF-1α and IL-8 knockdown on angiogenesis and tumour growth in hepatocellular carcinoma (HCC). METHODS Hepatocellular carcinoma cell lines were infected with adenoviruses expressing small-hairpin RNA (shRNA) specific for HIF-1α or IL-8, cultured under hypoxic conditions (1% O2), and examined for their levels of HIF-1α, IL-8, and angiogenesis factors using immunoblot. The effects of adenovirus-mediated shRNA-induced HIF-1α and IL-8 knockdown on tumour growth and angiogenesis were also investigated in a subcutaneous Hep3B-tumour mouse model. RESULTS Hypoxia-inducible factor-1α knockdown directly repressed tumour growth, whereas IL-8 knockdown indirectly repressed tumour growth. Combined knockdown of HIF-1α and IL-8 increased survival rates of mice. HIF-1α and IL-8 knockdown also decreased microvessel density and tumour volume in vivo. Similarly, HIF-1α and IL-8 knockdown inhibited the angiogenic effects of HCC cell-conditioned media on tube formation and invasion by endothelial cells in vitro. CONCLUSION These findings indicate that shRNA-induced HIF-1α and IL-8 knockdown inhibit angiogenesis and tumour growth in HCC. Further development of HIF-1α and IL-8 shRNA technologies could lead to effective therapies for HCC.
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Affiliation(s)
- Sung Hoon Choi
- Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
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27
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Bi LK, Zhou N, Liu C, Lu FD, Lin TX, Xuan XJ, Jiang C, Han JL, Huang H, Zhang CX, Dong W, Liu H, Huang J, Xu KW. Kidney cancer cells secrete IL-8 to activate Akt and promote migration of mesenchymal stem cells. Urol Oncol 2014; 32:607-12. [PMID: 24412633 DOI: 10.1016/j.urolonc.2013.10.018] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2013] [Revised: 10/21/2013] [Accepted: 10/25/2013] [Indexed: 10/25/2022]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are multipotent adult stem cells that have the capability of homing to cancer cells. Thus, MSCs play an important role in the development, metastasis, and drug resistance of cancers. The mechanisms underlying the homing of MSCs in kidney cancer are still poorly understood. METHODS In the present study, enzyme-linked immunosorbent assay was used to measure the level of IL-8 in patients with kidney cancer and in the culture medium of kidney cancer cells. Immunofluorescence staining and reverse transcription polymerase chain reaction were utilized to explore the main receptor for IL-8 in MSCs. Transwell migration assay was performed to measure the migration ability of MSCs and Western blot test was performed to test the activation of signaling pathways. RESULTS The serum level of IL-8 was markedly increased in patients with kidney cancer, and 2 kidney cancer cell lines were found to secrete IL-8. MSCs had high expression of the IL-8 receptor (CXCR2). Blocking IL-8 or CXCR2 could decrease the migration ability of MSCs. IL-8 could significantly increase Akt phosphorylation in MSCs. CONCLUSIONS Kidney cancer cells secrete IL-8 to activate the Akt signaling pathway via CXCR2 on MSCs, inducing the migration of MSCs, which may be one of the important mechanisms underlying the homing of MSCs in kidney cancer.
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Affiliation(s)
- Liang-kuan Bi
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Nan Zhou
- Department of Obstetrics and Gynecology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Cheng Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Fu-Ding Lu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Tian-Xin Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xu-Jun Xuan
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Chun Jiang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jin-Li Han
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Hai Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Cai-Xia Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Wen Dong
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Hao Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jian Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ke-Wei Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
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28
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Green BB, Kerr DE. Epigenetic contribution to individual variation in response to lipopolysaccharide in bovine dermal fibroblasts. Vet Immunol Immunopathol 2013; 157:49-58. [PMID: 24268632 DOI: 10.1016/j.vetimm.2013.10.015] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Revised: 10/22/2013] [Accepted: 10/24/2013] [Indexed: 12/17/2022]
Abstract
The innate immune signaling pathway plays a crucial role in the recognition and early response to pathogens associated with disease. Genetic analysis has been unable to completely account for individual variability in the strength of the innate immune response. The aim of this study was to determine the role of the epigenetic markers (DNA methylation or histone acetylation) in controlling bovine gene expression in relation to the response to lipopolysaccharide (LPS). To determine the impact epigenetics may have in controlling innate immunity, dermal fibroblasts from fifteen dairy heifers having previously displayed a differential response to LPS were exposed to 5-aza-2'-deoxycytidine (AZA) and trichostatin A (TSA); de-methylating and hyper-acetylating agents, respectively. The AZA-TSA exposure resulted in a loss of variability between individuals' response to LPS as measured by fibroblast IL-8 protein production. Transcriptomic analysis by microarray was used to elucidate the role of epigenetics in innate immune signaling at 2, 4, and 8h post-LPS exposure. A subset of genes displayed altered expression due to AZA-TSA alone, suggesting an epigenetic regulatory element modifying expression under normal conditions. Treatment with AZA-TSA also led to increased expression of IL-8 (7.0-fold), IL-6 (2.5-fold), TNF-α (1.6-fold), and serum amyloid A 3 (SAA3) (11.3-fold) among other genes compared to control cultures for at least one of the measured times following LPS exposure. These data support the conclusion that epigenetic regulation significantly alters LPS-induced responses and constitutive cytokine gene expression.
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Affiliation(s)
- Benjamin B Green
- Terrill Hall, University of Vermont, 570 Main Street, Burlington 05405, United States
| | - David E Kerr
- Terrill Hall, University of Vermont, 570 Main Street, Burlington 05405, United States.
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29
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Renoir JM, Marsaud V, Lazennec G. Estrogen receptor signaling as a target for novel breast cancer therapeutics. Biochem Pharmacol 2013; 85:449-65. [DOI: 10.1016/j.bcp.2012.10.018] [Citation(s) in RCA: 122] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2012] [Revised: 10/11/2012] [Accepted: 10/19/2012] [Indexed: 02/07/2023]
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30
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The depletion of Interleukin-8 causes cell cycle arrest and increases the efficacy of docetaxel in breast cancer cells. Biochem Biophys Res Commun 2013; 431:535-41. [DOI: 10.1016/j.bbrc.2013.01.022] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Accepted: 01/07/2013] [Indexed: 02/08/2023]
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31
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Li J, Li J, Li F, Li F, Wang H, Wang H, Wang X, Wang X, Jiang Y, Jiang Y, Li D, Li D. Wortmannin reduces metastasis and angiogenesis of human breast cancer cells via nuclear factor-κB-dependent matrix metalloproteinase-9 and interleukin-8 pathways. J Int Med Res 2013; 40:867-76. [PMID: 22906259 DOI: 10.1177/147323001204000305] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVE To investigate whether inhibition of Akt phosphorylation by the phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin, reduces metastasis and angiogenesis in a human breast cancer cell line via nuclear factor (NF)-κB-dependent matrix metalloproteinase (MMP)-9 and interleukin (IL)-8 pathways. METHODS MDA-MB-231 cells were treated with wortmannin 0-200 nM for 4 h. Restoration of Akt activity was evaluated by transfection of cells with constitutively active myristoylated Akt (myr-Akt). NF-κB, MMP-9 and IL-8 proteins were detected by electrophoretic mobility shift assay, Western blot or enzyme-linked immunosorbent assay. The chicken embryo chorio-allantoic membrane assay, cell motility and migration assays were used to evaluate angiogenesis and invasion in vitro. A mouse pseudo metastatic breast cancer model was used to assess the effects of wortmannin on metastasis and angiogenesis in vivo. RESULTS Wortmannin inhibited the phosphorylation of Akt, upregulation of NF-κB, MMP-9, IL-8, and in vitro cell invasion and angiogenesis, in a dose-dependent manner. Transfection of myr-Akt reversed the cellular and biochemical effects of wortmannin in vitro. Wortmannin also significantly inhibited tumour metastasis and angiogenesis in vivo. CONCLUSION The findings of the present study suggest that wortmannin inhibits metastasis and angiogenesis in breast cancer cells via PI3K/Akt/NF-κB-mediated MMP-9 and IL-8 signalling pathways.
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Affiliation(s)
- Jianguo Li
- Centre of Breast Disease, Affiliated Hospital of Qingdao University Medical College, Qingdao University, Qingdao, Shandong Province, China
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32
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Venza I, Visalli M, Fortunato C, Ruggeri M, Ratone S, Caffo M, Caruso G, Alafaci C, Tomasello F, Teti D, Venza M. PGE2 induces interleukin-8 derepression in human astrocytoma through coordinated DNA demethylation and histone hyperacetylation. Epigenetics 2012; 7:1315-30. [PMID: 23051921 PMCID: PMC3499332 DOI: 10.4161/epi.22446] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
We have recently reported that in astrocytoma cells the expression of interleukin-8 (IL-8) is upregulated by prostaglandin E2 (PGE2). Unfortunately, the exact mechanism by which this happens has not been clarified yet. Here, we have investigated whether IL-8 activation by PGE2 involves changes in DNA methylation and/or histone modifications in 46 astrocytoma specimens, two astrocytoma cell lines and normal astrocytic cells. The DNA methylation status of the IL-8 promoter was analyzed by bisulphite sequencing and by methylation DNA immunoprecipitation analysis. The involvement of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), as well as histone acetylation levels, was assayed by chromatin immunoprecipitation. IL-8 expression at promoter, mRNA and protein level was explored by transfection, real-time PCR and enzyme immunoassay experiments in cells untreated or treated with PGE2, 5-aza-2'-deoxycytidine (5-aza-dC) and HDAC inhibitors, alone or in combination. EMSA was performed with crude cell extracts or recombinant protein. We observed that PGE2 induced IL-8 activation through: (1) demethylation of the single CpG site 5 located at position -83 within the binding region for CEBP-β in the IL-8 promoter; (2) C/EBP-β and p300 co-activator recruitment; (3) H3 acetylation enhancement and (4) reduction in DNMT1, DNMT3a, HDAC2 and HDAC3 association to CpG site 5 region. Treatment with 5-aza-dC or HDAC inhibitors of class I HDACs strengthened either basal or PGE2-mediated IL-8 expression. These findings have elucidated an orchestrated mechanism triggered by PGE2 whereby concurrent association of site-specific demethylation and histone H3 hyperacetylation resulted in derepression of IL-8 gene expression in human astrocytoma.
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Affiliation(s)
- Isabella Venza
- Department of Surgical Specialities, University of Messina, Messina, Italy
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33
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Rosa DD, Lourenço FC, da Fonseca ACM, de Sales RL, Ribeiro SMR, Neves CA, Peluzio MDCG. Fish oil improves the lipid profile and reduces inflammatory cytokines in Wistar rats with precancerous colon lesions. Nutr Cancer 2012; 64:569-79. [PMID: 22483364 DOI: 10.1080/01635581.2012.665563] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
A fatty diet is regarded as one of the most important risk factors related to the etiology of colorectal cancer, and this effect is linked to the quantity and principal types of fatty acids consumed. In this study, the chemopreventive effects of different oils on rats were investigated. Forty Wistar rats received 1,2-dimetilhidrazine (DMH) and were divided into 4 groups fed normal lipid diets to which 4% olive, fish, flaxseed, or soybean oils (control) were added. The group fed with fish oil presented higher levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid in hepatic tissue and greater levels of linolenic acid and EPA in adipose tissue compared to the other treatments. In the proximal portion of the colon, lower levels of aberrant crypt foci were found in the fish and flaxseed oil groups; however, this behavior was not observed in the middle and distal regions. Via a benchmarking method, the fish oil group showed a greater transforming growth factor β expression and lower interleukin-8 expression in relation to the other treatments. Fish oil in a normal lipid diet demonstrated a limited protective effect on the colonic precancerous mucosa in carcinogen-treated rodents, whereas it had a beneficial effect on inflammatory modulation.
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Affiliation(s)
- Damiana Diniz Rosa
- Department of Nutrition and Health, Federal University of Viçosa, Viçosa, Brazil
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Kuai WX, Wang Q, Yang XZ, Zhao Y, Yu R, Tang XJ. Interleukin-8 associates with adhesion, migration, invasion and chemosensitivity of human gastric cancer cells. World J Gastroenterol 2012; 18:979-85. [PMID: 22408359 PMCID: PMC3297059 DOI: 10.3748/wjg.v18.i9.979] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2011] [Revised: 09/30/2011] [Accepted: 12/31/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationship between Interleukin-8 (IL-8) and proliferation, adhesion, migration, invasion and chemosensitivity of gastric cancer (GC) cells.
METHODS: The IL-8 cDNA was stably transfected into human GC cell line MKN-45 and selected IL-8-secreting transfectants. The expression of IL-8 in human GC cell line KATO-III was inhibited by RNA interference. The expressions of mRNA and protein of IL-8 in GC cells were detected by real-time reverse transcription-polymerase chain reaction or enzyme-linked immunosorbent assay (ELISA).
RESULTS: The overexpression of IL-8 resulted in an increased cell adhesion, migration and invasion, and a significant resistance to oxaliplatin in MKN-45 cells. Inhibition of IL-8 expression with small interfering RNA decreased the adhesion, migration and invasion functions and oxaliplatin resistance in KATO-III cells. IL-8 increased NF-κB and Akt activities and adhesion molecules ICAM-1, VCAM-1, and CD44 expression in GC cells.
CONCLUSION: Overexpression of IL-8 promotes the adhesion, migration, invasion, and chemoresistance of GC cells, indicating that IL-8 is an important therapeutic target in GC.
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Ben-Baruch A. The Tumor-Promoting Flow of Cells Into, Within and Out of the Tumor Site: Regulation by the Inflammatory Axis of TNFα and Chemokines. CANCER MICROENVIRONMENT 2011; 5:151-64. [PMID: 22190050 DOI: 10.1007/s12307-011-0094-3] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2011] [Accepted: 12/08/2011] [Indexed: 12/19/2022]
Abstract
Tumors are dynamic organs, in which active processes of cell motility affect disease course by regulating the composition of cells at the tumor site. While sub-populations of tumor-promoting leukocytes are recruited inward and endothelial cell migration stands in the basis of vascular branching throughout the tumor, cancer cells make their way out of the primary site towards specific metastatic sites. This review describes the independent and cross-regulatory roles of inflammatory chemokines and of the inflammatory cytokine tumor necrosis factor α (TNFα) in determining cell motility processes that eventually have profound effects on tumor growth and metastasis. First, the effects of inflammatory chemokines such as CCL2 (MCP-1), CCL5 (RANTES) and CXCL8 (IL-8) are described, regulating the inward flow of leukocyte sub-populations with pro-tumoral activities, such as tumor-associated macrophages (TAM), myeloid-derived suppressor cells (MDSC), tumor-associated neutrophils (TAN), Th17 cells and Tregs. Then, the ability of inflammatory chemokines to induce endothelial cell migration, sprouting and tube formation is discussed, with its implications on tumor angiogenesis. This part is followed by an in depth description of the manners by which TNFα potentiates the above activities of the inflammatory chemokines, alongside with its ability to directly induce migratory processes in the tumor cells thus promoting metastasis. Note worthy is the ability of TNFα to induce in the tumor cells the important process of epithelial-to-mesenchymal transition (EMT). Emphasis is given to the ability of TNFα to establish an inflammatory network with the chemokines, and in parallel to form a cell re-modeling network together with transforming growth factor β (TGFβ). The review concludes by discussing the implications of such networks on disease course, and on the future design of therapeutic measures in cancer.
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Affiliation(s)
- Adit Ben-Baruch
- Department Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 69978, Israel,
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Dai Y, Chen S, Wang L, Pei XY, Funk VL, Kramer LB, Dent P, Grant S. Disruption of IkappaB kinase (IKK)-mediated RelA serine 536 phosphorylation sensitizes human multiple myeloma cells to histone deacetylase (HDAC) inhibitors. J Biol Chem 2011; 286:34036-34050. [PMID: 21816815 PMCID: PMC3190767 DOI: 10.1074/jbc.m111.284216] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2011] [Indexed: 02/05/2023] Open
Abstract
Post-translational modifications of RelA play an important role in regulation of NF-κB activation. We previously demonstrated that in malignant hematopoietic cells, histone deacetylase inhibitors (HDACIs) induced RelA hyperacetylation and NF-κB activation, attenuating lethality. We now present evidence that IκB kinase (IKK) β-mediated RelA Ser-536 phosphorylation plays a significant functional role in promoting RelA acetylation, inducing NF-κB activation, and limiting HDACI lethality in human multiple myeloma (MM) cells. Immunoblot profiling revealed that although basal RelA phosphorylation varied in MM cells, Ser-536 phosphorylation correlated with IKK activity. Exposure to the pan-HDACIs vorinostat or LBH-589 induced phosphorylation of IKKα/β (Ser-180/Ser-181) and RelA (Ser-536) in MM cells, including cells expressing an IκBα "super-repressor," accompanied by increased RelA nuclear translocation, acetylation, DNA binding, and transactivation activity. These events were substantially blocked by either pan-IKK or IKKβ-selective inhibitors, resulting in marked apoptosis. Consistent with these events, inhibitory peptides targeting either the NF-κB essential modulator (NEMO) binding domain for IKK complex formation or RelA phosphorylation sites also significantly increased HDACI lethality. Moreover, IKKβ knockdown by shRNA prevented Ser-536 phosphorylation and significantly enhanced HDACI susceptibility. Finally, introduction of a nonphosphorylatable RelA mutant S536A, which failed to undergo acetylation in response to HDACIs, impaired NF-κB activation and increased cell death. These findings indicate that HDACIs induce Ser-536 phosphorylation of the NF-κB subunit RelA through an IKKβ-dependent mechanism, an action that is functionally involved in activation of the cytoprotective NF-κB signaling cascade primarily through facilitation of RelA acetylation rather than nuclear translocation.
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Affiliation(s)
- Yun Dai
- From the Departments of Medicine
| | | | - Li Wang
- From the Departments of Medicine
| | | | | | | | | | - Steven Grant
- From the Departments of Medicine
- Biochemistry, and
- Pharmacology, Virginia Commonwealth University/Massey Cancer Center, Richmond, Virginia 23298
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Epidermal growth factor and estrogen act by independent pathways to additively promote the release of the angiogenic chemokine CXCL8 by breast tumor cells. Neoplasia 2011; 13:230-43. [PMID: 21390186 DOI: 10.1593/neo.101340] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Revised: 12/19/2010] [Accepted: 12/30/2010] [Indexed: 02/03/2023] Open
Abstract
The tumor microenvironment contains multiple cancer-supporting factors, whose joint activities promote malignancy. Here, we show that epidermal growth factor (EGF) and estrogen upregulate in an additive manner the transcription and the secretion of the angiogenic chemokine CXCL8 (interleukin 8 [IL-8]) in breast tumor cells. In view of published findings on cross-regulatory interactions between EGF receptors and estrogen receptors in breast tumor cells, we asked whether the additive effects of EGF and estrogen were due to their ability to (1) induce intracellular cross talk and amplify shared regulatory pathways or (2) act in independent mechanisms, which complement each other. We found that stimulation by EGF alone induced the release of CXCL8 through signaling pathways involving ErbB2, ErbB1, Erk, and phosphoinositide 3-kinase (PI3K). ErbB2 and Erk were also involved in estrogen activities on CXCL8 but to a lower extent than with EGF. However, in the joint stimulatory setup, the addition of estrogen to EGF has led to partial (ErbB2, ErbB1, Erk) or complete (PI3K) shutoff of the involvement of these activation pathways in CXCL8 up-regulation. Furthermore, when costimulation by EGF + estrogen was applied, the effects of estrogen were channeled to regulation of CXCL8 at the transcription level, acting through the transcription factor estrogen receptor α (ERα). In parallel, in the joint stimulation, EGF acted independently at the transcription level through AP-1, to upregulate CXCL8 expression. The independent activities of EGF and estrogen on CXCL8 transcription reinforce the need to introduce simultaneous targeting of ErbBs and ERα to achieve effective therapy in breast cancer.
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Hu N, Zhang J, Cui W, Kong G, Zhang S, Yue L, Bai X, Zhang Z, Zhang W, Zhang X, Ye L. miR-520b regulates migration of breast cancer cells by targeting hepatitis B X-interacting protein and interleukin-8. J Biol Chem 2011; 286:13714-22. [PMID: 21343296 DOI: 10.1074/jbc.m110.204131] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
MicroRNAs play important roles in tumor metastasis. Recently, we reported that the level of miR-520b is inversely related to the metastatic potential of breast cancer cells. In this study, we investigated the role of miR-520b in breast cancer cell migration. We found that miR-520b suppressed the migration of breast cancer cells with high metastatic potential, including MDA-MB-231 and LM-MCF-7 cells, although the inhibition of miR-520b enhanced the migration of low metastatic potential MCF-7 cells. We further discovered that miR-520b directly targets the 3'-untranslated region (3'UTR) of either hepatitis B X-interacting protein (HBXIP) or interleukin-8 (IL-8), which has been reported to contribute to cell migration. Surprisingly, tissue array assays showed that 75% (38:49) and 94% (36:38) of breast cancer tissues and metastatic lymph tissues, respectively, were positive for HBXIP expression. Moreover, overexpression of HBXIP was able to promote the migration of MCF-7 cells. Interestingly, HBXIP was able to regulate IL-8 transcription by NF-κB, suggesting that the two target genes of miR-520b are functionally connected. In addition, we found that miR-520b could indirectly regulate IL-8 transcription by targeting HBXIP. Thus, we conclude that miR-520b is involved in regulating breast cancer cell migration by targeting HBXIP and IL-8 via a network in which HBXIP promotes migration by stimulating NF-κB-mediated IL-8 expression. These studies point to HBXIP as a potential therapeutic target for breast cancer.
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Affiliation(s)
- Nan Hu
- Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin 300071, China
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Baird AM, Gray SG, O'Byrne KJ. Epigenetics underpinning the regulation of the CXC (ELR+) chemokines in non-small cell lung cancer. PLoS One 2011; 6:e14593. [PMID: 21298036 PMCID: PMC3029265 DOI: 10.1371/journal.pone.0014593] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2010] [Accepted: 01/02/2011] [Indexed: 12/21/2022] Open
Abstract
Background Angiogenesis may play a role in the pathogenesis of Non-Small Cell Lung cancer (NSCLC). The CXC (ELR+) chemokine family are powerful promoters of the angiogenic response. Methods The expression of the CXC (ELR+) family members (CXCL1-3/GROα-γ, CXCL8/IL-8, CXCR1/2) was examined in a series of resected fresh frozen NSCLC tumours. Additionally, the expression and epigenetic regulation of these chemokines was examined in normal bronchial epithelial and NSCLC cell lines. Results Overall, expression of the chemokine ligands (CXCL1, 2, 8) and their receptors (CXCR1/2) were down regulated in tumour samples compared with normal, with the exception of CXCL3. CXCL8 and CXCR1/2 were found to be epigenetically regulated by histone post-translational modifications. Recombinant CXCL8 did not stimulate cell growth in either a normal bronchial epithelial or a squamous carcinoma cell line (SKMES-1). However, an increase was observed at 72 hours post treatment in an adenocarcinoma cell line. Conclusions CXC (ELR+) chemokines are dysregulated in NSCLC. The balance of these chemokines may be critical in the tumour microenvironment and requires further elucidation. It remains to be seen if epigenetic targeting of these pathways is a viable therapeutic option in lung cancer treatment.
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MESH Headings
- Biopsy
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/metabolism
- Carcinoma, Non-Small-Cell Lung/pathology
- Cell Line
- Cell Line, Tumor
- Chemokine CXCL1
- Chemokine CXCL2
- Chemokines, CXC/analysis
- Chemokines, CXC/genetics
- Epigenesis, Genetic
- Gene Expression Regulation, Neoplastic/genetics
- Humans
- Interleukin-8
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Lung Neoplasms/pathology
- Neovascularization, Pathologic/genetics
- Protein Processing, Post-Translational
- Receptors, Interleukin-8A
- Receptors, Interleukin-8B
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Affiliation(s)
- Anne-Marie Baird
- Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity College, Dublin, Ireland
| | - Steven G. Gray
- Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity College, Dublin, Ireland
| | - Kenneth J. O'Byrne
- Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity College, Dublin, Ireland
- HOPE Directorate, St. James's Hospital, Dublin, Ireland
- * E-mail:
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40
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McNally RS, Davis BK, Clements CM, Accavitti-Loper MA, Mak TW, Ting JPY. DJ-1 enhances cell survival through the binding of Cezanne, a negative regulator of NF-kappaB. J Biol Chem 2010; 286:4098-106. [PMID: 21097510 DOI: 10.1074/jbc.m110.147371] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Heightened DJ-1 (Park7) expression is associated with a reduction in chemotherapeutic-induced cell death and poor prognosis in several cancers, whereas the loss of DJ-1 function is found in a subgroup of Parkinson disease associated with neuronal death. This study describes a novel pathway by which DJ-1 modulates cell survival. Mass spectrometry shows that DJ-1 interacts with BBS1, CLCF1, MTREF, and Cezanne/OTUD7B/Za20d1. Among these, Cezanne is a known deubiquitination enzyme that inhibits NF-κB activity. DJ-1/Cezanne interaction is confirmed by co-immunoprecipitation of overexpressed and endogenous proteins, maps to the amino-terminal 70 residues of DJ-1, and leads to the inhibition of the deubiquitinating activity of Cezanne. Microarray profiling of shRNA-transduced cells shows that DJ-1 and Cezanne regulate IL-8 and ICAM-1 expression in opposing directions. Similarly, DJ-1 enhances NF-κB nuclear translocation and cell survival, whereas Cezanne reduces these outcomes. Analysis of mouse Park7(-/-) primary cells confirms the regulation of ICAM-1 by DJ-1 and Cezanne. As NF-κB is important in cellular survival and transformation, IL-8 functions as an angiogenic factor and pro-survival signal, and ICAM-1 has been implicated in tumor progression, invasion, and metastasis; these data provide an additional modality by which DJ-1 controls cell survival and possibly tumor progression via interaction with Cezanne.
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Affiliation(s)
- R Sean McNally
- Department of Microbiology-Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7295, USA
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41
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Wang X, Jackson LN, Johnson SM, Wang Q, Evers BM. Suppression of neurotensin receptor type 1 expression and function by histone deacetylase inhibitors in human colorectal cancers. Mol Cancer Ther 2010; 9:2389-98. [PMID: 20663927 DOI: 10.1158/1535-7163.mct-09-1080] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Neurotensin, a gut peptide, stimulates the growth of colorectal cancers that possess the high-affinity neurotensin receptor (NTR1). Sodium butyrate (NaBT) is a potent histone deacetylase inhibitor (HDACi) that induces growth arrest, differentiation, and apoptosis of colorectal cancers. Previously, we had shown that NaBT increases nuclear GSK-3beta expression and kinase activity; GSK-3beta functions as a negative regulator of extracellular signal-regulated kinase (ERK) signaling. The purpose of our current study was to determine: (a) whether HDACi alters NTR1 expression and function, and (b) the role of GSK-3beta/ERK in NTR1 regulation. Human colorectal cancers with NTR1 were treated with various HDACi, and NTR1 expression and function were assessed. Treatment with HDACi dramatically decreased endogenous NTR1 mRNA, protein, and promoter activity. Overexpression of GSK-3beta decreased NTR1 promoter activity (> 30%); inhibition of GSK-3beta increased NTR1 expression in colorectal cancer cells, indicating that GSK-3beta is a negative regulator of ERK and NTR1. Consistent with our previous findings, HDACi significantly decreased phosphorylated ERK while increasing GSK-3beta. Selective MAP/ERK kinase/ERK inhibitors suppressed NTR1 mRNA expression in a time- and dose-dependent fashion, and reduced NTR1 promoter activity by approximately 70%. Finally, pretreatment with NaBT prevented neurotensin-mediated cyclooxygenase-2 and c-myc expression and attenuated neurotensin-induced interleukin-8 expression. HDACi suppresses endogenous NTR1 expression and function in colorectal cancer cell lines; this effect is mediated, at least in part, through the GSK-3beta/ERK pathway. The downregulation of NTR1 in colorectal cancers may represent an important mechanism for the anticancer effects of HDACi.
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Affiliation(s)
- Xiaofu Wang
- Department of Surgery, The University of Texas Medical Branch, Galveston, Texas, USA
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42
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Maguire JA, Mulugeta S, Beers MF. Endoplasmic reticulum stress induced by surfactant protein C BRICHOS mutants promotes proinflammatory signaling by epithelial cells. Am J Respir Cell Mol Biol 2010; 44:404-14. [PMID: 20463293 DOI: 10.1165/rcmb.2009-0382oc] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Chronic interstitial lung disease in both adults and children is associated with mutations of the surfactant protein C (SP-C) proprotein. Among these, mutations within the distal COOH propeptide, known as the BRICHOS domain, are associated with a severe disease phenotype. We showed that prolonged expression of the BRICHOS mutants, SP-C(Δexon4) and SP-C(L188Q), destabilizes endoplasmic reticulum (ER) quality-control mechanisms (the unfolded protein response, or UPR), resulting in the induction of ER stress signaling, an inhibition of the ubiquitin/proteasome system, and the activation of apoptotic pathways. Based on recent observations that the UPR and ER stress can be linked to the induction of proinflammatory signaling, we hypothesized that the epithelial cell dysfunction mediated by SP-C BRICHOS mutants would activate proinflammatory signaling pathways. In a test of this hypothesis, A549 and human embryonic kidney epithelial (HEK293) cells, transiently transfected with either SP-C(Δexon4) or SP-C(L188Q) mutants, each promoted the upregulation of multiple UPR response genes, including homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1 (HERPUD1) and GRP78. Commensurate with these results, increases in IL-8 secretion occurred and were accompanied by the activation of c-Jun N-terminal kinase (JNK)/activating protein-1 signaling. The stimulation of IL-8 cytokine release was completely attenuated by treatment with the JNK-specific inhibitor, SP600125. In addition, SP-C(Δexon4), but not SP-C(L188Q), activated NFκB. The treatment of SP-C(Δexon4) transfected cells with 4-phenylbutyric acid, a small molecule chaperone known to improve protein folding, blocked the activation of NFκB, but not the release of IL-8. Taken together, the results support the role of JNK signaling in mediating SP-C BRICHOS-induced cytokine release, and provide a link between SP-C BRICHOS mutants and proinflammatory cytokine signaling.
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Affiliation(s)
- Jean Ann Maguire
- Surfactant Biology Laboratories, Pulmonary and Critical Care Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, USA
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43
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Krishnan M, Singh AB, Smith JJ, Sharma A, Chen X, Eschrich S, Yeatman TJ, Beauchamp RD, Dhawan P. HDAC inhibitors regulate claudin-1 expression in colon cancer cells through modulation of mRNA stability. Oncogene 2009; 29:305-12. [PMID: 19881542 DOI: 10.1038/onc.2009.324] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Expression and cellular distribution of claudin-1, a tight junction protein, is dysregulated in colon cancer and its overexpression in colon cancer cells induced dedifferentiation and increased invasion. However, the molecular mechanism(s) underlying dysregulated claudin-1 expression in colon cancer remains poorly understood. Histone deacetylase (HDAC)-dependent histone acetylation is an important mechanism of the regulation of cancer-related genes and inhibition of HDACs induces epithelial differentiation and decreased invasion. Therefore, in this study, we examined the role of HDAC-dependent epigenetic regulation of claudin-1 in colon cancer. In this study, we show that sodium butyrate and Trichostatin A (TSA), two structurally different and widely used HDAC inhibitors, inhibited claudin-1 expression in multiple colon cancer cell lines. Further studies revealed modulation of claudin-1 mRNA stability by its 3'-UTR as the major mechanism underlying HDAC-dependent claudin-1 expression. In addition, overexpression of claudin-1 abrogated the TSA-induced inhibition of invasion in colon cancer cells suggesting functional crosstalk. Analysis of mRNA expression in colon cancer patients, showed a similar pattern of increase in claudin-1 and HDAC-2 mRNA expression throughout all stages of colon cancer. Inhibition of claudin-1 expression by HDAC-2-specific small interfering RNA further supported the role of HDAC-2 in this regulation. Taken together, we report a novel post-transcriptional regulation of claudin-1 expression in colon cancer cells and further show a functional correlation between claudin-1 expression and TSA-mediated regulation of invasion. As HDAC inhibitors are considered to be promising anticancer drugs, these new findings will have implications in both laboratory and clinical settings.
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Affiliation(s)
- M Krishnan
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
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Singh RK, Lokeshwar BL. Depletion of intrinsic expression of Interleukin-8 in prostate cancer cells causes cell cycle arrest, spontaneous apoptosis and increases the efficacy of chemotherapeutic drugs. Mol Cancer 2009; 8:57. [PMID: 19646263 PMCID: PMC2729725 DOI: 10.1186/1476-4598-8-57] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2009] [Accepted: 07/31/2009] [Indexed: 12/11/2022] Open
Abstract
Background The progression of all cancers is characterized by increased-cell proliferation and decreased-apoptosis. The androgen-independent prostate cancer (AIPC) is the terminal stage of the disease. Many chemokines and cytokines are suspects to cause this increased tumor cell survival that ultimately leads to resistance to therapy and demise of the host. The AIPC cells, but not androgen-responsive cells, constitutively express abundant amount of the pro-inflammatory chemokine, Interleukin-8 (IL-8). The mechanism of IL-8 mediated survival and therapeutic resistance in AIPC cells is unclear at present. The purpose of this report is to show the pervasive role of IL-8 in malignant progression of androgen-independent prostate cancer (AIPC) and to provide a potential new therapeutic avenue, using RNA interference. Results The functional consequence of IL-8 depletion in AIPC cells was investigated by RNA interference in two IL-8 secreting AIPC cell lines, PC-3 and DU145. The non-IL-8 secreting LNCaP and LAPC-4 cells served as controls. Cells were transfected with RISC-free siRNA (control) or validated-pool of IL-8 siRNA. Transfection with 50 nM IL-8 siRNA caused >95% depletion of IL-8 mRNA and >92% decrease in IL-8 protein. This reduction in IL-8 led to cell cycle arrest at G1/S boundary and decreases in cell cycle-regulated proteins: Cyclin D1 and Cyclin B1 (both decreased >50%) and inhibition of ERK1/2 activity by >50%. Further, the spontaneous apoptosis was increased by >43% in IL-8 depleted cells, evidenced by increases in caspase-9 activation and cleaved-PARP. IL-8 depletion caused significant decreases in anti-apoptotic proteins, BCL-2, BCL-xL due to decrease in both mRNA and post-translational stability, and increased levels of pro-apoptotic BAX and BAD proteins. More significantly, depletion of intracellular IL-8 increased the cytotoxic activity of multiple chemotherapeutic drugs. Specifically, the cytotoxicity of Docetaxel, Staurosporine and Rapamycin increased significantly (>40% at IC50 dose) in IL-8 depleted cells as compared to that in C-siRNA transfected cells. Conclusion These results show the pervasive role of IL-8 in promoting tumor cell survival, and resistance to cytotoxic drugs, regardless of the cytotoxic mechanism of antiproliferative drugs, and point to potential therapeutic significance of IL-8 depletion in men with AIPC.
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Affiliation(s)
- Rajendra K Singh
- Department of Urology and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida, USA.
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45
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Schauer IG, Ressler SJ, Rowley DR. Keratinocyte-derived chemokine induces prostate epithelial hyperplasia and reactive stroma in a novel transgenic mouse model. Prostate 2009; 69:373-84. [PMID: 19021203 PMCID: PMC2719820 DOI: 10.1002/pros.20886] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Interleukin-8 (IL-8) is upregulated in fibrotic and malignant diseases and is a key mediator of proliferative responses. Elevated IL-8 was recently correlated with benign prostatic hyperplasia epithelium and a myofibroblast reactive stroma. Thus, we sought to determine whether overexpressed IL-8 and keratinocyte-derived chemokine (KC), the functional murine homolog of IL-8, induce prostate epithelial hyperplasia and a reactive phenotype. METHODS Transgenic mice that overexpress KC within prostate epithelia and xenograft models with engineered human cells that overexpress IL-8 were developed. RESULTS Overexpression of KC in transgenic mice produced hyperplastic prostate epithelial acini associated with a periacinar reactive stroma. KC induced an altered epithelial/stroma proliferation index ratio, increased acini diameter, epithelial infolding, and expression of prototypical reactive stroma markers. Overexpression of IL-8 in normal human prostate epithelial xenografts correlated with elevated epithelial proliferation index and altered morphology. Elevated human prostate stromal and epithelial cell proliferation, nodule-like morphology and increased xenograft survival were observed in IL-8-overexpressing orthotopic xenografts. CONCLUSIONS Together, these data demonstrate that overexpression of IL-8/KC results in a prostate epithelial hyperplasia with an associated reactive stroma phenotype. The novel transgenic mouse and human xenograft models described here may be useful in dissecting key mechanisms of IL-8 induced prostate hyperplasia and reactive stroma.
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Affiliation(s)
| | | | - David R. Rowley
- To whom requests for reprints should be addressed: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, 325D, Houston, TX 77030. Phone: (713) 798-6220; Fax: (713) 790-1275; E-mail:
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