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Zhang T, Wei D, Zhan Y, Long Z, Lu T, Zhao P, Gao R, Kang Q, Zhang L, Liu M, Yang X, Wang J. Heme oxygenase 1 confers gilteritinib resistance in FLT3-ITD acute myeloid leukemia in a STAT6-dependent manner. Cancer Cell Int 2025; 25:129. [PMID: 40186248 PMCID: PMC11969713 DOI: 10.1186/s12935-025-03757-3] [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: 08/02/2024] [Accepted: 03/18/2025] [Indexed: 04/07/2025] Open
Abstract
BACKGROUND Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. We previously discovered that heme oxygenase 1 (HO1) is crucial for chemoresistance in AML, but the detailed molecular mechanism of that remains unclear. METHODS RNA sequencing was conducted to assess transcriptomic changes in three pairs of AML cells after regulating the expression of HO1. The molecular mechanism by which HO1 induces gilteritinib resistance in FLT3-ITD (FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD)) AML was evaluated by quantitative real-time PCR (qRT-PCR), CCK-8, flow cytometry, and western blotting. FLT3-ITD AML mouse models were established to investigate the effects of HO1 expression on gilteritinib resistance in vivo. RESULTS In these three pairs of AML cells, we discovered that HO1-mediated drug resistance is connected to the interleukin-4-mediated signaling pathway (specifically STAT6) only in MV4-11 cells with the FLT3-ITD mutation. Further findings revealed that HO1 overexpression confers gilteritinib resistance in FLT3-ITD AML cell lines and primary individual specimens. While suppression of HO1 sensitized FLT3-ITD AML cell lines and primary individual specimens to gilteritinib. Mechanistically, western blotting and flow cytometry confirmed that HO1-mediated gilteritinib resistance is related to STAT6 phosphorylation in FLT3-ITD AML cell lines and primary individual specimens. Moreover, tumor-bearing mice were employed to determine that HO1 overexpression conferred gilteritinib resistance in vivo. CONCLUSIONS Collectively, these studies illustrate that HO1 may act as a successful treatment target for gilteritinib-resistant FLT3-ITD AML patients.
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Affiliation(s)
- Tianzhuo Zhang
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
- Guizhou Province Hematopoietic Stem Cell Transplantation Center, Guizhou Province Institute of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Danna Wei
- Department of Pediatric Hematology, Guiyang Maternal and Child Health Care Hospital, Guiyang Children's Hospital, Guiyang, 550002, China
| | - Yun Zhan
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
- Guizhou Province Hematopoietic Stem Cell Transplantation Center, Guizhou Province Institute of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Zhengmei Long
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
- Guizhou Province Hematopoietic Stem Cell Transplantation Center, Guizhou Province Institute of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Tingting Lu
- Center for Clinical Laboratories, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Peng Zhao
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
- Guizhou Province Hematopoietic Stem Cell Transplantation Center, Guizhou Province Institute of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Rui Gao
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
- Guizhou Province Hematopoietic Stem Cell Transplantation Center, Guizhou Province Institute of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Qian Kang
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
- Guizhou Province Hematopoietic Stem Cell Transplantation Center, Guizhou Province Institute of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Luxin Zhang
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
- Guizhou Province Hematopoietic Stem Cell Transplantation Center, Guizhou Province Institute of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Min Liu
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
- Guizhou Province Hematopoietic Stem Cell Transplantation Center, Guizhou Province Institute of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Xueying Yang
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
- Guizhou Province Hematopoietic Stem Cell Transplantation Center, Guizhou Province Institute of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Jishi Wang
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
- Guizhou Province Hematopoietic Stem Cell Transplantation Center, Guizhou Province Institute of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
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Wang X, Li Z, Shen J, Liu L. Targeting protein tyrosine phosphatase non-receptor type 6 (PTPN6) as a therapeutic strategy in acute myeloid leukemia. Cell Biol Toxicol 2024; 41:11. [PMID: 39707066 PMCID: PMC11662038 DOI: 10.1007/s10565-024-09965-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 11/29/2024] [Indexed: 12/23/2024]
Abstract
Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid progenitor cells. Despite advancements in treatment, the prognosis for AML patients remains poor, highlighting the need for novel therapeutic targets. Protein Tyrosine Phosphatase Non-Receptor Type 6 (PTPN6), also known as SHP-1, is a critical regulator of hematopoietic cell signaling and has been implicated in various leukemias. This study investigates the therapeutic potential of targeting PTPN6 in AML. We employed both in vitro and in vivo models to evaluate the effects of PTPN6 inhibition on AML cell proliferation, apoptosis, and differentiation. Our results demonstrate that PTPN6 inhibition leads to a significant reduction in AML cell viability, induces apoptosis, and promotes differentiation of leukemic cells into mature myeloid cells. Mechanistic studies revealed that PTPN6 inhibition disrupts key signaling pathways involved in AML pathogenesis, including the JAK/STAT and PI3K/AKT pathways. Furthermore, the combination of PTPN6 inhibitors with standard chemotherapeutic agents exhibited a synergistic effect, enhancing the overall therapeutic efficacy. These findings suggest that PTPN6 is a promising therapeutic target in AML and warrants further investigation into the development of PTPN6 inhibitors for clinical application in AML treatment.
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Affiliation(s)
- Xiaoou Wang
- Department of Hematology, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, People's Republic of China
| | - Zhenggang Li
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, 110001, People's Republic of China
| | - Jing Shen
- Department of Hematology, Shengjing Hospital of China Medical University, Shenyang, 110001, People's Republic of China.
| | - Lin Liu
- Department of Hematology, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, People's Republic of China.
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3
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Leal AS, Liby KT. The BRD4 Inhibitor I-BET-762 Reduces HO-1 Expression in Macrophages and the Pancreas of Mice. Int J Mol Sci 2024; 25:9985. [PMID: 39337472 PMCID: PMC11432103 DOI: 10.3390/ijms25189985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 09/10/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
In pancreatic cancer, the tumor microenvironment (TME) accounts for up to 90% of the tumor mass. Pancreatitis, characterized by the increased infiltration of macrophages into the pancreas, is a known risk factor for pancreatic cancer. The NRF2 (nuclear factor erythroid 2-related factor 2) transcription factor regulates responses to oxidative stress and can promote cancer and chemoresistance. NRF2 also attenuates inflammation through the regulation of macrophage-specific genes. Heme oxygenase 1 (HO-1) is expressed by anti-inflammatory macrophages to degrade heme, and its expression is dependent on NRF2 translocation to the nucleus. In macrophages stimulated with conditioned media from pancreatic cancer cells, HO-1 protein levels increased, which correlated with higher NRF2 expression in the nuclear fraction. Significant differences in macrophage infiltration and HO-1 expression were detected in LSL-KrasG12D/+; Pdx-1-Cre (KC) mice, Nrf2 whole-body knockout (KO) mice and wildtype mice with pancreatitis. Since epigenetic modulation is a mechanism used by tumors to regulate the TME, using small molecules as epigenetic modulators to activate immune recognition is therapeutically desirable. When the bromodomain inhibitor I-BET-762 was used to treat macrophages or mice with pancreatitis, high levels of HO-1 were reduced. This study shows that bromodomain inhibitors can be used to prevent physiological responses to inflammation that promote tumorigenesis.
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Affiliation(s)
- Ana S. Leal
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - Karen T. Liby
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Alsharabasy AM, Lagarias PI, Papavasileiou KD, Afantitis A, Farràs P, Glynn S, Pandit A. Examining Hemin and its Derivatives: Induction of Heme-Oxygenase-1 Activity and Oxidative Stress in Breast Cancer Cells through Collaborative Experimental Analysis and Molecular Dynamics Simulations. J Med Chem 2024; 67:15411-15427. [PMID: 39159487 PMCID: PMC11403666 DOI: 10.1021/acs.jmedchem.4c00989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/21/2024]
Abstract
Hemin triggers intracellular reactive oxygen species (ROS) accumulation and enhances heme oxygenase-1 (HOX-1) activity, indicating its potential as an anticancer agent, though precise control of its intracellular levels is crucial. The study explores the impact of hemin and its derivatives, hemin-tyrosine, and hemin-styrene (H-Styr) conjugates on migration, HOX-1 expression, specific apoptosis markers, mitochondrial functions, and ROS generation in breast cancer cells. Molecular docking and dynamics simulations were used to understand the interactions among HOX-1, heme, and the compounds. Hemin outperforms its derivatives in inducing HOX-1 expression, exhibiting pro-oxidative effects and reducing cell migration. Molecular simulations show that heme binds favorably to HOX-1, followed by the other compounds, primarily through van der Waals and electrostatic forces. However, only van der Waals forces determine the H-Styr complexation. These interactions, influenced by metalloporphyrin characteristics, provide insights into HOX-1 regulation and ROS generation, potentially guiding the development of breast cancer therapies targeting oxidative stress.
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Affiliation(s)
- Amir M Alsharabasy
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway H91 W2TY, Ireland
| | | | - Konstantinos D Papavasileiou
- Department of ChemoInformatics, Novamechanics Ltd., Nicosia 1070, Cyprus
- Department of Chemoinformatics, Novamechanics MIKE, Piraeus 18545, Greece
- Division of Data Driven Innovation, Entelos Institute, Larnaca 6059, Cyprus
| | - Antreas Afantitis
- Department of ChemoInformatics, Novamechanics Ltd., Nicosia 1070, Cyprus
- Department of Chemoinformatics, Novamechanics MIKE, Piraeus 18545, Greece
- Division of Data Driven Innovation, Entelos Institute, Larnaca 6059, Cyprus
| | - Pau Farràs
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway H91 W2TY, Ireland
- School of Biological and Chemical Sciences, Ryan Institute, University of Galway, Galway H91 TK33, Ireland
| | - Sharon Glynn
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway H91 W2TY, Ireland
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, University of Galway, Galway H91 YR71, Ireland
| | - Abhay Pandit
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway H91 W2TY, Ireland
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5
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Han S, Guo X, Wang M, Liu H, Song Y, He Y, Hsueh KL, Cui W, Su W, Kuai L, Deng J. Highly Selective Novel Heme Oxygenase-1 Hits Found by DNA-Encoded Library Machine Learning beyond the DEL Chemical Space. ACS Med Chem Lett 2024; 15:1456-1466. [PMID: 39291011 PMCID: PMC11403747 DOI: 10.1021/acsmedchemlett.4c00121] [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: 03/15/2024] [Revised: 07/19/2024] [Accepted: 08/01/2024] [Indexed: 09/19/2024] Open
Abstract
DNA-encoded library (DEL) technology, especially when combined with machine learning (ML), is a powerful method to discover novel inhibitors. DEL-ML can expand a larger chemical space and boost cost-effectiveness during hit finding. Heme oxygenase-1 (HO-1), a heme-degrading enzyme, is linked to diseases such as cancer and neurodegenerative disorders. The discovery of five series of new scaffold HO-1 hits is reported here, using a DEL-ML workflow, which emphasizes the model's uncertainty quantification and domain of applicability. This model exhibits a strong extrapolation ability, identifying new structures beyond the DEL chemical space. About 37% of predicted molecules showed a binding affinity of K D < 20 μM, with the strongest being 141 nM, amd 14 of those molecules displayed >100-fold selectivity for HO-1 over heme oxygenase-2 (HO-2). These molecules also showed structural novelty compared to existing HO-1 inhibitors. Docking simulations provided insights into possible selectivity rationale.
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Affiliation(s)
- Shuai Han
- WuXi AppTec (Shanghai) Co., Ltd., 240 Hedan Road, Shanghai 200131, China
| | - Xinyun Guo
- WuXi AppTec (Shanghai) Co., Ltd., 240 Hedan Road, Shanghai 200131, China
| | - Min Wang
- WuXi AppTec (Shanghai) Co., Ltd., 240 Hedan Road, Shanghai 200131, China
| | - Huan Liu
- WuXi AppTec (Shanghai) Co., Ltd., 240 Hedan Road, Shanghai 200131, China
| | - Yidan Song
- WuXi AppTec (Shanghai) Co., Ltd., 240 Hedan Road, Shanghai 200131, China
| | - Yunyun He
- WuXi AppTec (Shanghai) Co., Ltd., 240 Hedan Road, Shanghai 200131, China
| | - Kuang-Lung Hsueh
- WuXi AppTec (Shanghai) Co., Ltd., 240 Hedan Road, Shanghai 200131, China
| | - Weiren Cui
- WuXi AppTec (Shanghai) Co., Ltd., 240 Hedan Road, Shanghai 200131, China
| | - Wenji Su
- WuXi AppTec (Shanghai) Co., Ltd., 240 Hedan Road, Shanghai 200131, China
| | - Letian Kuai
- WuXi AppTec, 22 Strathmore Road, Natick, Massachusetts 01760, United States
| | - Jason Deng
- WuXi AppTec, 22 Strathmore Road, Natick, Massachusetts 01760, United States
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6
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Myeza N, Slabber C, Munro OQ, Sookai S, Zacharias SC, Martins-Furness C, Harmse L. An 8-aminoquinoline-naphthyl copper complex causes apoptotic cell death by modulating the expression of apoptotic regulatory proteins in breast cancer cells. Eur J Pharmacol 2024; 978:176764. [PMID: 38908670 DOI: 10.1016/j.ejphar.2024.176764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 06/08/2024] [Accepted: 06/19/2024] [Indexed: 06/24/2024]
Abstract
Breast cancer is one of the most common cancers globally and a leading cause of cancer-related deaths among women. Despite the combination of chemotherapy with targeted therapy, including monoclonal antibodies and kinase inhibitors, drug resistance and treatment failure remain a common occurrence. Copper, complexed to various organic ligands, has gained attention as potential chemotherapeutic agents due to its perceived decreased toxicity to normal cells. The cytotoxic efficacy and the mechanism of cell death of an 8-aminoquinoline-naphthyl copper complex (Cu8AqN) in MCF-7 and MDA-MB-231 breast cancer cell lines was investigated. The complex inhibited the growth of MCF-7 and MDA-MB-231 cells with IC50 values of 2.54 ± 0.69 μM and 3.31 ± 0.06 μM, respectively. Nuclear fragmentation, annexin V binding, and increased caspase-3/7 activity indicated apoptotic cell death. The loss of mitochondrial membrane potential, an increase in caspase-9 activity, the absence of active caspase-8 and a decrease of tumour necrosis factor receptor 1(TNFR1) expression supported activation of the intrinsic apoptotic pathway. Increased ROS formation and increased expression of haem oxygenase-1 (HMOX-1) indicated activation of cellular stress pathways. Expression of p21 protein in the nuclei was increased indicating cell cycle arrest, whilst the expression of inhibitor of apoptosis proteins (IAPs); cIAP1, XIAP and survivin were decreased, creating a pro-apoptotic environment. Phosphorylated p53 species; phospho-p53(S15), phospho-p53(S46), and phospho-p53(S392) accumulated in MCF-7 cells indicating the potential of Cu8AqN to restore p53 function in the cells. In combination, the data indicates that Cu8AqN is a useful lead molecule worthy of further exploration as a potential anti-cancer drug.
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Affiliation(s)
- Nonzuzo Myeza
- Division of Pharmacology, Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, South Africa
| | - Cathy Slabber
- Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, 1 Jan Smut Ave, Braamfontein, Johannesburg, 2017, South Africa
| | - Orde Q Munro
- Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, 1 Jan Smut Ave, Braamfontein, Johannesburg, 2017, South Africa; School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK
| | - Sheldon Sookai
- Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, 1 Jan Smut Ave, Braamfontein, Johannesburg, 2017, South Africa
| | - Savannah C Zacharias
- School of Chemistry and Physics, University of KwaZulu-Natal, King Edward Drive, Pietermaritzburg, Scottsville, 3209, South Africa
| | - Carla Martins-Furness
- Division of Pharmacology, Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, South Africa
| | - Leonie Harmse
- Division of Pharmacology, Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, South Africa.
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7
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Tonelotto V, Costa-Garcia M, O'Reilly E, Smith KF, Slater K, Dillon ET, Pendino M, Higgins C, Sist P, Bosch R, Passamonti S, Piulats JM, Villanueva A, Tramer F, Vanella L, Carey M, Kennedy BN. 1,4-dihydroxy quininib activates ferroptosis pathways in metastatic uveal melanoma and reveals a novel prognostic biomarker signature. Cell Death Discov 2024; 10:70. [PMID: 38341410 DOI: 10.1038/s41420-023-01773-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 12/01/2023] [Accepted: 12/11/2023] [Indexed: 02/12/2024] Open
Abstract
Uveal melanoma (UM) is an ocular cancer, with propensity for lethal liver metastases. When metastatic UM (MUM) occurs, as few as 8% of patients survive beyond two years. Efficacious treatments for MUM are urgently needed. 1,4-dihydroxy quininib, a cysteinyl leukotriene receptor 1 (CysLT1) antagonist, alters UM cancer hallmarks in vitro, ex vivo and in vivo. Here, we investigated the 1,4-dihydroxy quininib mechanism of action and its translational potential in MUM. Proteomic profiling of OMM2.5 cells identified proteins differentially expressed after 1,4-dihydroxy quininib treatment. Glutathione peroxidase 4 (GPX4), glutamate-cysteine ligase modifier subunit (GCLM), heme oxygenase 1 (HO-1) and 4 hydroxynonenal (4-HNE) expression were assessed by immunoblots. Biliverdin, glutathione and lipid hydroperoxide were measured biochemically. Association between the expression of a specific ferroptosis signature and UM patient survival was performed using public databases. Our data revealed that 1,4-dihydroxy quininib modulates the expression of ferroptosis markers in OMM2.5 cells. Biochemical assays validated that GPX4, biliverdin, GCLM, glutathione and lipid hydroperoxide were significantly altered. HO-1 and 4-HNE levels were significantly increased in MUM tumor explants from orthotopic patient-derived xenografts (OPDX). Expression of genes inhibiting ferroptosis is significantly increased in UM patients with chromosome 3 monosomy. We identified IFerr, a novel ferroptosis signature correlating with UM patient survival. Altogether, we demontrated that in MUM cells and tissues, 1,4-dihydroxy quininib modulates key markers that induce ferroptosis, a relatively new type of cell death driven by iron-dependent peroxidation of phospholipids. Furthermore, we showed that high expression of specific genes inhibiting ferroptosis is associated with a worse UM prognosis, thus, the IFerr signature is a potential prognosticator for which patients develop MUM. All in all, ferroptosis has potential as a clinical biomarker and therapeutic target for MUM.
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Affiliation(s)
- Valentina Tonelotto
- UCD Conway Institute, University College Dublin, D04 V1W8, Dublin, Ireland
- UCD School of Biomolecular and Biomedical Science, University College Dublin, D04 V1W8, Dublin, Ireland
| | - Marcel Costa-Garcia
- Medical Oncology Department, Catalan Institute of Cancer (ICO), IDIBELL-OncoBell, Barcelona, Spain
| | - Eve O'Reilly
- UCD Conway Institute, University College Dublin, D04 V1W8, Dublin, Ireland
- UCD School of Biomolecular and Biomedical Science, University College Dublin, D04 V1W8, Dublin, Ireland
| | - Kaelin Francis Smith
- UCD Conway Institute, University College Dublin, D04 V1W8, Dublin, Ireland
- UCD School of Biomolecular and Biomedical Science, University College Dublin, D04 V1W8, Dublin, Ireland
| | - Kayleigh Slater
- UCD Conway Institute, University College Dublin, D04 V1W8, Dublin, Ireland
- UCD School of Biomolecular and Biomedical Science, University College Dublin, D04 V1W8, Dublin, Ireland
| | - Eugene T Dillon
- Mass Spectrometry Resource, Conway Institute of Biomolecular & Biomedical Research, University College Dublin, D04 V1W8, Dublin, Ireland
| | - Marzia Pendino
- UCD Conway Institute, University College Dublin, D04 V1W8, Dublin, Ireland
- UCD School of Biomolecular and Biomedical Science, University College Dublin, D04 V1W8, Dublin, Ireland
| | - Catherine Higgins
- UCD School of Mathematics & Statistics, University College Dublin, D04 V1W8, Dublin, Ireland
| | - Paola Sist
- Department of Life Sciences, University of Trieste, 34127, Trieste, Italy
| | - Rosa Bosch
- Xenopat S.L., Business Bioincubator, Bellvitge Health Science Campus, 08907 L'Hospitalet de Llobregat, Barcelona, Spain
| | - Sabina Passamonti
- Department of Life Sciences, University of Trieste, 34127, Trieste, Italy
| | - Josep M Piulats
- Medical Oncology Department, Catalan Institute of Cancer (ICO), IDIBELL-OncoBell, Barcelona, Spain
| | - Alberto Villanueva
- Xenopat S.L., Business Bioincubator, Bellvitge Health Science Campus, 08907 L'Hospitalet de Llobregat, Barcelona, Spain
- Program Against Cancer Therapeutic Resistance (ProCURE), ICO, IDIBELL, Barcelona, Spain
| | - Federica Tramer
- Department of Life Sciences, University of Trieste, 34127, Trieste, Italy
| | - Luca Vanella
- Department of Drug and Health Sciences, University of Catania, 95125, Catania, Italy
- CERNUT-Research Centre on Nutraceuticals and Health Products, University of Catania, 95125, Catania, Italy
| | - Michelle Carey
- Mass Spectrometry Resource, Conway Institute of Biomolecular & Biomedical Research, University College Dublin, D04 V1W8, Dublin, Ireland
| | - Breandán N Kennedy
- UCD Conway Institute, University College Dublin, D04 V1W8, Dublin, Ireland.
- UCD School of Biomolecular and Biomedical Science, University College Dublin, D04 V1W8, Dublin, Ireland.
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8
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Wang H, Cheng Q, Bao L, Li M, Chang K, Yi X. Cytoprotective Role of Heme Oxygenase-1 in Cancer Chemoresistance: Focus on Antioxidant, Antiapoptotic, and Pro-Autophagy Properties. Antioxidants (Basel) 2023; 12:1217. [PMID: 37371947 DOI: 10.3390/antiox12061217] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/23/2023] [Accepted: 05/25/2023] [Indexed: 06/29/2023] Open
Abstract
Chemoresistance remains the foremost challenge in cancer therapy. Targeting reactive oxygen species (ROS) manipulation is a promising strategy in cancer treatment since tumor cells present high levels of intracellular ROS, which makes them more vulnerable to further ROS elevation than normal cells. Nevertheless, dynamic redox evolution and adaptation of tumor cells are capable of counteracting therapy-induced oxidative stress, which leads to chemoresistance. Hence, exploring the cytoprotective mechanisms of tumor cells is urgently needed to overcome chemoresistance. Heme oxygenase-1 (HO-1), a rate-limiting enzyme of heme degradation, acts as a crucial antioxidant defense and cytoprotective molecule in response to cellular stress. Recently, emerging evidence indicated that ROS detoxification and oxidative stress tolerance owing to the antioxidant function of HO-1 contribute to chemoresistance in various cancers. Enhanced HO-1 expression or enzymatic activity was revealed to promote apoptosis resistance and activate protective autophagy, which also involved in the development of chemoresistance. Moreover, inhibition of HO-1 in multiple cancers was identified to reversing chemoresistance or improving chemosensitivity. Here, we summarize the most recent advances regarding the antioxidant, antiapoptotic, and pro-autophagy properties of HO-1 in mediating chemoresistance, highlighting HO-1 as a novel target for overcoming chemoresistance and improving the prognosis of cancer patients.
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Affiliation(s)
- Huan Wang
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China
| | - Qi Cheng
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China
| | - Lingjie Bao
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China
| | - Mingqing Li
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China
| | - Kaikai Chang
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China
| | - Xiaofang Yi
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China
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9
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Soghli N, Yousefi H, Naderi T, Fallah A, Moshksar A, Darbeheshti F, Vittori C, Delavar MR, Zare A, Rad HS, Kazemi A, Bitaraf A, Hussen BM, Taheri M, Jamali E. NRF2 signaling pathway: A comprehensive prognostic and gene expression profile analysis in breast cancer. Pathol Res Pract 2023; 243:154341. [PMID: 36739754 DOI: 10.1016/j.prp.2023.154341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/23/2023] [Accepted: 01/23/2023] [Indexed: 01/27/2023]
Abstract
Breast cancer is the most frequently diagnosed malignant tumor in women and a major public health concern. NRF2 axis is a cellular protector signaling pathway protecting both normal and cancer cells from oxidative damage. NRF2 is a transcription factor that binds to the gene promoters containing antioxidant response element-like sequences. In this report, differential expression of NRF2 signaling pathway elements, as well as the correlation of NRF2 pathway mRNAs with various clinicopathologic characteristics, including molecular subtypes, tumor grade, tumor stage, and methylation status, has been investigated in breast cancer using METABRIC and TCGA datasets. In the current report, our findings revealed the deregulation of several NRF2 signaling elements in breast cancer patients. Moreover, there were negative correlations between the methylation of NRF2 genes and mRNA expression. The expression of NRF2 genes significantly varied between different breast cancer subtypes. In conclusion, substantial deregulation of NRF2 signaling components suggests an important role of these genes in breast cancer. Because of the clear associations between mRNA expression and methylation status, DNA methylation could be one of the mechanisms that regulate the NRF2 pathway in breast cancer. Differential expression of Hippo genes among various breast cancer molecular subtypes suggests that NRF2 signaling may function differently in different subtypes of breast cancer. Our data also highlights an interesting link between NRF2 components' transcription and tumor grade/stage in breast cancer.
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Affiliation(s)
- Negin Soghli
- Babol University of Medical Sciences, Faculty of Dentistry, Babol, Iran
| | - Hassan Yousefi
- Louisiana State University Health Science Center (LSUHSC), Biochemistry & Molecular Biology, New Orleans, LA, USA; Stanley S. Scott Cancer Research Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Tohid Naderi
- Department of Laboratory Hematology and Blood Bank, School of Allied Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Aysan Fallah
- Department of hematology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Amin Moshksar
- University of Texas Medical Branch (UTMB), Interventional Radiology, Galveston, TX, USA
| | - Farzaneh Darbeheshti
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Cecilia Vittori
- Stanley S. Scott Cancer Research Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Mahsa Rostamian Delavar
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Ali Zare
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Habib Sadeghi Rad
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia
| | - Abtin Kazemi
- Fasa University of Medical Sciences, School of Medicine, Fasa, Iran
| | - Amirreza Bitaraf
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq
| | - Mohammad Taheri
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Institute of Human Genetics, Jena University Hospital, Jena, Germany.
| | - Elena Jamali
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Expression and Signaling Pathways of Nerve Growth Factor (NGF) and Pro-NGF in Breast Cancer: A Systematic Review. Curr Oncol 2022; 29:8103-8120. [PMID: 36354700 PMCID: PMC9689427 DOI: 10.3390/curroncol29110640] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/19/2022] [Accepted: 10/25/2022] [Indexed: 11/07/2022] Open
Abstract
Breast cancer represents the most common type of cancer and is the leading cause of death due to cancer among women. Thus, the prevention and early diagnosis of breast cancer is of primary urgency, as well as the development of new treatments able to improve its prognosis. Nerve Growth Factor (NGF) is a neurotrophic factor involved in the regulation of neuronal functions through the binding of the Tropomyosin receptor kinase A (TrkA) and the Nerve Growth Factor receptor or Pan-Neurotrophin Receptor 75 (NGFR/p75NTR). In addition, its precursor (pro-NGF) can extert biological activity by forming a trimeric complex with NGFR/p75NTR and sortilin, or by binding to TrkA receptors with low affinity. Several examples of in vitro and in vivo evidence show that NGF is both synthesized and released by breast cancer cells, and has mitogen, antiapoptotic and angiogenic effects on these cells through the activation of different signaling cascades that involve TrkA and NGFR/p75NTR receptors. Conversely, pro-NGF signaling has been related to breast cancer invasion and metastasis. Other studies suggested that NGF and its receptors could represent a good diagnostic and prognostic tool, as well as promising therapeutic targets for breast cancer. In this paper, we comprehensively summarize and systematically review the current experimental evidence on this topic. INPLASY ID: INPLASY2022100017.
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Ho HY, Chen PJ, Chuang YC, Lo YS, Lin CC, Hsieh MJ, Chen MK. Picrasidine I Triggers Heme Oxygenase-1-Induced Apoptosis in Nasopharyngeal Carcinoma Cells via ERK and Akt Signaling Pathways. Int J Mol Sci 2022; 23:ijms23116103. [PMID: 35682782 PMCID: PMC9181417 DOI: 10.3390/ijms23116103] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 12/16/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) has a higher incidence in Taiwan than worldwide. Although it is a radiosensitive malignancy, cancer recurrence is still high in the advanced stages because of its ability to induce lymph node metastasis. Picrasidine I from Picrasma quassioides has been reported as a potential drug for targeting multiple signaling pathways. The present study aimed to explore the role of picrasidine I in the apoptosis of NPC cells. Our results show that picrasidine I induced cytotoxic effects in NPC cells and caused cell cycle arrest in the sub-G1, S, and G2/M phases. Western blot analysis further demonstrated that the modulation of apoptosis through the extrinsic and intrinsic pathways was involved in picrasidine I-induced cell death. Downregulation of the ERK1/2 and Akt signaling pathways was also found in picrasidine I-induced apoptosis. Additionally, the apoptosis array showed that picrasidine I significantly increased heme oxygenase-1 (HO-1) expression, which could act as a critical molecule in picrasidine I-induced apoptosis in NPC cells. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets also revealed that the HMOX1 mRNA level (HO-1) is lower in patients with head and neck squamous carcinoma (HNSCC) and NPC than in patients without cancer. Our study indicated that picrasidine I exerts anticancer effects in NPC by modulating HO-1 via the ERK and Akt signaling pathways.
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Affiliation(s)
- Hsin-Yu Ho
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan; (H.-Y.H.); (Y.-C.C.); (Y.-S.L.); (C.-C.L.)
| | - Ping-Ju Chen
- Department of Dentistry, Changhua Christian Hospital, Changhua 500, Taiwan;
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
| | - Yi-Ching Chuang
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan; (H.-Y.H.); (Y.-C.C.); (Y.-S.L.); (C.-C.L.)
| | - Yu-Sheng Lo
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan; (H.-Y.H.); (Y.-C.C.); (Y.-S.L.); (C.-C.L.)
| | - Chia-Chieh Lin
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan; (H.-Y.H.); (Y.-C.C.); (Y.-S.L.); (C.-C.L.)
| | - Ming-Ju Hsieh
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan; (H.-Y.H.); (Y.-C.C.); (Y.-S.L.); (C.-C.L.)
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan
- Correspondence: (M.-J.H.); (M.-K.C.); Tel.: +886-4-7238595 (M.-J.H. & M.-K.C.); Fax: +886-4-7232942 (M.-J.H. & M.-K.C.)
| | - Mu-Kuan Chen
- Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua 500, Taiwan
- Correspondence: (M.-J.H.); (M.-K.C.); Tel.: +886-4-7238595 (M.-J.H. & M.-K.C.); Fax: +886-4-7232942 (M.-J.H. & M.-K.C.)
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Consoli V, Sorrenti V, Pittalà V, Greish K, D’Amico AG, Romeo G, Intagliata S, Salerno L, Vanella L. Heme Oxygenase Modulation Drives Ferroptosis in TNBC Cells. Int J Mol Sci 2022; 23:ijms23105709. [PMID: 35628518 PMCID: PMC9143660 DOI: 10.3390/ijms23105709] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/17/2022] [Accepted: 05/19/2022] [Indexed: 02/06/2023] Open
Abstract
The term ferroptosis refers to a peculiar type of programmed cell death (PCD) mainly characterized by extensive iron-dependent lipid peroxidation. Recently, ferroptosis has been suggested as a potential new strategy for the treatment of several cancers, including breast cancer (BC). In particular, among the BC subtypes, triple negative breast cancer (TNBC) is considered the most aggressive, and conventional drugs fail to provide long-term efficacy. In this context, our study's purpose was to investigate the mechanism of ferroptosis in breast cancer cell lines and reveal the significance of heme oxygenase (HO) modulation in the process, providing new biochemical approaches. HO's effect on BC was evaluated by MTT tests, gene silencing, Western blot analysis, and measurement of reactive oxygen species (ROS), glutathione (GSH) and lipid hydroperoxide (LOOH) levels. In order to assess HO's implication, different approaches were exploited, using two distinct HO-1 inducers (hemin and curcumin), a well-known HO inhibitor (SnMP) and a selective HO-2 inhibitor. The data obtained showed HO's contribution to the onset of ferroptosis; in particular, HO-1 induction seemed to accelerate the process. Moreover, our results suggest a potential role of HO-2 in erastin-induced ferroptosis. In view of the above, HO modulation in ferroptosis can offer a novel approach for breast cancer treatment.
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Affiliation(s)
- Valeria Consoli
- Department of Drug and Health Science, University of Catania, 95125 Catania, Italy; (V.C.); (V.P.); (A.G.D.); (G.R.); (S.I.); (L.S.); (L.V.)
| | - Valeria Sorrenti
- Department of Drug and Health Science, University of Catania, 95125 Catania, Italy; (V.C.); (V.P.); (A.G.D.); (G.R.); (S.I.); (L.S.); (L.V.)
- CERNUT-Research Centre on Nutraceuticals and Health Products, University of Catania, 95125 Catania, Italy
- Correspondence:
| | - Valeria Pittalà
- Department of Drug and Health Science, University of Catania, 95125 Catania, Italy; (V.C.); (V.P.); (A.G.D.); (G.R.); (S.I.); (L.S.); (L.V.)
- CERNUT-Research Centre on Nutraceuticals and Health Products, University of Catania, 95125 Catania, Italy
| | - Khaled Greish
- Princess Al-Jawhara Centre for Molecular Medicine, Department of Molecular Medicine, School of Medicine and Medical Sciences, Arabian Gulf University, Manama 329, Bahrain;
| | - Agata Grazia D’Amico
- Department of Drug and Health Science, University of Catania, 95125 Catania, Italy; (V.C.); (V.P.); (A.G.D.); (G.R.); (S.I.); (L.S.); (L.V.)
| | - Giuseppe Romeo
- Department of Drug and Health Science, University of Catania, 95125 Catania, Italy; (V.C.); (V.P.); (A.G.D.); (G.R.); (S.I.); (L.S.); (L.V.)
- CERNUT-Research Centre on Nutraceuticals and Health Products, University of Catania, 95125 Catania, Italy
| | - Sebastiano Intagliata
- Department of Drug and Health Science, University of Catania, 95125 Catania, Italy; (V.C.); (V.P.); (A.G.D.); (G.R.); (S.I.); (L.S.); (L.V.)
- CERNUT-Research Centre on Nutraceuticals and Health Products, University of Catania, 95125 Catania, Italy
| | - Loredana Salerno
- Department of Drug and Health Science, University of Catania, 95125 Catania, Italy; (V.C.); (V.P.); (A.G.D.); (G.R.); (S.I.); (L.S.); (L.V.)
- CERNUT-Research Centre on Nutraceuticals and Health Products, University of Catania, 95125 Catania, Italy
| | - Luca Vanella
- Department of Drug and Health Science, University of Catania, 95125 Catania, Italy; (V.C.); (V.P.); (A.G.D.); (G.R.); (S.I.); (L.S.); (L.V.)
- CERNUT-Research Centre on Nutraceuticals and Health Products, University of Catania, 95125 Catania, Italy
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Predictive and prognostic effect of HO-1 expression in breast cancer patients undergoing neoadjuvant chemotherapy. Breast Cancer Res Treat 2022; 193:393-403. [PMID: 35304903 DOI: 10.1007/s10549-022-06565-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 01/22/2022] [Indexed: 11/02/2022]
Abstract
PURPOSE Heme oxygenase-1 (HO-1) has complex biological function, and is a candidate oncogene with a wide variety of deleterious functions in breast cancer. Here, we evaluated the relationship between expression of HO-1 protein with clinical response to neoadjuvant chemotherapy (NAC) in breast cancer patients. METHODS We used immunohistochemistry (IHC) to determine expression of HO-1 protein from core needle biopsy before NAC, then applied univariate and multivariate analyses to understand the relationship between HO-1 with pathological complete response (pCR) outcomes. Next, Kaplan-Meier and Log-rank tests were used to compare disease-free survival (DFS) and overall survival (OS), between groups, and Cox proportional hazards regression analysis applied for prognostic evaluation. RESULTS A total of 575 patients with locally advanced invasive breast cancer were included in the study, of which 111 (19.3%) achieved pCR after NAC. Results from multivariate analysis showed that high HO-1 expression was an independent predictor of low pCR rate (OR 0.254, 95% CI 0.026-0.643, p = 0.002). Moreover, results from survival analysis showed that high HO-1 expression was significantly associated with shorter DFS (HR 4.843, 95% CI 1.205-32.572, p = 0.026), but not with OS (HR 3.219, 95% CI 0.928-32.124, p = 0.071). Furthermore, HO-1 expression was significantly associated with lower pCR rate (OR 0.102, 95% CI 0.013-0.352), p = 0.001), poor DFS (HR 8.562, 95% CI 1.592-34.950, p = 0.009), and OS (HR 7.835, 95% CI 1.220-56.213, p = 0.023) of patients with triple-negative breast cancer (TNBC) patients. CONCLUSION Our results indicated that HO-1 expression is not only a biomarker for predicting pCR, but also a prognostic factor in breast cancer patients in a neoadjuvant setting, especially in TNBC subgroups.
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Zhu L, Chen M, Huang B, Zhang T, Chen K, Lian H, Liu M, Zhao K, Pang Y, Zhang J, Li Q, Zhong C. Genomic Analysis Uncovers Immune Microenvironment Characteristics and Drug Sensitivity of Ferroptosis in Breast Cancer Brain Metastasis. Front Genet 2022; 12:819632. [PMID: 35154262 PMCID: PMC8830939 DOI: 10.3389/fgene.2021.819632] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 12/24/2021] [Indexed: 01/31/2023] Open
Abstract
Background: The role of ferroptosis in breast cancer brain metastasis (BCBM) is unclear. This study aimed to explore the ferroptosis-related genes (FRG) relations with the tumor microenvironment, as well as evaluate their values in predicting survival and drug sensitivity in patients with BCBM. Materials and Methods: Genes expression and clinical data were downloaded from Gene Expression Omnibus (GEO). Univariate and multivariate Cox regression analyses were performed to explore the independent prognostic factors. Consensus cluster principal component analysis (PCA) was used to establish the ferroptosis score. Immunological signatures were analyzed by the single-sample gene set enrichment analysis (ssGSEA). Drug sensitivity was evaluated through the estimated half-maximal inhibitory concentration (IC50). Finally, results were validated in external cohorts. Results: Fourteen significantly different FRG were identified between breast cancer (BC) and BCBM tissues. Survival analysis demonstrated HMOX1, PEBP1, KEAP1, and LPCAT3 were significantly associated with overall survival (OS) and relapse-free survival (RFS) (all p < 0.05). High ferroptosis score was correlated with iron ion homeostasis, iron metabolism, higher stromal cells and immune cells scores. Patients with high- and low-ferroptosis scores were characterized by different drug sensitivities. Following external validations, the ferroptosis had distinct expression profiles between the BC and BCBM, and could serve as biomarkers for OS and drug response. Conclusion: Our findings suggested that ferroptosis may be involved in the process of BCBM, and ferroptosis could serve as prognostic biomarkers. Evaluation of ferroptosis may deepen our understanding about the tumor microenvironment, and could help clinicians to make individualized therapy.
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Affiliation(s)
- Lei Zhu
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- Department of Thoracic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Mu Chen
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Bingsong Huang
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Tao Zhang
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Kui Chen
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Hao Lian
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Min Liu
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Kaijun Zhao
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Ying Pang
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Ying Pang, ; Jing Zhang, ; Qinchuan Li, ; Chunlong Zhong,
| | - Jing Zhang
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- Institute for Advanced Study, Tongji University, Shanghai, China
- *Correspondence: Ying Pang, ; Jing Zhang, ; Qinchuan Li, ; Chunlong Zhong,
| | - Qinchuan Li
- Department of Thoracic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Ying Pang, ; Jing Zhang, ; Qinchuan Li, ; Chunlong Zhong,
| | - Chunlong Zhong
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Ying Pang, ; Jing Zhang, ; Qinchuan Li, ; Chunlong Zhong,
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Ye W, Liu Z, Liu F, Luo C. Heme Oxygenase-1 Predicts Risk Stratification and Immunotherapy Efficacy in Lower Grade Gliomas. Front Cell Dev Biol 2021; 9:760800. [PMID: 34858984 PMCID: PMC8631111 DOI: 10.3389/fcell.2021.760800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 10/11/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Gliomas are the most common tumors in human brains with unpleasing outcomes. Heme oxygenase-1 (HMOX1, HO-1) was a potential target for human cancers. However, their relationship remains incompletely discussed. Methods: We employed a total of 952 lower grade glioma (LGG) patients from TCGA and CGGA databases, and 29 samples in our hospital for subsequent analyses. Expression, mutational, survival, and immune profiles of HMOX1 were comprehensively evaluated. We constructed a risk signature using the LASSO Cox regression model, and further generated a nomogram model to predict survival of LGG patients. Single-cell transcriptomic sequencing data were also employed to investigated the role of HMOX1 in cancer cells. Results: We found that HMOX1 was overexpressed and was related to poorer survival in gliomas. HMOX1-related genes (HRGs) were involved in immune-related pathways. Patients in the high-risk group exhibited significantly poorer overall survival. The risk score was positively correlated with the abundance of resting memory CD4+ T cells, M1, M2 macrophages, and activated dendritic cells. Additionally, immunotherapy showed potent efficacy in low-risk group. And patients with lower HMOX1 expression were predicted to have better response to immunotherapies, suggesting that immunotherapies combined with HMOX1 inhibition may execute good responses. Moreover, significant correlations were found between HMOX1 expression and single-cell functional states including angiogenesis, hypoxia, and metastasis. Finally, we constructed a nomogram which could predict 1-, 3-, and 5-year survival in LGG patients. Conclusion: HMOX1 is involved in immune infiltration and predicts poor survival in patients with lower grade glioma. Importantly, HMOX1 were related to oncological functional states including angiogenesis, hypoxia, and metastasis. A nomogram integrated with the risk signature was obtained to robustly predict glioma patient outcomes, with the potential to guide clinical decision-making.
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Affiliation(s)
- Wenrui Ye
- Department of Neurosurgery, Xiangya Hospital, Central South University (CSU), Changsha, China
| | - Zhixiong Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University (CSU), Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University (CSU), Changsha, China
| | - Fangkun Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University (CSU), Changsha, China
| | - Cong Luo
- Department of Urology, Xiangya Hospital, Central South University (CSU), Changsha, China
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Williams MM, Hafeez SA, Christenson JL, O’Neill KI, Hammond NG, Richer JK. Reversing an Oncogenic Epithelial-to-Mesenchymal Transition Program in Breast Cancer Reveals Actionable Immune Suppressive Pathways. Pharmaceuticals (Basel) 2021; 14:ph14111122. [PMID: 34832904 PMCID: PMC8622696 DOI: 10.3390/ph14111122] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 12/16/2022] Open
Abstract
Approval of checkpoint inhibitors for treatment of metastatic triple negative breast cancer (mTNBC) has opened the door for the use of immunotherapies against this disease. However, not all patients with mTNBC respond to current immunotherapy approaches such as checkpoint inhibitors. Recent evidence demonstrates that TNBC metastases are more immune suppressed than primary tumors, suggesting that combination or additional immunotherapy strategies may be required to activate an anti-tumor immune attack at metastatic sites. To identify other immune suppressive mechanisms utilized by mTNBC, our group and others manipulated oncogenic epithelial-to-mesenchymal transition (EMT) programs in TNBC models to reveal differences between this breast cancer subtype and its more epithelial counterpart. This review will discuss how EMT modulation revealed several mechanisms, including tumor cell metabolism, cytokine milieu and secretion of additional immune modulators, by which mTNBC cells may suppress both the innate and adaptive anti-tumor immune responses. Many of these pathways/proteins are under preclinical or clinical investigation as therapeutic targets in mTNBC and other advanced cancers to enhance their response to chemotherapy and/or checkpoint inhibitors.
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Heme Oxygenase-1 Signaling and Redox Homeostasis in Physiopathological Conditions. Biomolecules 2021; 11:biom11040589. [PMID: 33923744 PMCID: PMC8072688 DOI: 10.3390/biom11040589] [Citation(s) in RCA: 150] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/07/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Heme-oxygenase is the enzyme responsible for degradation of endogenous iron protoporphyirin heme; it catalyzes the reaction’s rate-limiting step, resulting in the release of carbon monoxide (CO), ferrous ions, and biliverdin (BV), which is successively reduced in bilirubin (BR) by biliverdin reductase. Several studies have drawn attention to the controversial role of HO-1, the enzyme inducible isoform, pointing out its implications in cancer and other diseases development, but also underlining the importance of its antioxidant activity. The contribution of HO-1 in redox homeostasis leads to a relevant decrease in cells oxidative damage, which can be reconducted to its cytoprotective effects explicated alongside other endogenous mechanisms involving genes like TIGAR (TP53-induced glycolysis and apoptosis regulator), but also to the therapeutic functions of heme main transformation products, especially carbon monoxide (CO), which has been shown to be effective on GSH levels implementation sustaining body’s antioxidant response to oxidative stress. The aim of this review was to collect most of the knowledge on HO-1 from literature, analyzing different perspectives to try and put forward a hypothesis on revealing yet unknown HO-1-involved pathways that could be useful to promote development of new therapeutical strategies, and lay the foundation for further investigation to fully understand this important antioxidant system.
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Rahimian N, Razavi ZS, Aslanbeigi F, Mirkhabbaz AM, Piroozmand H, Shahrzad MK, Hamblin MR, Mirzaei H. Non-coding RNAs related to angiogenesis in gynecological cancer. Gynecol Oncol 2021; 161:896-912. [PMID: 33781555 DOI: 10.1016/j.ygyno.2021.03.020] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 03/19/2021] [Indexed: 02/07/2023]
Abstract
Gynecological cancer affects the female reproductive system, including ovarian, uterine, endometrial, cervical, vulvar, and vaginal tumors. Non-coding RNAs (ncRNAs), and in particular microRNAs, function as regulatory molecules, which can control gene expression in a post-transcriptional manner. Normal physiological processes like cellular proliferation, differentiation, and apoptosis, and pathological processes such as oncogenesis and metastasis are regulated by microRNAs. Numerous reports have shown a direct role of microRNAs in the modulation of angiogenesis in gynecological cancer, via targeting pro-angiogenic factors and signaling pathways. Understanding the molecular mechanism involved in the regulation of angiogenesis by microRNAs may lead to new treatment options. Recently the regulatory role of some long non-coding RNAs in gynecological cancer has also been explored, but the information on this function is more limited. The aim of this article is to explore the pathways responsible for angiogenesis, and to what extent ncRNAs may be employed as biomarkers or therapeutic targets in gynecological cancer.
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Affiliation(s)
- Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | | | | | | | - Haleh Piroozmand
- Faculty of Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mohammad Karim Shahrzad
- Department of Internal Medicine and endocrinology, Shohadae Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Kim EH, Kim SJ, Na HK, Han W, Kim NJ, Suh YG, Surh YJ. 15-Deoxy-Δ 12,14-prostaglandin J 2 Upregulates VEGF Expression via NRF2 and Heme Oxygenase-1 in Human Breast Cancer Cells. Cells 2021; 10:cells10030526. [PMID: 33801351 PMCID: PMC8002112 DOI: 10.3390/cells10030526] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Revised: 02/23/2021] [Accepted: 02/25/2021] [Indexed: 12/12/2022] Open
Abstract
There is a plethora of evidence to support that inflammation is causally linked to carcinogenesis. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the biosynthesis of prostaglandins, is inappropriately overexpressed in various cancers and hence recognized as one of the hallmarks of chronic inflammation-associated malignancies. However, the mechanistic role of COX-2 as a link between inflammation and cancer remains largely undefined. In this study, we found that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), one of the final products of COX-2, induced upregulation of vascular endothelial growth factor (VEGF) and capillary formation and migration through nuclear factor erythroid 2-related factor 2 (NRF2)-dependent heme oxygenase-1 (HO-1) induction in MCF-7 cells. Analysis of the publicly available TCGA data set showed that high mRNA levels of both COX-2 and NRF2 correlated with the poor clinical outcomes in breast cancer patients. Moreover, human tissue analysis showed that the levels of 15d-PGJ2 as well the expression of COX-2, NRF2, and HO-1 were found to be increased in human breast cancer tissues. In conclusion, the elevated levels of 15d-PGJ2 during inflammatory response activate VEGF expression through NRF2-driven induction of HO-1 in human breast cancer cells, proposing a novel mechanism underlying the oncogenic function of 15d-PGJ2.
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Affiliation(s)
- Eun-Hee Kim
- College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam 13488, Korea;
- Correspondence: (E.-H.K.); (Y.-J.S.); Tel.: +82-31-881-7179 (E.-H.K.); +82-2-880-7845 (Y.-J.S.)
| | - Su-Jung Kim
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Korea;
| | - Hye-Kyung Na
- Department of Food Science and Biotechnology, College of Knowledge-Based Services Engineering, Sungshin Women’s University, Seoul 01133, Korea;
| | - Wonshik Han
- Cancer Research Institute, Seoul National University, Seoul 03080, Korea;
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Nam-Jung Kim
- College of Pharmacy, Kyung Hee University, Seoul 02447, Korea;
| | - Young-Ger Suh
- College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam 13488, Korea;
| | - Young-Joon Surh
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Korea;
- Cancer Research Institute, Seoul National University, Seoul 03080, Korea;
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Korea
- Correspondence: (E.-H.K.); (Y.-J.S.); Tel.: +82-31-881-7179 (E.-H.K.); +82-2-880-7845 (Y.-J.S.)
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20
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Bukowska-Strakova K, Włodek J, Pitera E, Kozakowska M, Konturek-Cieśla A, Cieśla M, Gońka M, Nowak W, Wieczorek A, Pawińska-Wąsikowska K, Józkowicz A, Siedlar M. Role of HMOX1 Promoter Genetic Variants in Chemoresistance and Chemotherapy Induced Neutropenia in Children with Acute Lymphoblastic Leukemia. Int J Mol Sci 2021; 22:ijms22030988. [PMID: 33498175 PMCID: PMC7863945 DOI: 10.3390/ijms22030988] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 01/15/2021] [Indexed: 12/17/2022] Open
Abstract
Whilst the survival rates of childhood acute lymphoblastic leukemia (ALL) have increased remarkably over the last decades, the therapy resistance and toxicity are still the major causes of treatment failure. It was shown that overexpression of heme oxygenase-1 (HO-1) promotes proliferation and chemoresistance of cancer cells. In humans, the HO-1 gene (HMOX1) expression is modulated by two polymorphisms in the promoter region: (GT)n-length polymorphism and single-nucleotide polymorphism (SNP) A(−413)T, with short GT repeat sequences and 413-A variants linked to an increased HO-1 inducibility. We found that the short alleles are significantly more frequent in ALL patients in comparison to the control group, and that their presence may be associated with a higher risk of treatment failure, reflecting the role of HO-1 in chemoresistance. We also observed that the presence of short alleles may predispose to develop chemotherapy-induced neutropenia. In case of SNP, the 413-T variant co-segregated with short or long alleles, while 413-A almost selectively co-segregated with long alleles, hence it is not possible to determine if SNPs are actually of phenotypic significance. Our results suggest that HO-1 can be a potential target to overcome the treatment failure in ALL patients.
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Affiliation(s)
- Karolina Bukowska-Strakova
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, 31-663 Kraków, Poland; (J.W.); (E.P.)
- Correspondence: (K.B.-S.); (A.J.); (M.S.); Tel.: +48-(12)-664-6411 (A.J.); +48-(12)-658-2486 (M.S.); Fax: +48-(12)-658-1756 (M.S.)
| | - Joanna Włodek
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, 31-663 Kraków, Poland; (J.W.); (E.P.)
| | - Ewelina Pitera
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, 31-663 Kraków, Poland; (J.W.); (E.P.)
| | - Magdalena Kozakowska
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 31-007 Kraków, Poland; (M.K.); (A.K.-C.); (M.C.); (M.G.); (W.N.)
| | - Anna Konturek-Cieśla
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 31-007 Kraków, Poland; (M.K.); (A.K.-C.); (M.C.); (M.G.); (W.N.)
| | - Maciej Cieśla
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 31-007 Kraków, Poland; (M.K.); (A.K.-C.); (M.C.); (M.G.); (W.N.)
| | - Monika Gońka
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 31-007 Kraków, Poland; (M.K.); (A.K.-C.); (M.C.); (M.G.); (W.N.)
| | - Witold Nowak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 31-007 Kraków, Poland; (M.K.); (A.K.-C.); (M.C.); (M.G.); (W.N.)
| | - Aleksandra Wieczorek
- Pediatric, Oncology and Hematology Department, Institute of Pediatrics, Jagiellonian University Medical College, 30-387 Krakow, Poland; (A.W.); (K.P.-W.)
| | - Katarzyna Pawińska-Wąsikowska
- Pediatric, Oncology and Hematology Department, Institute of Pediatrics, Jagiellonian University Medical College, 30-387 Krakow, Poland; (A.W.); (K.P.-W.)
| | - Alicja Józkowicz
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 31-007 Kraków, Poland; (M.K.); (A.K.-C.); (M.C.); (M.G.); (W.N.)
- Correspondence: (K.B.-S.); (A.J.); (M.S.); Tel.: +48-(12)-664-6411 (A.J.); +48-(12)-658-2486 (M.S.); Fax: +48-(12)-658-1756 (M.S.)
| | - Maciej Siedlar
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, 31-663 Kraków, Poland; (J.W.); (E.P.)
- Correspondence: (K.B.-S.); (A.J.); (M.S.); Tel.: +48-(12)-664-6411 (A.J.); +48-(12)-658-2486 (M.S.); Fax: +48-(12)-658-1756 (M.S.)
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21
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Jasmer KJ, Hou J, Mannino P, Cheng J, Hannink M. Heme oxygenase promotes B-Raf-dependent melanosphere formation. Pigment Cell Melanoma Res 2020; 33:850-868. [PMID: 32558263 DOI: 10.1111/pcmr.12905] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 05/09/2020] [Accepted: 06/07/2020] [Indexed: 12/22/2022]
Abstract
Biosynthesis and degradation of heme, an iron-bound protoporphyrin molecule utilized by a wide variety of metabolic processes, are tightly regulated. Two closely related enzymes, heme oxygenase 1 (HMOX1) and heme oxygenase 2 (HMOX2), degrade free heme to produce carbon monoxide, Fe2+ , and biliverdin. HMOX1 expression is controlled via the transcriptional activator, NFE2L2, and the transcriptional repressor, Bach1. Transcription of HMOX1 and other NFE2L2-dependent genes is increased in response to electrophilic and reactive oxygen species. Many tumor-derived cell lines have elevated levels of NFE2L2. Elevated expression of NFE2L2-dependent genes contributes to tumor growth and acquired resistance to therapies. Here, we report a novel role for heme oxygenase activity in melanosphere formation by human melanoma-derived cell lines. Transcriptional induction of HMOX1 through derepression of Bach1 or transcriptional activation of HMOX2 by oncogenic B-RafV600E results in increased melanosphere formation. Genetic ablation of HMOX1 diminishes melanosphere formation. Further, inhibition of heme oxygenase activity with tin protoporphyrin markedly reduces melanosphere formation driven by either Bach1 derepression or B-RafV600E expression. Global transcriptome analyses implicate genes involved in focal adhesion and extracellular matrix interactions in melanosphere formation.
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Affiliation(s)
- Kimberly J Jasmer
- Division of Biological Sciences, University of Missouri, Columbia, Missouri, USA.,Christopher Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA
| | - Jie Hou
- Computer Science Department, University of Missouri, Columbia, Missouri, USA
| | - Philip Mannino
- Christopher Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA.,Department of Biochemistry, University of Missouri, Columbia, Missouri, USA
| | - Jianlin Cheng
- Computer Science Department, University of Missouri, Columbia, Missouri, USA
| | - Mark Hannink
- Christopher Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA.,Department of Biochemistry, University of Missouri, Columbia, Missouri, USA
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22
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Jang HY, Hong OY, Chung EY, Park KH, Kim JS. Roles of JNK/Nrf2 Pathway on Hemin-Induced Heme Oxygenase-1 Activation in MCF-7 Human Breast Cancer Cells. ACTA ACUST UNITED AC 2020; 56:medicina56060268. [PMID: 32485912 PMCID: PMC7353851 DOI: 10.3390/medicina56060268] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/23/2020] [Accepted: 05/27/2020] [Indexed: 11/16/2022]
Abstract
Heme oxygenase-1 (HO-1) is highly induced in various human disease states, including cancer, indicating that HO-1 is an emerging target of cancer therapy. In this study, we investigated that the mechanisms of hemin-induced HO-1 expression and its signaling pathways in human breast cancer cell. We used MCF-7 cells, a human breast cancer cell line. Hemin increased HO-1 expression in MCF-7 cells in a dose- and time-dependent manner. Hemin enhanced HO-1 expression through the activation of c-Jun N-terminal kinases (JNK) signaling pathway. Hemin also induced activation of Nrf2, a major transcription factor of HO-1 expression. These responses in MCF-7 cells were completely blocked by pretreatment with brazilin, a HO-1 regulator. These results indicated that brazilin inhibits hemin-induced HO-1 expressions through inactivation of JNK/Nrf2 in MCF-7 cells. Thus, our findings suggest that HO-1 is an important anticancer-target of brazilin in human breast cancer.
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Affiliation(s)
- Hye-Yeon Jang
- Department of Biochemistry and Institute of Cardiovascular Research, Chonbuk National University Medical School, Jeonju 54896, Korea; (H.-Y.J.); (O.-Y.H.)
| | - On-Yu Hong
- Department of Biochemistry and Institute of Cardiovascular Research, Chonbuk National University Medical School, Jeonju 54896, Korea; (H.-Y.J.); (O.-Y.H.)
| | - Eun-Yong Chung
- Department of Anesthesiology and Pain Medicine, Bucheon St. Mary’s Hospital, Catholic University of Korea, Bucheon 14647, Korea;
| | - Kwang-Hyun Park
- Department of Emergency Medical Rescue, Nambu University, Gwangju 62271, Korea
- Department of Emergency Medicine, Graduate School of Chonnam National University, Gwangju 61469, Korea
- Correspondence: (K.-H.P.); (J.-S.K.); Tel.: +82-62-970-0220 (K.-H.P.); +82-63-270-3085 (J.-S.K.)
| | - Jong-Suk Kim
- Department of Biochemistry and Institute of Cardiovascular Research, Chonbuk National University Medical School, Jeonju 54896, Korea; (H.-Y.J.); (O.-Y.H.)
- Correspondence: (K.-H.P.); (J.-S.K.); Tel.: +82-62-970-0220 (K.-H.P.); +82-63-270-3085 (J.-S.K.)
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23
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Zhao Y, Zhang X, Liu Y, Ma Y, Kong P, Bai T, Han M, Li B. Inhibition of ALAS1 activity exerts anti-tumour effects on colorectal cancer in vitro. Saudi J Gastroenterol 2020; 26:144-152. [PMID: 32270771 PMCID: PMC7392291 DOI: 10.4103/sjg.sjg_477_19] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND/AIMS Colorectal cancer (CRC) is the third most common malignant tumour worldwide and the second leading cause of cancer-related deaths. Commonly, 5'-aminolevulinic acid synthase1 (ALAS1) is the rate-limiting enzyme for haem biosynthesis. Recent studies have shown that ALAS1 is involved in a number of cellular functions and has significant effects on non-small cell lung cancer (NSCLC). However, current concepts of disease pathogenesis fail to fully explain the role of ALAS1 expression and biological functions in CRC. MATERIALS AND METHODS A total of 67 paired tumour tissues and adjacent colorectal tissues were used to detect ALAS1 levels and further analyse the correlation between ALAS1 expression levels and clinical features. Using HCT116 cell lines, we studied the impact of ALAS1 on biological function by knocking down or inhibiting ALAS1. RESULTS We found an increase in the levels of ALAS1 in cancer tissues compared to adjacent colorectal tissues. The increase in ALAS1 expression was closely related to the invasion depth, N staging and tumour size of CRC patients. The proliferation and metastasis of CRC cells could be inhibited by suppressing ALAS1. CONCLUSIONS The abnormal expression of ALAS1 is closely related to the proliferation and metastasis of CRC cells, suggesting that ALAS1 may be a novel therapeutic target for the treatment of CRC.
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Affiliation(s)
- Yalei Zhao
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, P. R. China
| | - Xiaoyun Zhang
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, P. R. China
| | - Yabin Liu
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, P. R. China
| | - Yiping Ma
- Department of Respiratory Medicine, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, P. R. China
| | - Pong Kong
- Department of Biochemistry and Molecular Biology, Hebei Medical University, Shijiazhuang, Hebei, P. R. China
| | - Tianliang Bai
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, P. R. China
| | - Mei Han
- Department of Biochemistry and Molecular Biology, Hebei Medical University, Shijiazhuang, Hebei, P. R. China
| | - Binghui Li
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, P. R. China,Address for correspondence: Prof. Binghui Li, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, Hebei, P. R, P. R. China. E-mail:
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24
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Non-competitive heme oxygenase-1 activity inhibitor reduces non-small cell lung cancer glutathione content and regulates cell proliferation. Mol Biol Rep 2020; 47:1949-1964. [PMID: 32056044 DOI: 10.1007/s11033-020-05292-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 01/24/2020] [Accepted: 01/29/2020] [Indexed: 12/30/2022]
Abstract
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death mainly due to its high metastatic rate. Impairment of redox homeostasis mechanisms has been previously described in NSCLC and is associated with the disease itself as well as with comorbidities such as smoking. The aim of the present in vitro study was to evaluate the effect of selective and non-competitive inhibition of heme oxygenase-1 (HO-1) on cancer redox homeostasis with particular regards to glutathione (GSH) metabolism related enzymes. NSCLC cell line (A549) was treated with the HO-1 activity inhibitor VP13/47 (10 µM) and we further evaluated cell viability, apoptosis, mitochondrial dysfunction and oxidative stress. Our results showed that VP13/47 significantly reduced HO-1 expression and total HO activity thus, resulting in a significant reduction of cell viability, proliferation and increased apoptosis, mitochondrial dysfunction and oxidative stress. Consistently with increased oxidative stress, we also showed that reduced GSH was significantly decreased and such effect was also accompanied by a significant downregulation of the enzymes involved in its biosynthesis. Taken all together our results show that selective HO-1 inhibition significantly impairs NSCLC progression and may represent a possible pharmacological strategy for new chemotherapy agents.
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25
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Duvigneau JC, Esterbauer H, Kozlov AV. Role of Heme Oxygenase as a Modulator of Heme-Mediated Pathways. Antioxidants (Basel) 2019; 8:antiox8100475. [PMID: 31614577 PMCID: PMC6827082 DOI: 10.3390/antiox8100475] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 09/27/2019] [Accepted: 10/07/2019] [Indexed: 02/07/2023] Open
Abstract
The heme oxygenase (HO) system is essential for heme and iron homeostasis and necessary for adaptation to cell stress. HO degrades heme to biliverdin (BV), carbon monoxide (CO) and ferrous iron. Although mostly beneficial, the HO reaction can also produce deleterious effects, predominantly attributed to excessive product formation. Underrated so far is, however, that HO may exert effects additionally via modulation of the cellular heme levels. Heme, besides being an often-quoted generator of oxidative stress, plays also an important role as a signaling molecule. Heme controls the anti-oxidative defense, circadian rhythms, activity of ion channels, glucose utilization, erythropoiesis, and macrophage function. This broad spectrum of effects depends on its interaction with proteins ranging from transcription factors to enzymes. In degrading heme, HO has the potential to exert effects also via modulation of heme-mediated pathways. In this review, we will discuss the multitude of pathways regulated by heme to enlarge the view on HO and its role in cell physiology. We will further highlight the contribution of HO to pathophysiology, which results from a dysregulated balance between heme and the degradation products formed by HO.
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Affiliation(s)
- J Catharina Duvigneau
- Institute for Medical Biochemistry, University of Veterinary Medicine, Veterinaerplatz 1, 1210 Vienna, Austria.
| | - Harald Esterbauer
- Department of Laboratory Medicine, Medical University of Vienna, 1210 Vienna, Austria.
| | - Andrey V Kozlov
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, 1200 Vienna, Austria.
- Laboratory of Navigational Redox Lipidomics, Department of Human Pathology, IM Sechenov Moscow State Medical University, 119992 Moscow, Russia.
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26
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Garrido MP, Torres I, Vega M, Romero C. Angiogenesis in Gynecological Cancers: Role of Neurotrophins. Front Oncol 2019; 9:913. [PMID: 31608227 PMCID: PMC6761325 DOI: 10.3389/fonc.2019.00913] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 09/02/2019] [Indexed: 12/13/2022] Open
Abstract
Angiogenesis, or generation of new blood vessels from other pre-existing, is a key process to maintain the supply of nutrients and oxygen in tissues. Unfortunately, this process is exacerbated in pathologies such as retinopathies and cancers with high angiogenesis as ovarian cancer. Angiogenesis is regulated by multiple systems including growth factors and neurotrophins. One of the most studied angiogenic growth factors is the vascular endothelial growth factor (VEGF), which is overexpressed in several cancers. It has been recently described that neurotrophins could regulate angiogenesis through direct and indirect mechanisms. Neurotrophins are a family of proteins that include nerve growth factor (NGF), brain-derived growth factor (BDNF), and neurotrophins 3 and 4/5 (NT 3, NT 4/5). These molecules and their high affinity receptors (TRKs) regulate the development, maintenance, and plasticity of the nervous system. Furthermore, it was recently described that they display essential functions in non-neuronal tissues, such as reproductive organs among others. Studies have shown that several types of cancer overexpress neurotrophins such as NGF and BDNF, which might contribute to tumor progression and angiogenesis. Besides, in recent years the FDA has approved the use of pharmacologic inhibitors of pan-TRK receptors in patients with TRKs fusion-positive cancers. In this review, we discuss the mechanisms by which neurotrophins stimulate tumor progression and angiogenesis, with emphasis on gynecological cancers.
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Affiliation(s)
- Maritza P Garrido
- Laboratory of Endocrinology and Reproductive Biology, Hospital Clínico Universidad de Chile, Santiago, Chile.,Departamento de Obstetricia y Ginecología, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Ignacio Torres
- Laboratory of Endocrinology and Reproductive Biology, Hospital Clínico Universidad de Chile, Santiago, Chile
| | - Margarita Vega
- Laboratory of Endocrinology and Reproductive Biology, Hospital Clínico Universidad de Chile, Santiago, Chile.,Departamento de Obstetricia y Ginecología, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Carmen Romero
- Laboratory of Endocrinology and Reproductive Biology, Hospital Clínico Universidad de Chile, Santiago, Chile.,Departamento de Obstetricia y Ginecología, Facultad de Medicina, Universidad de Chile, Santiago, Chile
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27
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Gawecki R, Malarz K, Rejmund M, Polanski J, Mrozek-Wilczkiewicz A. Impact of thiosemicarbazones on the accumulation of PpIX and the expression of the associated genes. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2019; 199:111585. [PMID: 31450131 DOI: 10.1016/j.jphotobiol.2019.111585] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 07/30/2019] [Accepted: 08/07/2019] [Indexed: 01/10/2023]
Abstract
Thiosemicarbazone derivatives are known for their broad biological activity including their antitumor potency. The aim of the current study was to examine the effect of a novel series of non-toxic iron chelators on the accumulation of protoporphyrin IX after external 5-aminolevulonic acid administration. From this series we selected one the most promising derivative which causes a pronounced increase in the concentration of protoporphyrin IX. The increase of the photosensitizer concentration is necessary for the trigger the efficient therapeutic effect of the photodynamic reaction. For selected compound 2 we performed an examination of a panel of the genes that are involved in the heme biosynthesis and degradation. Results indicated the crucial roles of ferrochelatase and heme oxygenase in the described processes. Surprisingly, there was a strict dependence on the type of the tested cell line. A decrease in the expression of the two aforementioned enzymes after incubation with compound 2 and 5-aminolevulonic acid is a commonly known fact and we detected this trend for the MCF-7 and HCT 116 cell lines. However, we noticed the upregulation of the tested targets for the Hs683 cells. These unconventional results prompted us to do a more in-depth analysis of the described processes. In conclusion, we found that compound 2 is a novel, highly effective booster of photodynamic therapy that has prospective applications.
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Affiliation(s)
- Robert Gawecki
- A. Chelkowski Institute of Physics, Silesian Center for Education and Interdisciplinary Research, University of Silesia, Chorzow, Poland
| | - Katarzyna Malarz
- A. Chelkowski Institute of Physics, Silesian Center for Education and Interdisciplinary Research, University of Silesia, Chorzow, Poland
| | - Marta Rejmund
- Institute of Chemistry, University of Silesia, Katowice, Poland
| | | | - Anna Mrozek-Wilczkiewicz
- A. Chelkowski Institute of Physics, Silesian Center for Education and Interdisciplinary Research, University of Silesia, Chorzow, Poland.
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28
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McNicholas K, MacGregor MN, Gleadle JM. In order for the light to shine so brightly, the darkness must be present-why do cancers fluoresce with 5-aminolaevulinic acid? Br J Cancer 2019; 121:631-639. [PMID: 31406300 PMCID: PMC6889380 DOI: 10.1038/s41416-019-0516-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Revised: 05/23/2019] [Accepted: 06/14/2019] [Indexed: 02/07/2023] Open
Abstract
Photodynamic diagnosis and therapy have emerged as a promising tool in oncology. Using the visible fluorescence from photosensitisers excited by light, clinicians can both identify and treat tumour cells in situ. Protoporphyrin IX, produced in the penultimate step of the haem synthesis pathway, is a naturally occurring photosensitiser that visibly fluoresces when exposed to light. This fluorescence is enhanced considerably by the exogenous administration of the substrate 5-aminolaevulinic acid (5-ALA). Significantly, 5-ALA-induced protoporphyrin IX accumulates preferentially in cancer cells, and this enhanced fluorescence has been harnessed for the detection and photodynamic treatment of brain, skin and bladder tumours. However, surprisingly little is known about the mechanistic basis for this phenomenon. This review focuses on alterations in the haem pathway in cancer and considers the unique features of the cancer environment, such as altered glucose metabolism, oncogenic mutations and hypoxia, and their potential effects on the protoporphyrin IX phenomenon. A better understanding of why cancer cells fluoresce with 5-ALA would improve its use in cancer diagnostics and therapies.
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Affiliation(s)
- Kym McNicholas
- Department of Renal Medicine, Flinders Medical Centre, Flinders University, Bedford Park, SA, 5042, Australia. .,College of Medicine and Public Health, Flinders University, Bedford Park, SA, 5042, Australia.
| | - Melanie N MacGregor
- Future Industries Institute, School of Engineering, University of South Australia, Adelaide, SA, 5095, Australia
| | - Jonathan M Gleadle
- Department of Renal Medicine, Flinders Medical Centre, Flinders University, Bedford Park, SA, 5042, Australia.,College of Medicine and Public Health, Flinders University, Bedford Park, SA, 5042, Australia
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29
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Gandini NA, Alonso EN, Fermento ME, Mascaró M, Abba MC, Coló GP, Arévalo J, Ferronato MJ, Guevara JA, Núñez M, Pichel P, Curino AC, Facchinetti MM. Heme Oxygenase-1 Has an Antitumor Role in Breast Cancer. Antioxid Redox Signal 2019; 30:2030-2049. [PMID: 30484334 DOI: 10.1089/ars.2018.7554] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Aims: Heme oxygenase-1 (HO-1) is an enzyme involved in cellular responses to oxidative stress and has also been shown to regulate processes related to cancer progression. In this regard, HO-1 has been shown to display a dual effect with either antitumor or protumor activity, which is also true for breast cancer (BC). In this work, we address this discrepancy regarding the role of HO-1 in BC. Results: HO-1 was detected in human BC tissues, and its protein levels correlated with reduced tumor size and longer overall survival time of patients, thus suggesting the clinical importance of HO-1 in this type of cancer. Contrariwise, nuclear localization of HO-1 correlated with higher tumor grade suggesting that the effect of HO-1 is dependent on its cellular localization. In vivo experiments showed that both pharmacological activation and genetic overexpression of HO-1 reduce the tumor burden in two different animal models of BC. Furthermore, the pharmacological and genetic activation of HO-1 in several BC cell lines reduce the cellular viability by inducing apoptosis and cell cycle arrest and decrease the cellular migration and invasion rates by modulating pathways involved in the epithelial-mesenchymal transition. Furthermore, HO-1 activation impaired in vivo the metastatic dissemination. Innovation and Conclusion: By using various BC cell lines and animal models as well as human tumor samples, we demonstrated that total HO-1 displays antitumor activities in BC. Furthermore, our study suggests that HO-1 subcellular localization may explain the differential effects observed for the protein in different tumor types.
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Affiliation(s)
- Norberto Ariel Gandini
- 1 Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Universidad Nacional del Sur (UNS)-CONICET, Dpto. de Biología, Bioquímica y Farmacia (UNS), Bahía Blanca, Argentina
| | - Eliana Noelia Alonso
- 1 Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Universidad Nacional del Sur (UNS)-CONICET, Dpto. de Biología, Bioquímica y Farmacia (UNS), Bahía Blanca, Argentina
| | - María Eugenia Fermento
- 1 Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Universidad Nacional del Sur (UNS)-CONICET, Dpto. de Biología, Bioquímica y Farmacia (UNS), Bahía Blanca, Argentina
| | - Marilina Mascaró
- 1 Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Universidad Nacional del Sur (UNS)-CONICET, Dpto. de Biología, Bioquímica y Farmacia (UNS), Bahía Blanca, Argentina
| | - Martín Carlos Abba
- 2 CINIBA, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Georgina Pamela Coló
- 1 Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Universidad Nacional del Sur (UNS)-CONICET, Dpto. de Biología, Bioquímica y Farmacia (UNS), Bahía Blanca, Argentina
| | - Julián Arévalo
- 1 Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Universidad Nacional del Sur (UNS)-CONICET, Dpto. de Biología, Bioquímica y Farmacia (UNS), Bahía Blanca, Argentina.,3 Servicio de Patología del Hospital Interzonal de Agudos Dr. José Penna, Bahía Blanca, Argentina
| | - María Julia Ferronato
- 1 Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Universidad Nacional del Sur (UNS)-CONICET, Dpto. de Biología, Bioquímica y Farmacia (UNS), Bahía Blanca, Argentina
| | - Josefina Alejandra Guevara
- 1 Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Universidad Nacional del Sur (UNS)-CONICET, Dpto. de Biología, Bioquímica y Farmacia (UNS), Bahía Blanca, Argentina
| | - Myriam Núñez
- 4 Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Pamela Pichel
- 5 Hospital Municipal de Agudos Dr Leónidas Lucero, Bahía Blanca, Argentina
| | - Alejandro Carlos Curino
- 1 Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Universidad Nacional del Sur (UNS)-CONICET, Dpto. de Biología, Bioquímica y Farmacia (UNS), Bahía Blanca, Argentina
| | - María Marta Facchinetti
- 1 Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Universidad Nacional del Sur (UNS)-CONICET, Dpto. de Biología, Bioquímica y Farmacia (UNS), Bahía Blanca, Argentina
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Rogers TJ, Christenson JL, Greene LI, O'Neill KI, Williams MM, Gordon MA, Nemkov T, D'Alessandro A, Degala GD, Shin J, Tan AC, Cittelly DM, Lambert JR, Richer JK. Reversal of Triple-Negative Breast Cancer EMT by miR-200c Decreases Tryptophan Catabolism and a Program of Immunosuppression. Mol Cancer Res 2018; 17:30-41. [PMID: 30213797 DOI: 10.1158/1541-7786.mcr-18-0246] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Revised: 08/13/2018] [Accepted: 09/06/2018] [Indexed: 12/18/2022]
Abstract
Tryptophan-2,3-dioxygenase (TDO2), a rate-limiting enzyme in the tryptophan catabolism pathway, is induced in triple-negative breast cancer (TNBC) by inflammatory signals and anchorage-independent conditions. TNBCs express extremely low levels of the miR-200 family compared with estrogen receptor-positive (ER+) breast cancer. In normal epithelial cells and ER+ breast cancers and cell lines, high levels of the family member miR-200c serve to target and repress genes involved in epithelial-to-mesenchymal transition (EMT). To identify mechanism(s) that permit TNBC to express TDO2 and other proteins not expressed in the more well-differentiated ER+ breast cancers, miRNA-200c was restored in TNBC cell lines. The data demonstrate that miR-200c targeted TDO2 directly resulting in reduced production of the immunosuppressive metabolite kynurenine. Furthermore, in addition to reversing a classic EMT signature, miR-200c repressed many genes encoding immunosuppressive factors including CD274/CD273, HMOX-1, and GDF15. Restoration of miR-200c revealed a mechanism, whereby TNBC hijacks a gene expression program reminiscent of that used by trophoblasts to suppress the maternal immune system to ensure fetal tolerance during pregnancy. IMPLICATIONS: Knowledge of the regulation of tumor-derived immunosuppressive factors will facilitate development of novel therapeutic strategies that complement current immunotherapy to reduce mortality for patients with TNBC.
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Affiliation(s)
- Thomas J Rogers
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Jessica L Christenson
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Lisa I Greene
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Kathleen I O'Neill
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Michelle M Williams
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Michael A Gordon
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Travis Nemkov
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Angelo D'Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Greg D Degala
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Jimin Shin
- Department of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Aik-Choon Tan
- Department of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Diana M Cittelly
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - James R Lambert
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Jennifer K Richer
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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31
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Daneshmandpour Y, Darvish H, Emamalizadeh B. RIT2: responsible and susceptible gene for neurological and psychiatric disorders. Mol Genet Genomics 2018; 293:785-792. [DOI: 10.1007/s00438-018-1451-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 05/28/2018] [Indexed: 01/19/2023]
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Novel Structural Insight into Inhibitors of Heme Oxygenase-1 (HO-1) by New Imidazole-Based Compounds: Biochemical and In Vitro Anticancer Activity Evaluation. Molecules 2018; 23:molecules23051209. [PMID: 29783634 PMCID: PMC6099553 DOI: 10.3390/molecules23051209] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 05/13/2018] [Accepted: 05/15/2018] [Indexed: 12/13/2022] Open
Abstract
In this paper, the design, synthesis, and molecular modeling of a new azole-based HO-1 inhibitors was reported, using compound 1 as a lead compound, in which an imidazole moiety is linked to a hydrophobic group by means of an ethanolic spacer. The tested compounds showed a good inhibitor activity and possessed IC50 values in the micromolar range. These results were obtained by targeting the hydrophobic western region. Molecular modeling studies confirmed a consolidated binding mode in which the nitrogen of the imidazolyl moiety coordinated the heme ferrous iron, meanwhile the hydrophobic groups were located in the western region of HO-1 binding pocket. Moreover, the new compounds were screened for in silico ADME-Tox properties to predict drug-like behavior with convincing results. Finally, the in vitro antitumor activity profile of compound 1 was investigated in different cancer cell lines and nanomicellar formulation was synthesized with the aim of improving compound's 1 water solubility. Finally, compound 1 was tested in melanoma cells in combination with doxorubicin showing interesting synergic activity.
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33
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Bian C, Zhong M, Nisar MF, Wu Y, Ouyang M, Bartsch JW, Zhong JL. A novel heme oxygenase-1 splice variant, 14kDa HO-1, promotes cell proliferation and increases relative telomere length. Biochem Biophys Res Commun 2018; 500:429-434. [PMID: 29660345 DOI: 10.1016/j.bbrc.2018.04.096] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 04/12/2018] [Indexed: 12/16/2022]
Abstract
Alternative splicing is a routine phenomenon which greatly increases the diversity of proteins in eukaryotic cells. In humans, most multi-exonic genes are alternatively spliced and their splice variants confer distinct functions. Heme oxygenase-1 (HO-1, 32 kDa) is an inducible stress responsive protein, which possesses multiple functions in many cellular processes. In the current study, we identified a novel alternative splice isoform of 14 kDa HO-1 generated through exclusion of exon 3, and it is highly expressed in immortalized cells. In contrast to nuclear accumulation of the full-length 32 kDa HO-1, the novel 14 kDa HO-1 isoform is retained in the cytoplasm under ultraviolet (UV) irradiation. Interestingly, the 14 kDa HO-1 is shown to promote cell proliferation and an increase in relative telomere lengths in vivo and in vitro. Thus, we are pioneer to report and confirm the presence of a novel splice form of HO-1 and its distinct role in modulating telomere length and tumor growth.
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Affiliation(s)
- Chunxiang Bian
- The Base of "111 Project" for Biomechanics & Tissue Repair Engineering, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering college, Life Science College, Chongqing University, Chongqing, 400044, China
| | - Maojiao Zhong
- The Base of "111 Project" for Biomechanics & Tissue Repair Engineering, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering college, Life Science College, Chongqing University, Chongqing, 400044, China
| | - Muhammad Farrukh Nisar
- The Base of "111 Project" for Biomechanics & Tissue Repair Engineering, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering college, Life Science College, Chongqing University, Chongqing, 400044, China; Interdisciplinary Research Centre in Biomedical Materials (IRCBM), COMSATS Institute of Information Technology, Lahore, 54000, Pakistan
| | - Yan Wu
- The Base of "111 Project" for Biomechanics & Tissue Repair Engineering, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering college, Life Science College, Chongqing University, Chongqing, 400044, China
| | - Mingyue Ouyang
- The Base of "111 Project" for Biomechanics & Tissue Repair Engineering, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering college, Life Science College, Chongqing University, Chongqing, 400044, China
| | - Jörg W Bartsch
- Department of Neurosurgery, Philipps-University Marburg, Baldingerstr., 35033, Marburg, Germany
| | - Julia Li Zhong
- The Base of "111 Project" for Biomechanics & Tissue Repair Engineering, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering college, Life Science College, Chongqing University, Chongqing, 400044, China.
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Subashini G, Vidhya K, Arasakumar T, Angayarkanni J, Murugesh E, Saravanan A, Shanmughavel P, Mohan PS. Quinoline-Based Imidazole Derivative as Heme Oxygenase-1 Inhibitor: A Strategy for Cancer Treatment. ChemistrySelect 2018. [DOI: 10.1002/slct.201800173] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Gopalan Subashini
- Department of Chemistry; Bharathiar University; Coimbatore-641046, Tamilnadu India
| | - Kalieswaran Vidhya
- Department of Microbial Biotechnology; Bharathiar University; Coimbatore- 641046, Tamilnadu India
| | - Thangaraj Arasakumar
- Department of Chemistry; Bharathiar University; Coimbatore-641046, Tamilnadu India
| | - Jayaraman Angayarkanni
- Department of Microbial Biotechnology; Bharathiar University; Coimbatore- 641046, Tamilnadu India
| | - Easwaran Murugesh
- Department of Bioinformatics; Bharathiar University; Coimbatore- 641046, Tamilnadu India
| | - Arjunan Saravanan
- BU-DRDO CLS; Bharathiar University; Coimbatore- 641046, Tamilnadu India
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Jun SY, Hong SM, Bae YK, Kim HK, Jang KY, Eom DW. Clinicopathological and prognostic significance of heme oxygenase-1 expression in small intestinal adenocarcinomas. Pathol Int 2018. [PMID: 29537718 DOI: 10.1111/pin.12657] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Heme oxygenase-1 (HO-1), a stress-response protein, is highly induced in various carcinomas. It is implicated in carcinogenesis and tumor progression. High HO-1 expression is associated with better prognosis of patients with colorectal and gastric cancers. Induction or inhibition of HO-1 can mediate chemo-sensitivity, therefore it might be a therapeutic target to develop anticancer agents. To define the clinicopathological and prognostic significance of HO-1 expression in small-intestinal adenocarcinomas (SIACs), immunohistochemical microarray analysis of HO-1 expression was performed for 191 surgically resected SIAC cases and results were compared with various clinicopathologic variables, including survival. HO-1 was highly expressed in 127 (66.5%) cases. Patients with high HO-1 expression were associated with younger age (P = 0.048), lower pT category (P = 0.017), and less pancreatic invasion (P = 0.047). Patients with high HO-1 expression tended to have longer overall survival (median, 38.5 months) than those with low HO-1 expression (24.5 months), although the difference in overall survival was not statistically significant (P = 0.677). In summary, high HO-1 expression is frequently observed in SIACs. It is related to favorable clinicopathologic parameters, including younger age, lower T category, and less pancreatic invasion. Therefore, HO-1 may serve as a prognostic marker and a new target to modulate chemotherapeutic effects in patients with SIACs.
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Affiliation(s)
- Sun-Young Jun
- Department of Pathology, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Republic of Korea
| | - Seung-Mo Hong
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Young Kyung Bae
- Department of Pathology, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Hee Kyung Kim
- Department of Pathology, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea
| | - Kyu Yun Jang
- Department of Pathology, Chonbuk National University Medical School, Jeonju, Republic of Korea
| | - Dae Woon Eom
- Department of Pathology, University of Ulsan College of Medicine, Gangneung Asan Hospital, Gangneung, Republic of Korea
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Dichiara M, Prezzavento O, Marrazzo A, Pittalà V, Salerno L, Rescifina A, Amata E. Recent advances in drug discovery of phototherapeutic non-porphyrinic anticancer agents. Eur J Med Chem 2017; 142:459-485. [DOI: 10.1016/j.ejmech.2017.08.070] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 08/29/2017] [Accepted: 08/31/2017] [Indexed: 12/17/2022]
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Ren QG, Yang SL, Li PD, Xiong JR, Fang X, Hu JL, Wang QS, Chen RW, Chen YS, Wen L, Peng M. Low heme oxygenase-1 expression promotes gastric cancer cell apoptosis, inhibits proliferation and invasion, and correlates with increased overall survival in gastric cancer patients. Oncol Rep 2017; 38:2852-2858. [PMID: 29048628 DOI: 10.3892/or.2017.5967] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 08/11/2017] [Indexed: 11/06/2022] Open
Abstract
Heme oxygenase-1 (HO-1) plays a key role in anti-oxidation, anti-apoptosis, and anti-proliferation in various types of cancers. However, the relationship between HO-1 expression and gastric cancer development remains largely unknown. In this study, the protein expression of HO-1 in human gastric cancer was measured by immunohistochemistry on paraffin sections of 89 paired gastric carcinoma tissues and adjacent non-cancer tissues. The correlation of HO-1 expression with 5-year overall survival rate was estimated. The effects of decreased HO-1 expression by two strands of small interfered RNAs (siRNAs) on cell apoptosis, proliferation, and invasion of gastric cancer cell lines were examined by flow cytometry, the MTT assay, and the cell migration assay, respectively. High expression of HO-1 was detected in 11.2% (10/89) of gastric carcinoma tissues, compared with 1.1% (1/89) in matched adjacent normal tissues, and correlated with a decreased survival rate in gastric cancer patients. There were no significant correlations between HO-1 expression and clinical characteristics. Downregulation of HO-1 expression using two strands of siRNAs promoted apoptosis and inhibited the proliferation and invasion of two gastric cancer cell lines, SGC7901 and MKN-28 cells. This study demonstrated that HO-1 plays a vital role in the development of gastric cancer and may serve as a therapeutic target of this type of cancer.
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Affiliation(s)
- Quan-Guang Ren
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P.R. China
| | - Sheng-Li Yang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P.R. China
| | - Pin-Dong Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P.R. China
| | | | - Xiefan Fang
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Jian-Li Hu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P.R. China
| | - Qiu-Shuang Wang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P.R. China
| | - Ren-Wang Chen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P.R. China
| | - Ye-Shan Chen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P.R. China
| | - Lu Wen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P.R. China
| | - Miao Peng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P.R. China
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Noh SJ, Kim KM, Jang KY. Individual and co-expression patterns of nerve growth factor and heme oxygenase-1 predict shorter survival of gastric carcinoma patients. Diagn Pathol 2017; 12:48. [PMID: 28679437 PMCID: PMC5498870 DOI: 10.1186/s13000-017-0644-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Accepted: 06/30/2017] [Indexed: 02/09/2023] Open
Abstract
BACKGROUND Nerve growth factor (NGF) is a neurotrophic factor which regulates cell development and proliferation. Recently, it has been suggested that NGF induces heme oxygenase-1 (HO1) expression, and that both NGF and HO1 are involved in the progression of malignant human tumors. However, exact roles of NGF and HO1 in tumorigenesis remain controversial. Therefore, we investigated the expression and correlation of NGF and HO1 in human gastric carcinoma tissues. METHODS We examined immunohistochemical expression of NGF and HO1 in 167 gastric carcinomas and compared with various prognostic clinicopathological factors. RESULTS The expression of NGF and HO1 was positive in 40% (67/167) and 51% (85/167) of cases, respectively, and their expression was significantly correlated with each other (p < 0.001). Individual expression patterns of NGF and HO1, and co-expression pattern of these two molecules were significantly associated with shorter survival by univariate analysis. HO1 expression (overall survival; p < 0.001, relapse-free survival; p = 0.002) and co-expression pattern of NGF and HO1 (overall survival; p = 0.002, relapse-free survival; p = 0.003) were independent poor prognostic indicators of gastric carcinoma patients by multivariate analysis. CONCLUSIONS These results demonstrate that the individual and co-expression patterns of NGF and HO1 might be used as prognostic indicators for gastric carcinoma patients.
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Affiliation(s)
- Sang Jae Noh
- Department of Forensic Medicine, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, 20, Geonji-ro, Deokjin-gu, Jeonju, Jeonbuk, 54907, Republic of Korea
| | - Kyoung Min Kim
- Department of Pathology, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, 20, Geonji-ro, Deokjin-gu, Jeonju, Jeonbuk, 54907, Republic of Korea
| | - Kyu Yun Jang
- Department of Pathology, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, 20, Geonji-ro, Deokjin-gu, Jeonju, Jeonbuk, 54907, Republic of Korea.
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Chakravarthy R, Mnich K, Gorman AM. Nerve growth factor (NGF)-mediated regulation of p75(NTR) expression contributes to chemotherapeutic resistance in triple negative breast cancer cells. Biochem Biophys Res Commun 2016; 478:1541-7. [PMID: 27577679 DOI: 10.1016/j.bbrc.2016.08.149] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 08/26/2016] [Indexed: 01/09/2023]
Abstract
Triple negative breast cancer [TNBC] cells are reported to secrete the neurotrophin nerve growth factor [NGF] and express its receptors, p75 neurotrophin receptor [p75(NTR)] and TrkA, leading to NGF-activated pro-survival autocrine signaling. This provides a rationale for NGF as a potential therapeutic target for TNBC. Here we show that exposure of TNBC cells to NGF leads to increased levels of p75(NTR), which was diminished by NGF-neutralizing antibody or NGF inhibitors [Ro 08-2750 and Y1086]. NGF-mediated increase in p75(NTR) levels were partly due to increased transcription and partly due to inhibition of proteolytic processing of p75(NTR). In contrast, proNGF caused a decrease in p75(NTR) levels. Functionally, NGF-induced increase in p75(NTR) caused a decrease in the sensitivity of TNBC cells to apoptosis induction. In contrast, knock-down of p75(NTR) using shRNA or small molecule inhibition of NGF-p75(NTR) interaction [using Ro 08-2750] sensitized TNBC cells to drug-induced apoptosis. In patient samples, the expression of NGF and NGFR [the p75(NTR) gene] mRNA are positively correlated in several subtypes of breast cancer, including basal-like breast cancer. Together these data suggest a positive feedback loop through which NGF-mediated upregulation of p75(NTR) can contribute to the chemo-resistance of TNBC cells.
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Ren QG, Yang SL, Hu JL, Li PD, Chen YS, Wang QS. Evaluation of HO-1 expression, cellular ROS production, cellular proliferation and cellular apoptosis in human esophageal squamous cell carcinoma tumors and cell lines. Oncol Rep 2016; 35:2270-6. [PMID: 26780849 DOI: 10.3892/or.2016.4556] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2015] [Accepted: 11/24/2015] [Indexed: 11/05/2022] Open
Abstract
Patients with esophageal squamous cell carcinoma (ESCC) have a poor prognosis. However, the related mechanisms are unclear, thus we investigated the expression of HO-1 in ESCC tissue and explored possible mechanisms of tumor progression. Expression of HO-1 was examined by immunohistochemistry in 143 ESCC tumors. The correlation of HO-1 with clinicopathological characteristics was also examined. Two human ESCC cell lines, TE-13 and Eca109 were studied. Silencing of cell line HO-1 by specific small interfering RNA (siRNA) was evaluated using real-time quantitative PCR. Cell line viability, apoptosis and intracellular levels of reactive oxygen species (ROS) after transfection were determined using MTT and flow cytometry, respectively. HO-1, Bax, Bcl-2 and A-caspase-3/-9 expression was evaluated using western blot analyses. We found that HO-1 was expressed in 58 of 143 ESCC tumors, mainly in the cytoplasm. There was a significant association between HO-1 expression and tumor grade (P<0.001). Knockdown of HO-1 expression in cell lines was associated with significantly decreased cellular proliferation (P<0.05) and a higher rate of apoptosis (P<0.001) 48 h after treatment. Treatment of the cell lines with the ROS inhibitor N-acetylcysteine abrogated this effect. Knockdown of HO-1 was associated with increased A-caspase-3 and -9 expression, but no change in Bax or Bcl-2 expression or Bax/Bcl-2 ratio was observed. Thus, the present study identified that ESCC tumors frequently expressed HO-1. Knockdown of HO-1 promoted apoptosis through activation of a ROS-mediated caspase apoptosis pathway.
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Affiliation(s)
- Quan-Guang Ren
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jianghan, Wuhan, Hubei 430022, P.R. China
| | - Sheng-Li Yang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jianghan, Wuhan, Hubei 430022, P.R. China
| | - Jian-Li Hu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jianghan, Wuhan, Hubei 430022, P.R. China
| | - Pin-Dong Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jianghan, Wuhan, Hubei 430022, P.R. China
| | - Ye-Shan Chen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jianghan, Wuhan, Hubei 430022, P.R. China
| | - Qiu-Shuang Wang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jianghan, Wuhan, Hubei 430022, P.R. China
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Zhu XF, Li W, Ma JY, Shao N, Zhang YJ, Liu RM, Wu WB, Lin Y, Wang SM. Knockdown of heme oxygenase-1 promotes apoptosis and autophagy and enhances the cytotoxicity of doxorubicin in breast cancer cells. Oncol Lett 2015; 10:2974-2980. [PMID: 26722274 DOI: 10.3892/ol.2015.3735] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 05/29/2015] [Indexed: 01/11/2023] Open
Abstract
Heme oxygenase-1 (HMOX-1) is a microsomal enzyme that exerts anti-apoptotic and cytoprotective effects. In the present study, HMOX-1 was demonstrated to be overexpressed and able to be induced by doxorubicin in breast cancer cell lines. Knockdown of HMOX-1 using short interfering (si)RNA enhanced the cytotoxicity of doxorubicin in MDA-MB-231 and BT549 cells. Knockdown of HMOX-1 downregulated B cell lymphoma (Bcl)-2 and Bcl-extra large expression, and significantly enhanced doxorubicin-induced apoptosis in MDA-MB-231 and BT549 cells. Additionally, knockdown of HMOX-1 upregulated light chain 3B expression and markedly increased the accumulation of autophagic vacuoles in MDA-MB-231 and BT549 cells treated with doxorubicin. These results indicated that HMOX-1 may be involved in conferring the chemoresistance of breast cancer cells, by preventing apoptosis and autophagy. Therefore, HMOX-1 may represent a potential therapeutic target for enhancing the cytotoxicity and efficacy of doxorubicin during the treatment of breast cancer.
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Affiliation(s)
- Xiao-Feng Zhu
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Wen Li
- Laboratory of General Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China ; Guangdong Engineering Laboratory for Diagnosis and Treatment of Vascular Disease, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Jie-Yi Ma
- Laboratory of General Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Nan Shao
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Yun-Jian Zhang
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Rui-Ming Liu
- Laboratory of General Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China ; Guangdong Engineering Laboratory for Diagnosis and Treatment of Vascular Disease, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Wei-Bin Wu
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Ying Lin
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Shen-Ming Wang
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China ; Guangdong Engineering Laboratory for Diagnosis and Treatment of Vascular Disease, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
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Park SH, Noh SJ, Kim KM, Bae JS, Kwon KS, Jung SH, Kim JR, Lee H, Chung MJ, Moon WS, Kang MJ, Jang KY. Expression of DNA Damage Response Molecules PARP1, γH2AX, BRCA1, and BRCA2 Predicts Poor Survival of Breast Carcinoma Patients. Transl Oncol 2015; 8:239-49. [PMID: 26310369 PMCID: PMC4562981 DOI: 10.1016/j.tranon.2015.04.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Revised: 04/18/2015] [Accepted: 04/24/2015] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND: Poly(ADP-ribose) polymerase 1 (PARP1), γH2AX, BRCA1, and BRCA2 are conventional molecular indicators of DNA damage in cells and are often overexpressed in various cancers. In this study, we aimed, using immunohistochemical detection, whether the co-expression of PARP1, γH2AX, BRCA1, and BRCA2 in breast carcinoma (BCA) tissue can provide more reliable prediction of survival of BCA patients. MATERIALS AND METHODS: We investigated immunohistochemical expression and prognostic significance of the expression of PARP1, γH2AX, BRCA1, and BRCA2 in 192 cases of BCAs. RESULTS: The expression of these four molecules predicted earlier distant metastatic relapse, shorter overall survival (OS), and relapse-free survival (RFS) by univariate analysis. Multivariate analysis revealed the expression of PARP1, γH2AX, and BRCA2 as independent poor prognostic indicators of OS and RFS. In addition, the combined expressional pattern of BRCA1, BRCA2, PARP1, and γH2AX (CSbbph) was an additional independent prognostic predictor for OS (P < .001) and RFS (P < .001). The 10-year OS rate was 95% in the CSbbph-low (CSbbph scores 0 and 1) subgroup, but that was only 35% in the CSbbph-high (CSbbph score 4) subgroup. CONCLUSION: This study has demonstrated that the individual and combined expression patterns of PARP1, γH2AX, BRCA1, and BRCA2 could be helpful in determining an accurate prognosis for BCA patients and for the selection of BCA patients who could potentially benefit from anti-PARP1 therapy with a combination of genotoxic chemotherapeutic agents.
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Affiliation(s)
- See-Hyoung Park
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA
| | - Sang Jae Noh
- Department of Pathology, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University, Biomedical Research Institute of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju, Republic of Korea
| | - Kyoung Min Kim
- Department of Pathology, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University, Biomedical Research Institute of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju, Republic of Korea
| | - Jun Sang Bae
- Department of Pathology, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University, Biomedical Research Institute of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju, Republic of Korea
| | - Keun Sang Kwon
- Department of Preventive Medicine, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University, Biomedical Research Institute of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju, Republic of Korea
| | - Sung Hoo Jung
- Department of Surgery, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University, Biomedical Research Institute of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju, Republic of Korea
| | - Jung Ryul Kim
- Department of Orthopaedic Surgery, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University, Biomedical Research Institute of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju, Republic of Korea
| | - Ho Lee
- Department of Forensic Medicine, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University, Biomedical Research Institute of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju, Republic of Korea
| | - Myoung Ja Chung
- Department of Pathology, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University, Biomedical Research Institute of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju, Republic of Korea
| | - Woo Sung Moon
- Department of Pathology, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University, Biomedical Research Institute of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju, Republic of Korea
| | - Myoung Jae Kang
- Department of Pathology, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University, Biomedical Research Institute of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju, Republic of Korea
| | - Kyu Yun Jang
- Department of Pathology, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University, Biomedical Research Institute of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju, Republic of Korea.
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Solano ME, Arck PC. Heme oxygenase-1: for better, for worse, in sickness and in health. Oncotarget 2015; 6:14733-4. [PMID: 26142705 PMCID: PMC4558110 DOI: 10.18632/oncotarget.4440] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 06/10/2015] [Indexed: 12/26/2022] Open
Affiliation(s)
- María Emilia Solano
- Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Petra Clara Arck
- Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Salerno L, Pittalà V, Romeo G, Modica MN, Marrazzo A, Siracusa MA, Sorrenti V, Di Giacomo C, Vanella L, Parayath NN, Greish K. Novel imidazole derivatives as heme oxygenase-1 (HO-1) and heme oxygenase-2 (HO-2) inhibitors and their cytotoxic activity in human-derived cancer cell lines. Eur J Med Chem 2015; 96:162-72. [PMID: 25874340 DOI: 10.1016/j.ejmech.2015.04.003] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Revised: 04/02/2015] [Accepted: 04/04/2015] [Indexed: 11/26/2022]
Abstract
Heme oxygenase (HO) is a cytoprotective enzyme that can be overexpressed in some pathological conditions, including certain cancers. In this work, novel imidazole derivatives were designed and synthesized as inhibitors of heme oxygenase-1 (HO-1) and heme oxygenase-2 (HO-2). In these compounds the imidazole ring, crucial for the activity, is connected to a hydrophobic group, represented by aryloxy, benzothiazole, or benzoxazole moieties, by means of alkyl or thioalkyl chains of different length. Many of the tested compounds were potent and/or selective against one of the two isoforms of HO. Furthermore, most of the pentyl derivatives showed to be better inhibitors of HO-2 with respect to HO-1, revealing a critical role of the alkyl chain in discriminating between the two isoenzymes. Compounds which showed the better profile of HO inhibition were selected and tested to evaluate their cytotoxic properties in prostate and breast cancer cell lines (DU-145, PC3, LnCap, MDA-MB-231, and MCF-7). In these assays, aryloxyalkyl derivatives resulted more cytotoxic than benzothiazolethioalkyl ones; in particular compound 31 was active against all the cell lines tested, confirming the anti-proliferative properties of HO inhibitors and their potential use in the treatment of specific cancers.
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Affiliation(s)
- Loredana Salerno
- Department of Drug Sciences, Section of Medicinal Chemistry, University of Catania, viale A. Doria 6, 95125 Catania, Italy.
| | - Valeria Pittalà
- Department of Drug Sciences, Section of Medicinal Chemistry, University of Catania, viale A. Doria 6, 95125 Catania, Italy
| | - Giuseppe Romeo
- Department of Drug Sciences, Section of Medicinal Chemistry, University of Catania, viale A. Doria 6, 95125 Catania, Italy
| | - Maria N Modica
- Department of Drug Sciences, Section of Medicinal Chemistry, University of Catania, viale A. Doria 6, 95125 Catania, Italy
| | - Agostino Marrazzo
- Department of Drug Sciences, Section of Medicinal Chemistry, University of Catania, viale A. Doria 6, 95125 Catania, Italy
| | - Maria A Siracusa
- Department of Drug Sciences, Section of Medicinal Chemistry, University of Catania, viale A. Doria 6, 95125 Catania, Italy
| | - Valeria Sorrenti
- Department of Drug Sciences, Section of Biochemistry, University of Catania, viale A. Doria 6, 95125 Catania, Italy
| | - Claudia Di Giacomo
- Department of Drug Sciences, Section of Biochemistry, University of Catania, viale A. Doria 6, 95125 Catania, Italy
| | - Luca Vanella
- Department of Drug Sciences, Section of Biochemistry, University of Catania, viale A. Doria 6, 95125 Catania, Italy
| | - Neha N Parayath
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand
| | - Khaled Greish
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand; Department of Oncology, Faculty of Medicine, Suez Canal University, Egypt
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Abstract
Heme oxygenase-1 (HO-1) is a rate-limiting enzyme catalyzing oxidative degradation of cellular heme to liberate free iron, carbon monoxide (CO) and biliverdin in mammalian cells. In addition to its primary role in heme catabolism, HO-1 exhibits anti-oxidative and anti-inflammatory functions via the actions of biliverdin and CO, respectively. HO-1 is highly induced in various disease states, including cancer. Several lines of evidence have supported the implication of HO-1 in carcinogenesis and tumor progression. HO-1 deficiency in normal cells enhances DNA damage and carcinogenesis. Nevertheless, HO-1 overexpression in cancer cells promotes proliferation and survival. Moreover, HO-1 induces angiogenesis through modulating expression of angiogenic factors. Although HO-1 is an endoplasmic reticulum resident protein, HO-1 nuclear localization is evident in tumor cells of cancer tissues. It has been shown that HO-1 is susceptible to proteolytic cleavage and translocates to nucleus to facilitate tumor growth and invasion independent of its enzymatic activity. HO-1 also impacts cancer progression through modulating tumor microenvironment. This review summarizes the current understanding of the protumorigenic role of HO-1 and its potential as a molecular target for cancer therapy.
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Affiliation(s)
- Lee-Young Chau
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan.
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46
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Lin X, Fang Q, Chen S, Zhe N, Chai Q, Yu M, Zhang Y, Wang Z, Wang J. Heme oxygenase-1 suppresses the apoptosis of acute myeloid leukemia cells via the JNK/c-JUN signaling pathway. Leuk Res 2015; 39:544-52. [PMID: 25828744 DOI: 10.1016/j.leukres.2015.02.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Revised: 01/26/2015] [Accepted: 02/21/2015] [Indexed: 02/07/2023]
Abstract
There are few studies on the correlation between heme oxygenase-1 (HO-1) and acute myeloid leukemia (AML). We found that HO-1 was aberrantly overexpressed in the majority of AML patients, especially in patients with acute monocytic leukemia (M5) and leukocytosis, and inhibited the apoptosis of HL-60 and U937 cells. Moreover, silencing HO-1 prolonged the survival of xenograft mouse models. Further studies demonstrated that HO-1 suppressed the apoptosis of AML cells through activating the JNK/c-JUN signaling pathway. These data indicate a molecular role of HO-1 in inhibiting cell apoptosis, allowing it to be a potential target for treating AML.
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Affiliation(s)
- Xiaojing Lin
- Guiyang Medical College, Guiyang 550004, China; Department of Hematology, the Affiliated Hospital of Guiyang Medical College, Guiyang 550004, China; Guizhou Provincial Laboratory of Hematopoietic Stem Cell Transplantation Center, Guiyang 550004, China
| | - Qin Fang
- Department of Pharmacy, the Affiliated Baiyun Hospital of Guiyang Medical College, Guiyang 550004, China
| | - Shuya Chen
- Guiyang Medical College, Guiyang 550004, China; Department of Hematology, the Affiliated Hospital of Guiyang Medical College, Guiyang 550004, China; Guizhou Provincial Laboratory of Hematopoietic Stem Cell Transplantation Center, Guiyang 550004, China
| | - Nana Zhe
- Guiyang Medical College, Guiyang 550004, China; Department of Hematology, the Affiliated Hospital of Guiyang Medical College, Guiyang 550004, China; Guizhou Provincial Laboratory of Hematopoietic Stem Cell Transplantation Center, Guiyang 550004, China
| | - Qixiang Chai
- Guiyang Medical College, Guiyang 550004, China; Department of Hematology, the Affiliated Hospital of Guiyang Medical College, Guiyang 550004, China; Guizhou Provincial Laboratory of Hematopoietic Stem Cell Transplantation Center, Guiyang 550004, China
| | - Meisheng Yu
- Guiyang Medical College, Guiyang 550004, China; Department of Hematology, the Affiliated Hospital of Guiyang Medical College, Guiyang 550004, China; Guizhou Provincial Laboratory of Hematopoietic Stem Cell Transplantation Center, Guiyang 550004, China
| | - Yaming Zhang
- Department of Hematology, the Affiliated Hospital of Guiyang Medical College, Guiyang 550004, China; Guizhou Provincial Laboratory of Hematopoietic Stem Cell Transplantation Center, Guiyang 550004, China
| | - Ziming Wang
- Department of Hematology, the Affiliated Hospital of Guiyang Medical College, Guiyang 550004, China; Guizhou Provincial Laboratory of Hematopoietic Stem Cell Transplantation Center, Guiyang 550004, China
| | - Jishi Wang
- Guiyang Medical College, Guiyang 550004, China; Department of Hematology, the Affiliated Hospital of Guiyang Medical College, Guiyang 550004, China; Guizhou Provincial Laboratory of Hematopoietic Stem Cell Transplantation Center, Guiyang 550004, China.
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Cho D, Park H, Park SH, Kim K, Chung M, Moon W, Kang M, Jang K. The expression of DBC1/CCAR2 is associated with poor prognosis of ovarian carcinoma. J Ovarian Res 2015; 8:2. [PMID: 25823848 PMCID: PMC4335761 DOI: 10.1186/s13048-015-0129-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2014] [Accepted: 01/31/2015] [Indexed: 01/05/2023] Open
Abstract
Background Recent reports have shown that deleted in breast cancer 1 (DBC1/CCAR2) is an indicator of poor prognosis of various human cancers. However, its expression in ovarian carcinoma has not been reported. Methods We investigated the immunohistochemical expression of DBC1 and BRCA1 and their prognostic significance in 104 ovarian carcinomas. Survival analyses were performed according to the Kaplan-Meier method, as well as univariate and multivariate Cox proportional hazard regression analysis. Results Positive expression of DBC1 and BRCA1 were seen in 63% (66/104) and 44% (46/104) of overall ovarian carcinomas, respectively. DBC1 expression was significantly associated with advanced clinicopathological factors such as high tumor stage, latent distant metastasis, platinum-resistance, elevated serum levels of CA125, high histologic grade, and BRCA1 expression. In the histological subtypes of ovarian carcinomas, DBC1 expression was more common in serous carcinoma (72%, 54/75) than mucinous carcinoma (15%, 3/20). BRCA1 expression was significantly associated with latent distant metastasis, platinum-resistance, and higher histologic grade. In addition, DBC1 expression was significantly associated with shorter overall survival (OS) and relapse-free survival (RFS) in 104 ovarian carcinomas (OS; P < 0.001, RFS; P < 0.001) and 63 high-grade serous carcinomas (OS; P = 0.008, RFS; P = 0.023) by univariate analysis. BRCA1 expression was significantly associated with OS and RFS in 104 ovarian carcinomas (OS; P = 0.005, RFS; P = 0.002) and 75 serous carcinomas (OS; P = 0.047, RFS; P = 0.038) by univariate analysis. Moreover, DBC1 expression was an independent prognostic indicator for OS in both 104 ovarian carcinomas (P = 0.021) and 63 high-grade serous carcinomas (P = 0.011) by multivariate analysis. Conclusions These results indicate that the expression of DBC1 and BRCA1 are closely related with in the progression of ovarian carcinomas and may have clinical utility in the prediction of prognosis of ovarian carcinomas. Especially, DBC1 expression could be employed as a significant prognostic indicator for ovarian carcinomas especially in high-grade serous carcinomas.
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Zhao H, Ozen M, Wong RJ, Stevenson DK. Heme oxygenase-1 in pregnancy and cancer: similarities in cellular invasion, cytoprotection, angiogenesis, and immunomodulation. Front Pharmacol 2015; 5:295. [PMID: 25642189 PMCID: PMC4294126 DOI: 10.3389/fphar.2014.00295] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Accepted: 12/18/2014] [Indexed: 01/28/2023] Open
Abstract
Pregnancy can be defined as a “permissible” process, where a semi-allogeneic fetus and placenta are allowed to grow and survive within the mother. Similarly, in tumor growth, antigen-specific malignant cells proliferate and evade into normal tissues of the host. The microenvironments of the placenta and tumors are amazingly comparable, sharing similar mechanisms exploited by fetal or cancer cells with regard to surviving in a hypoxic microenvironment, invading tissues via degradation and vasculogenesis, and escaping host attack through immune privilege. Heme oxygease-1 (HO-1) is a stress-response protein that has antioxidative, anti-apoptotic, pro-angiogenic, and anti-inflammatory properties. Although a large volume of research has been published in recent years investigating the possible role(s) of HO-1 in pregnancy and in cancer development, the molecular mechanisms that regulate these “yin-yang” processes have still not been fully elucidated. Here, we summarize and compare pregnancy and cancer development, focusing primarily on the function of HO-1 in cellular invasion, cytoprotection, angiogenesis, and immunomodulation. Due to the similarities of both processes, a thorough understanding of the molecular mechanisms of each process may reveal and guide the development of new approaches to prevent not only pregnancy disorders; but also, to study cancer.
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Affiliation(s)
- Hui Zhao
- Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine Stanford, CA, USA
| | - Maide Ozen
- Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine Stanford, CA, USA
| | - Ronald J Wong
- Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine Stanford, CA, USA
| | - David K Stevenson
- Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine Stanford, CA, USA
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Schalper KA, Carvajal-Hausdorf D, Oyarzo MP. Possible role of hemichannels in cancer. Front Physiol 2014; 5:237. [PMID: 25018732 PMCID: PMC4073485 DOI: 10.3389/fphys.2014.00237] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Accepted: 06/09/2014] [Indexed: 12/12/2022] Open
Abstract
In humans, connexins (Cxs) and pannexins (Panxs) are the building blocks of hemichannels. These proteins are frequently altered in neoplastic cells and have traditionally been considered as tumor suppressors. Alteration of Cxs and Panxs in cancer cells can be due to genetic, epigenetic and post-transcriptional/post-translational events. Activated hemichannels mediate the diffusional membrane transport of ions and small signaling molecules. In the last decade hemichannels have been shown to participate in diverse cell processes including the modulation of cell proliferation and survival. However, their possible role in tumor growth and expansion remains largely unexplored. Herein, we hypothesize about the possible role of hemichannels in carcinogenesis and tumor progression. To support this theory, we summarize the evidence regarding the involvement of hemichannels in cell proliferation and migration, as well as their possible role in the anti-tumor immune responses. In addition, we discuss the evidence linking hemichannels with cancer in diverse models and comment on the current technical limitations for their study.
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Affiliation(s)
- Kurt A Schalper
- Servicio Anatomía Patológica, Clínica Alemana de Santiago, Facultad de Medicina Clinica Alemana Universidad del Desarrollo Santiago, Chile ; Department of Pathology, Yale School of Medicine New Haven, CT, USA
| | | | - Mauricio P Oyarzo
- Servicio Anatomía Patológica, Clínica Alemana de Santiago, Facultad de Medicina Clinica Alemana Universidad del Desarrollo Santiago, Chile
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Yang XQ, Xu YF, Guo S, Liu Y, Ning SL, Lu XF, Yang H, Chen YX. Clinical significance of nerve growth factor and tropomyosin-receptor-kinase signaling pathway in intrahepatic cholangiocarcinoma. World J Gastroenterol 2014; 20:4076-4084. [PMID: 24744599 PMCID: PMC3983466 DOI: 10.3748/wjg.v20.i14.4076] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 02/25/2014] [Accepted: 03/19/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the correlation between nerve growth factor-tropomyosin-receptor-kinase (NGF-TrkA) signaling pathway and prognosis in intrahepatic cholangiocarcinoma (IHCC).
METHODS: NGF and TrkA expression in 83 samples of IHCC was assessed by immunohistochemistry. Correlations between NGF-TrkA expression and clinicopathological features were analyzed by χ2 test. Moreover, we evaluated the association between NGF-TrkA and overall survival by univariate and multivariate analysis. With experiments in vitro, we investigated the crucial role of NGF-TrkA on proliferation and invasion of IHCC cells with recombinant NGF-β stimulation.
RESULTS: We found that NGF and TrkA expression was significantly related with differentiation (P = 0.024) and intraneural invasion (P = 0.003), respectively. Additionally, double higher expression of NGF and TrkA was identified as an independent prognostic factor in IHCC (P = 0.003). Moreover, we demonstrated that NGF-TrkA signaling pathway can promote IHCC proliferation and invasion.
CONCLUSION: NGF-TrkA double higher expression is an independent prognostic factor in IHCC. NGF-TrkA pathway can promote IHCC progression, indicating that NGF-TrkA may become a potential drug target.
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