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Yoshida Y, Takahashi M, Taniguchi S, Numakura R, Komine K, Ishioka C. Tretinoin synergistically enhances the antitumor effect of combined BRAF, MEK, and EGFR inhibition in BRAF V600E colorectal cancer. Cancer Sci 2024; 115:3740-3754. [PMID: 39175203 PMCID: PMC11531965 DOI: 10.1111/cas.16280] [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: 01/22/2024] [Revised: 06/27/2024] [Accepted: 06/28/2024] [Indexed: 08/24/2024] Open
Abstract
Patients with BRAF-mutated colorectal cancer (BRAFV600E CRC) are currently treated with a combination of BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor. A fundamental problem in treating patients with BRAFV600E CRC is intrinsic and/or acquired resistance to this combination therapy. By screening 78 compounds, we identified tretinoin, a retinoid, as a compound that synergistically enhances the antiproliferative effect of a combination of BRAF inhibition and MEK inhibition with or without EGFR inhibition on BRAFV600E CRC cells. This synergistic effect was also exerted by other retinoids. Tretinoin, added to BRAF inhibitor and MEK inhibitor, upregulated PARP, BAK, and p-H2AX. When either RARα or RXRα was silenced, the increase in cleaved PARP expression by the addition of TRE to ENC/BIN or ENC/BIN/CET was canceled. Our results suggest that the mechanism of the synergistic antiproliferative effect involves modulation of the Bcl-2 family and the DNA damage response that affects apoptotic pathways, and this synergistic effect is induced by RARα- or RXRα-mediated apoptosis. Tretinoin also enhanced the antitumor effect of a combination of the BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor in a BRAFV600E CRC xenograft mouse model. Our data provide a rationale for developing retinoids as a new combination agent to overcome resistance to the combination therapy for patients with BRAFV600E CRC.
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Affiliation(s)
- Yuya Yoshida
- Department of Clinical OncologyTohoku University Graduate School of MedicineSendaiMiyagiJapan
| | - Masanobu Takahashi
- Department of Clinical OncologyTohoku University Graduate School of MedicineSendaiMiyagiJapan
- Department of Medical OncologyTohoku University HospitalSendaiMiyagiJapan
| | - Sakura Taniguchi
- Department of Clinical OncologyTohoku University Graduate School of MedicineSendaiMiyagiJapan
| | - Ryunosuke Numakura
- Department of Clinical OncologyTohoku University Graduate School of MedicineSendaiMiyagiJapan
| | - Keigo Komine
- Department of Medical OncologyTohoku University HospitalSendaiMiyagiJapan
| | - Chikashi Ishioka
- Department of Clinical OncologyTohoku University Graduate School of MedicineSendaiMiyagiJapan
- Department of Medical OncologyTohoku University HospitalSendaiMiyagiJapan
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Masci D, Puxeddu M, Silvestri R, La Regina G. Targeting CBP and p300: Emerging Anticancer Agents. Molecules 2024; 29:4524. [PMID: 39407454 PMCID: PMC11482477 DOI: 10.3390/molecules29194524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/22/2024] [Accepted: 09/23/2024] [Indexed: 10/19/2024] Open
Abstract
CBP and p300 are versatile transcriptional co-activators that play essential roles in regulating a wide range of signaling pathways, including Wnt/β-catenin, p53, and HIF-1α. These co-activators influence various cellular processes such as proliferation, differentiation, apoptosis, and response to hypoxia, making them pivotal in normal physiology and disease progression. The Wnt/β-catenin signaling pathway, in particular, is crucial for cellular proliferation, differentiation, tissue homeostasis, and embryogenesis. Aberrant activation of this pathway is often associated with several types of cancer, such as colorectal tumor, prostate cancer, pancreatic and hepatocellular carcinomas. In recent years, significant efforts have been directed toward identifying and developing small molecules as novel anticancer agents capable of specifically inhibiting the interaction between β-catenin and the transcriptional co-activators CBP and p300, which are required for Wnt target gene expression and are consequently involved in the regulation of tumor cell proliferation, migration, and invasion. This review summarizes the most significant and original research articles published from 2010 to date, found by means of a PubMed search, highlighting recent advancements in developing both specific and non-specific inhibitors of CBP/β-catenin and p300/β-catenin interactions. For a more comprehensive view, we have also explored the therapeutic potential of CBP/p300 bromodomain and histone acetyltransferase inhibitors in disrupting the transcriptional activation of genes involved in various signaling pathways related to cancer progression. By focusing on these therapeutic strategies, this review aims to offer a detailed overview of recent approaches in cancer treatment that selectively target CBP and p300, with particular emphasis on their roles in Wnt/β-catenin-driven oncogenesis.
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Affiliation(s)
- Domiziana Masci
- Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy;
| | - Michela Puxeddu
- Laboratory Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (M.P.); (R.S.)
| | - Romano Silvestri
- Laboratory Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (M.P.); (R.S.)
| | - Giuseppe La Regina
- Laboratory Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (M.P.); (R.S.)
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Manickasamy MK, Jayaprakash S, Girisa S, Kumar A, Lam HY, Okina E, Eng H, Alqahtani MS, Abbas M, Sethi G, Kumar AP, Kunnumakkara AB. Delineating the role of nuclear receptors in colorectal cancer, a focused review. Discov Oncol 2024; 15:41. [PMID: 38372868 PMCID: PMC10876515 DOI: 10.1007/s12672-023-00808-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Accepted: 10/20/2023] [Indexed: 02/20/2024] Open
Abstract
Colorectal cancer (CRC) stands as one of the most prevalent form of cancer globally, causing a significant number of deaths, surpassing 0.9 million in the year 2020. According to GLOBOCAN 2020, CRC ranks third in incidence and second in mortality in both males and females. Despite extensive studies over the years, there is still a need to establish novel therapeutic targets to enhance the patients' survival rate in CRC. Nuclear receptors (NRs) are ligand-activated transcription factors (TFs) that regulate numerous essential biological processes such as differentiation, development, physiology, reproduction, and cellular metabolism. Dysregulation and anomalous expression of different NRs has led to multiple alterations, such as impaired signaling cascades, mutations, and epigenetic changes, leading to various diseases, including cancer. It has been observed that differential expression of various NRs might lead to the initiation and progression of CRC, and are correlated with poor survival outcomes in CRC patients. Despite numerous studies on the mechanism and role of NRs in this cancer, it remains of significant scientific interest primarily due to the diverse functions that various NRs exhibit in regulating key hallmarks of this cancer. Thus, modulating the expression of NRs with their agonists and antagonists, based on their expression levels, holds an immense prospect in the diagnosis, prognosis, and therapeutical modalities of CRC. In this review, we primarily focus on the role and mechanism of NRs in the pathogenesis of CRC and emphasized the significance of targeting these NRs using a variety of agents, which may represent a novel and effective strategy for the prevention and treatment of this cancer.
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Affiliation(s)
- Mukesh Kumar Manickasamy
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Sujitha Jayaprakash
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Aviral Kumar
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Hiu Yan Lam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Queenstown, 117600, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Queenstown, 117699, Singapore
| | - Elena Okina
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Queenstown, 117600, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Queenstown, 117699, Singapore
| | - Huiyan Eng
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Queenstown, 117600, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Queenstown, 117699, Singapore
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, 61421, Abha, Saudi Arabia
- BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester, LE1 7RH, UK
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, 61421, Abha, Saudi Arabia
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Queenstown, 117600, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Queenstown, 117699, Singapore
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Queenstown, 117600, Singapore.
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Queenstown, 117699, Singapore.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India.
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Kahn M. Taking the road less traveled - the therapeutic potential of CBP/β-catenin antagonists. Expert Opin Ther Targets 2021; 25:701-719. [PMID: 34633266 PMCID: PMC8745629 DOI: 10.1080/14728222.2021.1992386] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 10/08/2021] [Indexed: 10/20/2022]
Abstract
AREAS COVERED This perspective discusses the challenges of targeting the Wnt signaling cascade, the safety, efficacy, and therapeutic potential of specific CBP/β-catenin antagonists and a rationale for the pleiotropic effects of CBP/β-catenin antagonists beyond Wnt signaling. EXPERT OPINION CBP/β-catenin antagonists can correct lineage infidelity, enhance wound healing, both normal and aberrant (e.g. fibrosis) and force the differentiation and lineage commitment of stem cells and cancer stem cells by regulating enhancer and super-enhancer coactivator occupancy. Small molecule CBP/β-catenin antagonists rebalance the equilibrium between CBP/β-catenin versus p300/β-catenin dependent transcription and may be able to treat or prevent many diseases of aging, via maintenance of our somatic stem cell pool, and regulating mitochondrial function and metabolism involved in differentiation and immune cell function.
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Affiliation(s)
- Michael Kahn
- Department of Molecular Medicine, City of Hope, Beckman Research Institute, 1500 East Duarte Road Flower Building, Duarte, CA, USA
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Lai KKY, Hu X, Chosa K, Nguyen C, Lin DP, Lai KK, Kato N, Higuchi Y, Highlander SK, Melendez E, Eriguchi Y, Fueger PT, Ouellette AJ, Chimge NO, Ono M, Kahn M. p300 Serine 89: A Critical Signaling Integrator and Its Effects on Intestinal Homeostasis and Repair. Cancers (Basel) 2021; 13:cancers13061288. [PMID: 33799418 PMCID: PMC7999107 DOI: 10.3390/cancers13061288] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 03/07/2021] [Accepted: 03/10/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Given their high degree of identity and even greater similarity at the amino acid level, Kat3 coactivators, CBP (Kat3A) and p300 (Kat3B), have long been considered redundant. We describe the generation of novel p300 S89A knock-in mice carrying a single site directed amino acid mutation in p300, changing the highly evolutionarily conserved serine 89 to alanine, thus enhancing Wnt/CBP/catenin signaling (at the expense of Wnt/p300/catenin signaling). p300 S89A knock-in mice exhibit multiple organ system, immunologic and metabolic differences, compared with their wild type counterparts. In particular, these p300 S89A knock-in mice are highly sensitive to intestinal injury resulting in colitis which is known to significantly predispose to colorectal cancer. Our results highlight the critical role of this region in p300 as a signaling nexus and provide further evidence that p300 and CBP are non-redundant, playing definite and distinctive roles in development and disease. Abstract Differential usage of Kat3 coactivators, CBP and p300, by β-catenin is a fundamental regulatory mechanism in stem cell maintenance and initiation of differentiation and repair. Based upon our earlier pharmacologic studies, p300 serine 89 (S89) is critical for controlling differential coactivator usage by β-catenin via post-translational phosphorylation in stem/progenitor populations, and appears to be a target for a number of kinase cascades. To further investigate mechanisms of signal integration effected by this domain, we generated p300 S89A knock-in mice. We show that S89A mice are extremely sensitive to intestinal insult resulting in colitis, which is known to significantly increase the risk of developing colorectal cancer. We demonstrate cell intrinsic differences, and microbiome compositional differences and differential immune responses, in intestine of S89A versus wild type mice. Genomic and proteomic analyses reveal pathway differences, including lipid metabolism, oxidative stress response, mitochondrial function and oxidative phosphorylation. The diverse effects on fundamental processes including epithelial differentiation, metabolism, immune response and microbiome colonization, all brought about by a single amino acid modification S89A, highlights the critical role of this region in p300 as a signaling nexus and the rationale for conservation of this residue and surrounding region for hundreds of million years of vertebrate evolution.
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Affiliation(s)
- Keane K. Y. Lai
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; (K.K.Y.L.); (X.H.); (K.C.); (C.N.); (D.P.L.); (Y.H.); (E.M.); (N.-O.C.)
- City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;
| | - Xiaohui Hu
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; (K.K.Y.L.); (X.H.); (K.C.); (C.N.); (D.P.L.); (Y.H.); (E.M.); (N.-O.C.)
| | - Keisuke Chosa
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; (K.K.Y.L.); (X.H.); (K.C.); (C.N.); (D.P.L.); (Y.H.); (E.M.); (N.-O.C.)
| | - Cu Nguyen
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; (K.K.Y.L.); (X.H.); (K.C.); (C.N.); (D.P.L.); (Y.H.); (E.M.); (N.-O.C.)
| | - David P. Lin
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; (K.K.Y.L.); (X.H.); (K.C.); (C.N.); (D.P.L.); (Y.H.); (E.M.); (N.-O.C.)
| | - Keith K. Lai
- Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH 44195, USA;
| | - Nobuo Kato
- The Institute of Scientific and Industrial Research, Osaka University, Osaka 567-0047, Japan;
| | - Yusuke Higuchi
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; (K.K.Y.L.); (X.H.); (K.C.); (C.N.); (D.P.L.); (Y.H.); (E.M.); (N.-O.C.)
| | - Sarah K. Highlander
- Clinical Microbiome Service Center and Pathogen and Microbiome Division, Translational Genomics Research Institute, Flagstaff, AZ 86005, USA;
| | - Elizabeth Melendez
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; (K.K.Y.L.); (X.H.); (K.C.); (C.N.); (D.P.L.); (Y.H.); (E.M.); (N.-O.C.)
| | - Yoshihiro Eriguchi
- Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; (Y.E.); (A.J.O.)
| | - Patrick T. Fueger
- City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;
- Department of Molecular and Cellular Endocrinology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Andre J. Ouellette
- Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; (Y.E.); (A.J.O.)
- USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Nyam-Osor Chimge
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; (K.K.Y.L.); (X.H.); (K.C.); (C.N.); (D.P.L.); (Y.H.); (E.M.); (N.-O.C.)
| | - Masaya Ono
- Department of Clinical Proteomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan;
| | - Michael Kahn
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; (K.K.Y.L.); (X.H.); (K.C.); (C.N.); (D.P.L.); (Y.H.); (E.M.); (N.-O.C.)
- City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;
- USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Correspondence:
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Kasprzak A. Angiogenesis-Related Functions of Wnt Signaling in Colorectal Carcinogenesis. Cancers (Basel) 2020; 12:cancers12123601. [PMID: 33276489 PMCID: PMC7761462 DOI: 10.3390/cancers12123601] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/29/2020] [Accepted: 12/01/2020] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Angiogenesis belongs to the most clinical characteristics of colorectal cancer (CRC) and is strongly linked to the activation of Wnt/β-catenin signaling. The most prominent factors stimulating constitutive activation of this pathway, and in consequence angiogenesis, are genetic alterations (mainly mutations) concerning APC and the β-catenin encoding gene (CTNNB1), detected in a large majority of CRC patients. Wnt/β-catenin signaling is involved in the basic types of vascularization (sprouting and nonsprouting angiogenesis), vasculogenic mimicry as well as the formation of mosaic vessels. The number of known Wnt/β-catenin signaling components and other pathways interacting with Wnt signaling, regulating angiogenesis, and enabling CRC progression continuously increases. This review summarizes the current knowledge about the role of the Wnt/Fzd/β-catenin signaling pathway in the process of CRC angiogenesis, aiming to improve the understanding of the mechanisms of metastasis as well as improvements in the management of this cancer. Abstract Aberrant activation of the Wnt/Fzd/β-catenin signaling pathway is one of the major molecular mechanisms of colorectal cancer (CRC) development and progression. On the other hand, one of the most common clinical CRC characteristics include high levels of angiogenesis, which is a key event in cancer cell dissemination and distant metastasis. The canonical Wnt/β-catenin downstream signaling regulates the most important pro-angiogenic molecules including vascular endothelial growth factor (VEGF) family members, matrix metalloproteinases (MMPs), and chemokines. Furthermore, mutations of the β-catenin gene associated with nuclear localization of the protein have been mainly detected in microsatellite unstable CRC. Elevated nuclear β-catenin increases the expression of many genes involved in tumor angiogenesis. Factors regulating angiogenesis with the participation of Wnt/β-catenin signaling include different groups of biologically active molecules including Wnt pathway components (e.g., Wnt2, DKK, BCL9 proteins), and non-Wnt pathway factors (e.g., chemoattractant cytokines, enzymatic proteins, and bioactive compounds of plants). Several lines of evidence argue for the use of angiogenesis inhibition in the treatment of CRC. In the context of this paper, components of the Wnt pathway are among the most promising targets for CRC therapy. This review summarizes the current knowledge about the role of the Wnt/Fzd/β-catenin signaling pathway in the process of CRC angiogenesis, aiming to improve the understanding of the mechanisms of metastasis as well as improvements in the management of this cancer.
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Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, Poznan University of Medical Sciences, Swiecicki Street 6, 60-781 Poznań, Poland
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Costantini L, Molinari R, Farinon B, Merendino N. Retinoic Acids in the Treatment of Most Lethal Solid Cancers. J Clin Med 2020; 9:E360. [PMID: 32012980 PMCID: PMC7073976 DOI: 10.3390/jcm9020360] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 01/21/2020] [Accepted: 01/24/2020] [Indexed: 12/14/2022] Open
Abstract
Although the use of oral administration of pharmacological all-trans retinoic acid (ATRA) concentration in acute promyelocytic leukaemia (APL) patients was approved for over 20 years and used as standard therapy still to date, the same use in solid cancers is still controversial. In the present review the literature about the top five lethal solid cancers (lung, stomach, liver, breast, and colon cancer), as defined by The Global Cancer Observatory of World Health Organization, and retinoic acids (ATRA, 9-cis retinoic acid, and 13-cis retinoic acid, RA) was compared. The action of retinoic acids in inhibiting the cell proliferation was found in several cell pathways and compartments: from membrane and cytoplasmic signaling, to metabolic enzymes, to gene expression. However, in parallel in the most aggressive phenotypes several escape routes have evolved conferring retinoic acids-resistance. The comparison between different solid cancer types pointed out that for some cancer types several information are still lacking. Moreover, even though some pathways and escape routes are the same between the cancer types, sometimes they can differently respond to retinoic acid therapy, so that generalization cannot be made. Further studies on molecular pathways are needed to perform combinatorial trials that allow overcoming retinoic acids resistance.
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Affiliation(s)
- Lara Costantini
- Department of Ecological and Biological Sciences (DEB), Tuscia University, Largo dell’Università snc, 01100 Viterbo, Italy
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Bild A, Teo JL, Kahn M. Enhanced Kat3A/Catenin transcription: a common mechanism of therapeutic resistance. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2019; 2:917-932. [PMID: 32426696 PMCID: PMC7234864 DOI: 10.20517/cdr.2019.32] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 06/04/2019] [Accepted: 06/18/2019] [Indexed: 11/12/2022]
Abstract
Cancers are heterogeneous at the cellular level. Cancer stem cells/tumor initiating cells (CSC/TIC) both initiate tumorigenesis and are responsible for therapeutic resistance and disease relapse. Elimination of CSC/TIC should therefore be able to reverse therapy resistance. In principle, this could be accomplished by either targeting cancer stem cell surface markers or "stemness" pathways. Although the successful therapeutic elimination of "cancer stemness" is a critical goal, it is complex in that it should be achieved without depletion of or increases in somatic mutations in normal tissue stem cell populations. In this perspective, we will discuss the prospects for this goal via pharmacologically targeting differential Kat3 coactivator/Catenin usage, a fundamental transcriptional control mechanism in stem cell biology.
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Affiliation(s)
- Andrea Bild
- Department of Medical Oncology & Therapeutics Research, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA
| | - Jia-Ling Teo
- Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA
| | - Michael Kahn
- Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA
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Ono M, Lai KKY, Wu K, Nguyen C, Lin DP, Murali R, Kahn M. Nuclear receptor/Wnt beta-catenin interactions are regulated via differential CBP/p300 coactivator usage. PLoS One 2018; 13:e0200714. [PMID: 30020971 PMCID: PMC6051640 DOI: 10.1371/journal.pone.0200714] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 07/02/2018] [Indexed: 12/26/2022] Open
Abstract
Over 400 million years ago, the evolution of vertebrates gave rise to a life cycle in which the organism began to live longer particularly as an adult. To accommodate such a longer lifespan, the organism underwent adaptation, developing a mechanism for long-lived cellular homeostasis. This adaptation required a population of long-lived relatively quiescent somatic stem cells (SSCs) along with a more proliferative differentiated daughter cell population, and was necessary to safeguard the genetic attributes with which SSCs were endowed. Intriguingly, cAMP response element binding protein (CREB)-binding protein (CBP) and E1A-binding protein, 300 kDa (p300), the highly homologous Kat3 coactivators had diverged, through duplication of ancestral Kat3, immediately preceding the evolution of vertebrates, given that both CBP and p300 have been detected in nearly all vertebrates versus non-vertebrates. We now demonstrate that a relatively small, highly evolutionarily conserved, amino terminal 9 amino acid deletion in CBP versus p300, plays a critical role in allowing for both robust maintenance of genomic integrity in stem cells and the initiation of a feed-forward differentiation mechanism by tightly controlling the interaction of the nuclear receptor family with the Wnt signaling cascade in either an antagonistic or synergistic manner.
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Affiliation(s)
- Masaya Ono
- Department of Clinical Proteomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Keane K. Y. Lai
- Department of Pathology, Beckman Research Institute, City of Hope, Duarte, CA, United States of America
- Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA, United States of America
- Department of Pathology and Southern California Research Center for ALPD and Cirrhosis, University of Southern California, Los Angeles, CA, United States of America
| | - Kaijin Wu
- Center for Molecular Pathways and Drug Discovery, University of Southern California, Los Angeles, CA, United States of America
- Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, United States of America
| | - Cu Nguyen
- Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA, United States of America
- Center for Molecular Pathways and Drug Discovery, University of Southern California, Los Angeles, CA, United States of America
| | - David P. Lin
- Department of Pathology and Southern California Research Center for ALPD and Cirrhosis, University of Southern California, Los Angeles, CA, United States of America
| | - Ramachandran Murali
- Department of Biomedical Sciences, Research Division of Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America
| | - Michael Kahn
- Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA, United States of America
- Center for Molecular Pathways and Drug Discovery, University of Southern California, Los Angeles, CA, United States of America
- Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, United States of America
- Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, United States of America
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States of America
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Kahn M. Wnt Signaling in Stem Cells and Cancer Stem Cells: A Tale of Two Coactivators. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2018; 153:209-244. [PMID: 29389517 DOI: 10.1016/bs.pmbts.2017.11.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Wnt signaling in stem cells plays critical roles in development, normal adult physiology, and disease. In this chapter, we focus on the role of the Wnt signaling pathway in somatic stem cell biology and its critical role in normal tissue homeostasis and cancer. Wnt signaling can both maintain potency and initiate differentiation in somatic stem cells, depending on the cellular and environmental context. Based principally on studies from our lab, we will explain the dichotomous behavior of this signaling pathway in determining stem cell fate decisions, placing special emphasis on the interaction of β-catenin with either of the two highly homologous Kat3 coactivator proteins, CBP and p300. We will also discuss our results, both preclinical and clinical, demonstrating that small molecule modulators of the β-catenin/Kat3 coactivator interaction can be safely utilized to shift the balance between maintenance of potency and initiation of differentiation.
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Affiliation(s)
- Michael Kahn
- Beckman Research Institute of the City of Hope, Duarte, CA, United States.
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Kim YM, Gang EJ, Kahn M. CBP/Catenin antagonists: Targeting LSCs' Achilles heel. Exp Hematol 2017; 52:1-11. [PMID: 28479420 PMCID: PMC5526056 DOI: 10.1016/j.exphem.2017.04.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 04/07/2017] [Accepted: 04/20/2017] [Indexed: 12/18/2022]
Abstract
Cancer stem cells (CSCs), including leukemia stem cells (LSCs), exhibit self-renewal capacity and differentiation potential and have the capacity to maintain or renew and propagate a tumor/leukemia. The initial isolation of CSCs/LSCs was in adult myelogenous leukemia, although more recently, the existence of CSCs in a wide variety of other cancers has been reported. CSCs, in general, and LSCs, specifically with respect to this review, are responsible for initiation of disease, therapeutic resistance and ultimately disease relapse. One key focus in cancer research over the past decade has been the development of therapies that safely eliminate the LSC/CSC population. One major obstacle to this goal is the identification of key mechanisms that distinguish LSCs from normal endogenous hematopoietic stem cells. An additional daunting feature that has recently come to light with advances in next-generation sequencing and single-cell sequencing is the heterogeneity within leukemias/tumors, with multiple combinations of mutations, gain and loss of function of genes, and so on being capable of driving disease, even within the CSC/LSC population. The focus of this review/perspective is on our work in identifying and validating, in both chronic myelogenous leukemia and acute lymphoblastic leukemia, a safe and efficacious mechanism to target an evolutionarily conserved signaling nexus, which constitutes a common "Achilles heel" for LSCs/CSCs, using small molecule-specific CBP/catenin antagonists.
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Affiliation(s)
- Yong-Mi Kim
- Children's Hospital Los Angeles, Department of Pediatrics, Division of Blood and Bone Marrow Transplantation, University of Southern California, Los Angeles, CA
| | - Eun-Ji Gang
- Children's Hospital Los Angeles, Department of Pediatrics, Division of Blood and Bone Marrow Transplantation, University of Southern California, Los Angeles, CA
| | - Michael Kahn
- Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA; Department of Molecular Pharmacology and Toxicology, University of Southern California, Los Angeles, CA; Center for Molecular Pathways and Drug Discovery, University of Southern California, Los Angeles, CA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA.
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Tafrihi M, Nakhaei Sistani R. E-Cadherin/β-Catenin Complex: A Target for Anticancer and Antimetastasis Plants/Plant-derived Compounds. Nutr Cancer 2017; 69:702-722. [PMID: 28524727 DOI: 10.1080/01635581.2017.1320415] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Plants reputed to have cancer-inhibiting potential and putative active components derived from those plants have emerged as an exciting new field in cancer study. Some of these compounds have cancer-inhibiting potential in different clinical staging levels, especially metastasis. A few of them which stabilize cell-cell adhesions are controversial topics. This review article introduces some effective herbal compounds that target E-cadherin/β-catenin protein complex. In this article, at first, we briefly review the structure and function of E-cadherin and β-catenin proteins, Wnt signaling pathway, and its target genes. Then, effective compounds of the Teucrium persicum, Teucrium polium, Allium sativum (garlic), Glycine max (soy), and Brassica oleracea (broccoli) plants, which influence stability and cellular localization of E-cadherin/β-catenin complex, were studied. Based on literature review, there are some compounds in these plants, including genistein of soy, sulforaphane of broccoli, organosulfur compounds of garlic, and the total extract of Teucrium genus that change the expression of variety of Wnt target genes such as MMPs, E-cadherin, p21, p53, c-myc, and cyclin D1. So they may induce cell-cycle arrest, apoptosis and/or inhibition of Epithelial-Mesenchymal Transition (EMT) and metastasis.
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Affiliation(s)
- Majid Tafrihi
- a Molecular and Cell Biology Research Laboratory, Department of Molecular and Cell Biology, Faculty of Basic Sciences , University of Mazandaran , Babolsar , Mazandaran , Iran
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Christensen LL, True K, Hamilton MP, Nielsen MM, Damas ND, Damgaard CK, Ongen H, Dermitzakis E, Bramsen JB, Pedersen JS, Lund AH, Vang S, Stribolt K, Madsen MR, Laurberg S, McGuire SE, Ørntoft TF, Andersen CL. SNHG16 is regulated by the Wnt pathway in colorectal cancer and affects genes involved in lipid metabolism. Mol Oncol 2016; 10:1266-82. [PMID: 27396952 PMCID: PMC5423192 DOI: 10.1016/j.molonc.2016.06.003] [Citation(s) in RCA: 147] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 05/02/2016] [Accepted: 06/17/2016] [Indexed: 02/07/2023] Open
Abstract
It is well established that lncRNAs are aberrantly expressed in cancer where they have been shown to act as oncogenes or tumor suppressors. RNA profiling of 314 colorectal adenomas/adenocarcinomas and 292 adjacent normal colon mucosa samples using RNA-sequencing demonstrated that the snoRNA host gene 16 (SNHG16) is significantly up-regulated in adenomas and all stages of CRC. SNHG16 expression was positively correlated to the expression of Wnt-regulated transcription factors, including ASCL2, ETS2, and c-Myc. In vitro abrogation of Wnt signaling in CRC cells reduced the expression of SNHG16 indicating that SNHG16 is regulated by the Wnt pathway. Silencing of SNHG16 resulted in reduced viability, increased apoptotic cell death and impaired cell migration. The SNHG16 silencing particularly affected expression of genes involved in lipid metabolism. A connection between SNHG16 and genes involved in lipid metabolism was also observed in clinical tumors. Argonaute CrossLinking and ImmunoPrecipitation (AGO-CLIP) demonstrated that SNHG16 heavily binds AGO and has 27 AGO/miRNA target sites along its length, indicating that SNHG16 may act as a competing endogenous RNA (ceRNA) "sponging" miRNAs off their cognate targets. Most interestingly, half of the miRNA families with high confidence targets on SNHG16 also target the 3'UTR of Stearoyl-CoA Desaturase (SCD). SCD is involved in lipid metabolism and is down-regulated upon SNHG16 silencing. In conclusion, up-regulation of SNHG16 is a frequent event in CRC, likely caused by deregulated Wnt signaling. In vitro analyses demonstrate that SNHG16 may play an oncogenic role in CRC and that it affects genes involved in lipid metabolism, possible through ceRNA related mechanisms.
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Affiliation(s)
- Lise Lotte Christensen
- Department of Molecular Medicine (MOMA), Aarhus University Hospital, University of Aarhus, Aarhus, Denmark.
| | - Kirsten True
- Department of Molecular Medicine (MOMA), Aarhus University Hospital, University of Aarhus, Aarhus, Denmark.
| | - Mark P Hamilton
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
| | - Morten M Nielsen
- Department of Molecular Medicine (MOMA), Aarhus University Hospital, University of Aarhus, Aarhus, Denmark.
| | - Nkerorema D Damas
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
| | | | - Halit Ongen
- Department of Genetic Medicine and Development, Functional Population Genomics and Genetics of Complex Traits Lab, University of Geneva Medical School, Geneva, Switzerland.
| | - Emmanouil Dermitzakis
- Department of Genetic Medicine and Development, Functional Population Genomics and Genetics of Complex Traits Lab, University of Geneva Medical School, Geneva, Switzerland.
| | - Jesper B Bramsen
- Department of Molecular Medicine (MOMA), Aarhus University Hospital, University of Aarhus, Aarhus, Denmark.
| | - Jakob S Pedersen
- Department of Molecular Medicine (MOMA), Aarhus University Hospital, University of Aarhus, Aarhus, Denmark.
| | - Anders H Lund
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
| | - Søren Vang
- Department of Molecular Medicine (MOMA), Aarhus University Hospital, University of Aarhus, Aarhus, Denmark.
| | - Katrine Stribolt
- Department of Pathology, Aarhus University Hospital, University of Aarhus, Aarhus, Denmark.
| | - Mogens R Madsen
- Surgical Research Unit, Herning Regional Hospital, Herning, Denmark.
| | - Søren Laurberg
- Department of Surgery, Aarhus University Hospital, University of Aarhus, Aarhus, Denmark.
| | - Sean E McGuire
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA; Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Torben F Ørntoft
- Department of Molecular Medicine (MOMA), Aarhus University Hospital, University of Aarhus, Aarhus, Denmark.
| | - Claus L Andersen
- Department of Molecular Medicine (MOMA), Aarhus University Hospital, University of Aarhus, Aarhus, Denmark.
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Matsumoto T, Mochizuki W, Nibe Y, Akiyama S, Matsumoto Y, Nozaki K, Fukuda M, Hayashi A, Mizutani T, Oshima S, Watanabe M, Nakamura T. Retinol Promotes In Vitro Growth of Proximal Colon Organoids through a Retinoic Acid-Independent Mechanism. PLoS One 2016; 11:e0162049. [PMID: 27564706 PMCID: PMC5001647 DOI: 10.1371/journal.pone.0162049] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 08/16/2016] [Indexed: 01/21/2023] Open
Abstract
Retinol (ROL), the alcohol form of vitamin A, is known to control cell fate decision of various types of stem cells in the form of its active metabolite, retinoic acid (RA). However, little is known about whether ROL has regulatory effects on colonic stem cells. We examined in this study the effect of ROL on the growth of murine normal colonic cells cultured as organoids. As genes involved in RA synthesis from ROL were differentially expressed along the length of the colon, we tested the effect of ROL on proximal and distal colon organoids separately. We found that organoid forming efficiency and the expression level of Lgr5, a marker gene for colonic stem cells were significantly enhanced by ROL in the proximal colon organoids, but not in the distal ones. Interestingly, neither retinaldehyde (RAL), an intermediate product of the ROL-RA pathway, nor RA exhibited growth promoting effects on the proximal colon organoids, suggesting that ROL-dependent growth enhancement in organoids involves an RA-independent mechanism. This was confirmed by the observation that an inhibitor for RA-mediated gene transcription did not abrogate the effect of ROL on organoids. This novel role of ROL in stem cell maintenance in the proximal colon provides insights into the mechanism of region-specific regulation for colonic stem cell maintenance.
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Affiliation(s)
- Taichi Matsumoto
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113–8519, Japan
| | - Wakana Mochizuki
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113–8519, Japan
| | - Yoichi Nibe
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113–8519, Japan
| | - Shintaro Akiyama
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113–8519, Japan
| | - Yuka Matsumoto
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113–8519, Japan
| | - Kengo Nozaki
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113–8519, Japan
| | - Masayoshi Fukuda
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113–8519, Japan
| | - Ayumi Hayashi
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113–8519, Japan
| | - Tomohiro Mizutani
- Department of Advanced Therapeutics for GI Diseases, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113–8519, Japan
| | - Shigeru Oshima
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113–8519, Japan
| | - Mamoru Watanabe
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113–8519, Japan
| | - Tetsuya Nakamura
- Department of Advanced Therapeutics for GI Diseases, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113–8519, Japan
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Rudzinski WE, Palacios A, Ahmed A, Lane MA, Aminabhavi TM. Targeted delivery of small interfering RNA to colon cancer cells using chitosan and PEGylated chitosan nanoparticles. Carbohydr Polym 2016; 147:323-332. [PMID: 27178938 DOI: 10.1016/j.carbpol.2016.04.041] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Revised: 03/29/2016] [Accepted: 04/09/2016] [Indexed: 12/13/2022]
Abstract
Small interfering RNA (siRNA) molecules specifically target messenger RNA species, decreasing intracellular protein levels. β-Catenin protein concentrations are increased in 70-80% of colon tumors, promoting tumor progression. Chitosan exhibits low levels of toxicity and can be transported across mucosal membranes; therefore, our objective was to develop chitosan and poly(ethylene glycol)-grafted (PEGylated) chitosan nanoparticles, 100-150nm in diameter, encapsulating anti-β-catenin siRNA for transfection into colon cancer cells. Encapsulation efficiencies up to 97% were observed. Confocal microscopy visualized the entry of fluorescently-tagged siRNA into cells. Western blot analysis showed that both chitosan and PEGylated chitosan nanoparticles containing anti-β-catenin siRNA decreased β-catenin protein levels in cultured colon cancer cells. These results indicate that nanoparticles made with chitosan and PEGylated chitosan can successfully enter colon cancer cells and decrease the level of a protein that promotes tumor progression. These or similar nanoparticles may prove beneficial for the treatment of colon cancer in humans.
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Affiliation(s)
- Walter E Rudzinski
- Texas State University, Department of Chemistry and Biochemistry, San Marcos, TX 78666, USA.
| | - Adriana Palacios
- Texas State University, Department of Chemistry and Biochemistry, San Marcos, TX 78666, USA.
| | - Abuzar Ahmed
- Texas State University, Department of Chemistry and Biochemistry, San Marcos, TX 78666, USA.
| | - Michelle A Lane
- Texas State University, School of Family and Consumer Sciences, Nutrition and Foods Program, San Marcos, TX 78666, USA.
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Thomas PD, Kahn M. Kat3 coactivators in somatic stem cells and cancer stem cells: biological roles, evolution, and pharmacologic manipulation. Cell Biol Toxicol 2016; 32:61-81. [PMID: 27008332 PMCID: PMC7458431 DOI: 10.1007/s10565-016-9318-0] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 03/15/2016] [Indexed: 12/18/2022]
Abstract
Long-lived somatic stem cells regenerate adult tissues throughout our lifetime. However, with aging, there is a significant deterioration in the function of stem and progenitor cells, which contribute to diseases of aging. The decision for a long-lived somatic stem cell to become activated and subsequently to undergo either a symmetric or an asymmetric division is a critical cellular decision process. The decision to preferentially divide symmetrically or asymmetrically may be the major fundamental intrinsic difference between normal somatic stem cells and cancer stem cells. Based upon work done primarily in our laboratory over the past 15 years, this article provides a perspective on the critical role of somatic stem cells in aging. In particular, we discuss the importance of symmetric versus asymmetric divisions in somatic stem cells and the role of the differential usage of the highly similar Kat3 coactivators, CREB-binding protein (CBP) and p300, in stem cells. We describe and propose a more complete model for the biological mechanism and roles of these two coactivators, their evolution, and unique roles and importance in stem cell biology. Finally, we discuss the potential to pharmacologically manipulate Kat3 coactivator interactions in endogenous stem cells (both normal and cancer stem cells) to potentially ameliorate the aging process and common diseases of aging.
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Affiliation(s)
- Paul D Thomas
- Division of Bioinformatics, Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, 1450 Biggy Street, NRT 2501, Los Angeles, CA, 90033, USA
| | - Michael Kahn
- USC Center for Molecular Pathways and Drug Discovery, USC Norris Comprehensive Cancer Center, 1450 Biggy Street, NRT 4501, Los Angeles, CA, 90033, USA.
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17
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Applegate CC, Lane MA. Role of retinoids in the prevention and treatment of colorectal cancer. World J Gastrointest Oncol 2015; 7:184-203. [PMID: 26483874 PMCID: PMC4606174 DOI: 10.4251/wjgo.v7.i10.184] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 07/10/2015] [Accepted: 09/16/2015] [Indexed: 02/05/2023] Open
Abstract
Vitamin A and its derivatives, retinoids, have been widely studied for their use as cancer chemotherapeutic agents. With respect to colorectal cancer (CRC), several critical mutations dysregulate pathways implicated in progression and metastasis, resulting in aberrant Wnt/β-catenin signaling, gain-of-function mutations in K-ras and phosphatidylinositol-3-kinase/Akt, cyclooxygenase-2 over-expression, reduction of peroxisome proliferator-activated receptor γ activation, and loss of p53 function. Dysregulation leads to increased cellular proliferation and invasion and decreased cell-cell interaction and differentiation. Retinoids affect these pathways by various mechanisms, many involving retinoic acid receptors (RAR). RAR bind to all-trans-retinoic acid (ATRA) to induce the transcription of genes responsible for cellular differentiation. Although most research concerning the chemotherapeutic efficacy of retinoids focuses on the ability of ATRA to decrease cancer cell proliferation, increase differentiation, or promote apoptosis; as CRC progresses, RAR expression is often lost, rendering treatment of CRCs with ATRA ineffective. Our laboratory focuses on the ability of dietary vitamin A to decrease CRC cell proliferation and invasion via RAR-independent pathways. This review discusses our research and others concerning the ability of retinoids to ameliorate the defective signaling pathways listed above and decrease tumor cell proliferation and invasion through both RAR-dependent and RAR-independent mechanisms.
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Song L, Li Y, He B, Gong Y. Development of Small Molecules Targeting the Wnt Signaling Pathway in Cancer Stem Cells for the Treatment of Colorectal Cancer. Clin Colorectal Cancer 2015; 14:133-145. [PMID: 25799881 DOI: 10.1016/j.clcc.2015.02.001] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Revised: 01/13/2015] [Accepted: 02/06/2015] [Indexed: 12/15/2022]
Abstract
Colorectal cancer (CRC) was ranked third in morbidity and mortality in the United States in 2013. Although substantial progress has been made in surgical techniques and postoperative chemotherapy in recent years, the prognosis for colon cancer is still not satisfactory, mainly because of cancer recurrence and metastasis. The latest studies have shown that cancer stem cells (CSCs) play important roles in cancer recurrence and metastasis. Drugs that target CSCs might therefore have great therapeutic potential in prevention of cancer recurrence and metastasis. The wingless-int (Wnt) signaling pathway in CSCs has been suggested to play crucial roles in colorectal carcinogenesis, and has become a popular target for anti-CRC therapy. Dysregulation of the Wnt signaling pathway, mostly by inactivating mutations of the adenomatous polyposis coli tumor suppressor or oncogenic mutations of β-catenin, has been implicated as a key factor in colorectal tumorigenesis. Abnormal increases of β-catenin levels represents a common pathway in Wnt signaling activation and is also observed in other human malignancies. These findings highlight the importance of developing small-molecule drugs that target the Wnt pathway. Herein we provide an overview on the current development of small molecules that target the Wnt pathway in colorectal CSCs and discuss future research directions.
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Affiliation(s)
- Lele Song
- Department of Radiotherapy, the PLA 309 Hospital, Beijing, China; BioChain (Beijing) Science and Technology, Inc, Beijing, China.
| | - Yuemin Li
- Department of Radiotherapy, the PLA 309 Hospital, Beijing, China.
| | - Baoming He
- Department of Nuclear Medicine, the PLA 309 Hospital, Beijing, China
| | - Yuan Gong
- Department of Gastroenterology, the PLA General Hospital, Beijing, China
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Novellasdemunt L, Antas P, Li VSW. Targeting Wnt signaling in colorectal cancer. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms. Am J Physiol Cell Physiol 2015; 309:C511-21. [PMID: 26289750 PMCID: PMC4609654 DOI: 10.1152/ajpcell.00117.2015] [Citation(s) in RCA: 254] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Accepted: 08/14/2015] [Indexed: 02/06/2023]
Abstract
The evolutionarily conserved Wnt signaling pathway plays essential roles during embryonic development and tissue homeostasis. Notably, comprehensive genetic studies in Drosophila and mice in the past decades have demonstrated the crucial role of Wnt signaling in intestinal stem cell maintenance by regulating proliferation, differentiation, and cell-fate decisions. Wnt signaling has also been implicated in a variety of cancers and other diseases. Loss of the Wnt pathway negative regulator adenomatous polyposis coli (APC) is the hallmark of human colorectal cancers (CRC). Recent advances in high-throughput sequencing further reveal many novel recurrent Wnt pathway mutations in addition to the well-characterized APC and β-catenin mutations in CRC. Despite attractive strategies to develop drugs for Wnt signaling, major hurdles in therapeutic intervention of the pathway persist. Here we discuss the Wnt-activating mechanisms in CRC and review the current advances and challenges in drug discovery.
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Affiliation(s)
| | - Pedro Antas
- The Francis Crick Institute, Mill Hill Laboratory, London, United Kingdom
| | - Vivian S W Li
- The Francis Crick Institute, Mill Hill Laboratory, London, United Kingdom
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Sabatino L, Pancione M, Votino C, Colangelo T, Lupo A, Novellino E, Lavecchia A, Colantuoni V. Emerging role of the β-catenin-PPARγ axis in the pathogenesis of colorectal cancer. World J Gastroenterol 2014; 20:7137-7151. [PMID: 24966585 PMCID: PMC4064060 DOI: 10.3748/wjg.v20.i23.7137] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Revised: 01/15/2014] [Accepted: 05/05/2014] [Indexed: 02/06/2023] Open
Abstract
Multiple lines of evidence indicate that Wnt/β-catenin signaling plays a fundamental role in colorectal cancer (CRC) initiation and progression. Recent genome-wide data have confirmed that in CRC this pathway is one of the most frequently modified by genetic or epigenetic alterations affecting almost 90% of Wnt/β-catenin gene members. A major challenge is thus learning how the corrupted coordination of this pathway is tied to other signalings to enhance cell growth. Peroxisome proliferator activated receptor γ (PPARγ) is emerging as a growth-limiting and differentiation-promoting factor. In tumorigenesis it exerts a tumor suppressor role and is potentially linked with the Wnt/β-catenin pathway. Based on these results, the identification of new selective PPARγ modulators with inhibitory effects on the Wnt/β-catenin pathway is becoming an interesting perspective. Should, in fact, these molecules display such properties, new research avenues would be opened aimed at developing new molecular targeted drugs. Herein, we review the basic principles and present new hypotheses underlying the crosstalk between Wnt/β-catenin and PPARγ signaling. Furthermore, we discuss the advances in our understanding as to how their altered regulation can culminate in colon cancer and the efforts aimed at designing novel PPARγ agonists endowed with Wnt/β-catenin inhibitory effects to be used as therapeutic and/or preventive agents.
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Li X, Chen C, Wang F, Huang W, Liang Z, Xiao Y, Wei K, Wan Z, Hu X, Xiang S, Ding X, Zhang J. KCTD1 suppresses canonical Wnt signaling pathway by enhancing β-catenin degradation. PLoS One 2014; 9:e94343. [PMID: 24736394 PMCID: PMC3988066 DOI: 10.1371/journal.pone.0094343] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Accepted: 03/12/2014] [Indexed: 11/18/2022] Open
Abstract
The canonical Wnt signaling pathway controls normal embryonic development, cellular proliferation and growth, and its aberrant activity results in human carcinogenesis. The core component in regulation of this pathway is β-catenin, but molecular regulation mechanisms of β-catenin stability are not completely known. Here, our recent studies have shown that KCTD1 strongly inhibits TCF/LEF reporter activity. Moreover, KCTD1 interacted with β-catenin both in vivo by co-immunoprecipitation as well as in vitro through GST pull-down assays. We further mapped the interaction regions to the 1-9 armadillo repeats of β-catenin and the BTB domain of KCTD1, especially Position Ala-30 and His-33. Immunofluorescence analysis indicated that KCTD1 promotes the cytoplasmic accumulation of β-catenin. Furthermore, protein stability assays revealed that KCTD1 enhances the ubiquitination/degradation of β-catenin in a concentration-dependent manner in HeLa cells. And the degradation of β-catenin mediated by KCTD1 was alleviated by the proteasome inhibitor, MG132. In addition, KCTD1-mediated β-catenin degradation was dependent on casein kinase 1 (CK1)- and glycogen synthase kinase-3β (GSK-3β)-mediated phosphorylation and enhanced by the E3 ubiquitin ligase β-transducin repeat-containing protein (β-TrCP). Moreover, KCTD1 suppressed the expression of endogenous Wnt downstream genes and transcription factor AP-2α. Finally, we found that Wnt pathway member APC and tumor suppressor p53 influence KCTD1-mediated downregulation of β-catenin. These results suggest that KCTD1 functions as a novel inhibitor of Wnt signaling pathway.
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Affiliation(s)
- Xinxin Li
- Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China
| | - Cheng Chen
- Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China
| | - Fangmei Wang
- Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China
| | - Wenhuan Huang
- Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China
| | - Zhongheng Liang
- Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China
| | - Yuzhong Xiao
- Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China
| | - Ke Wei
- Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China
| | - Zhenxing Wan
- Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China
| | - Xiang Hu
- Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China
| | - Shuanglin Xiang
- Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China
| | - Xiaofeng Ding
- Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China
- * E-mail:
| | - Jian Zhang
- Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China
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Hydrogen sulfide-releasing aspirin inhibits the growth of leukemic Jurkat cells and modulates β-catenin expression. Leuk Res 2013; 37:1302-8. [PMID: 23896061 DOI: 10.1016/j.leukres.2013.07.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2013] [Accepted: 07/01/2013] [Indexed: 01/05/2023]
Abstract
Hydrogen sulfide-releasing aspirin (HS-ASA) is a novel compound with potential against cancer. It inhibited the growth of Jurkat T-leukemia cells with an IC₅₀ of 1.9 ± 0.2 μM whereas that of ASA was >5000 μM. It dose-dependently inhibited proliferation and induced apoptosis in these cells, causing a G₀/G₁ cell cycle arrest. HS-ASA down-regulated β-catenin protein levels and reduced mRNA and protein expression of β-catenin/TCF downstream target genes cyclinD1 and c-myc. Aspirin up to 5 mM had no effect on β-catenin expression. HS-ASA also increased caspase-3 protein levels and dose-dependently increased its activity. These effects were substantially blocked by z-VAD-fmk, a pan-caspase inhibitor.
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Avoranta ST, Korkeila EA, Ristamäki RH, Syrjänen KJ, Carpén OM, Pyrhönen SO, Sundström JTT. ALDH1 expression indicates chemotherapy resistance and poor outcome in node-negative rectal cancer. Hum Pathol 2013; 44:966-74. [PMID: 23332924 DOI: 10.1016/j.humpath.2012.10.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2012] [Revised: 10/01/2012] [Accepted: 10/05/2012] [Indexed: 01/12/2023]
Abstract
The cancer stem cell marker aldehyde dehydrogenase 1 (ALDH1) associates with treatment resistance and adverse outcome in several human cancers. We studied ALDH1 expression in rectal cancer, with special emphasis on its association with treatment response and disease outcome. Immunohistochemical staining for ALDH1 was conducted for 64 biopsies and 209 operative samples from rectal cancer patients treated with short- (n = 89) or long-course (n = 46) (chemo)radiotherapy plus surgery, or with surgery only (n = 74). The staining results were compared to clinicopathological variables, tumor regression grade (TRG) and disease outcome. Nuclear β-catenin expression pattern was analyzed from 197 operative samples. Positive ALDH1 expression was present in 149 operative samples (71%), correlating with deficient nuclear β-catenin regulation (P = .018). In a pairwise comparison of respective biopsy and operative samples, ALDH1 expression remained stable or increased after preoperative (chemo)radiotherapy in most of the cases, while it decreased in few cases only (P = .02 for positive/negative category; P <.001 for intensity). ALDH1 expression did not, however, relate to tumor regression grade. In node-negative rectal cancer, ALDH1 expression was an independent predictor of short disease-free and disease-specific survival (P = .044; P = .049), specifically among patients treated with adjuvant chemotherapy. We conclude that ALDH1 associates with deregulated β-catenin signaling, supporting the role of ALDH1 in rectal cancer stemness. ALDH1 expression relates to poor outcome in early stage rectal cancer, a group where new prognostic tools are particularly needed, and may indicate chemo- and radioresistance.
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Affiliation(s)
- S Tuulia Avoranta
- Department of Oncology and Radiotherapy, University of Turku and Turku University Hospital, Hämeentie 11, FIN-20521, Turku, Finland.
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24
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Dillard A, Matthan NR, Lichtenstein AH. Tamm-Horsfall protein 1 macrophage lipid accumulation unaffected by fatty acid double-bond geometric or positional configuration. Nutr Res 2012; 31:625-30. [PMID: 21925348 DOI: 10.1016/j.nutres.2011.08.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2011] [Revised: 07/29/2011] [Accepted: 08/02/2011] [Indexed: 12/16/2022]
Abstract
Dietary fatty acid type alters atherosclerotic lesion progression and macrophage lipid accumulation. Incompletely elucidated are the mechanisms by which fatty acids differing in double-bond geometric or positional configuration alter arterial lipid accumulation. The objective of this study was to evaluate the suitability of using Tamm-Horsfall protein 1 (THP-1) macrophages as a model for human monocytes/macrophages to address this issue. Our hypothesis was that THP-1 macrophages pretreated with ω-3 polyunsaturated fatty acids (PUFA) or fatty acid containing a cis double bond would accumulate less lipid, particularly cholesteryl ester, compared with ω-6 polyunsaturated fatty acids or a fatty acid containing a trans double bond, respectively. THP-1 monocytes were differentiated into macrophages and then incubated with fatty acids for 48 hours. There was an increase in intracellular lipid in response to all the fatty acids assessed, and by response was similar among the fatty acids. The increase in lipid accumulation was contributed to triglyceride and to a lesser extent cholesterol, primarily free cholesterol. These data suggest that free fatty acids bound to bovine serum albumin, regardless of double-bond geometric or positional configuration, induce triglyceride accumulation but had only a modest effect on cholesterol accumulation in THP-1 macrophages. The cells appeared to respond similarly to the assessed fatty acids in terms of amount and type of lipid accumulated. Hence, the THP-1 cell line was not appropriate to test the hypotheses of interest.
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Affiliation(s)
- Alice Dillard
- Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.
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25
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No evidence for PML-RARa bcr1 fusion gene in colorectal cancer. Mol Biol Rep 2011; 39:5387-91. [PMID: 22167334 DOI: 10.1007/s11033-011-1337-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2011] [Accepted: 12/03/2011] [Indexed: 01/01/2023]
Abstract
Colorectal cancer is the third most prevalent cancer and a leading cause of cancer death. Metastatic colorectal cancer patients are treated with anti-EGFR monoclonal antibodies in combination with chemotherapy; however, the efficiency is only 10-20% of such patients. An increasing amount of data has demonstrated that response to anti-EGFR therapies is confined to patients with KRAS and BRAF wild type tumors but still some of these patients are non responders to this treatment. The presence of oncogenic deregulation of different members of EGFR downstream signaling or crosstalk molecules could predict the lack of response in these patients. In this study, 40 wild type KRAS and BRAF colorectal tumors were analyzed to elucidate whether PML-RARa bcr1 fusion gene may play a role in colorectal carcinogenesis. Specifically we want to determine if this fusion could be responsible for the inability to respond to anti-EGFR monoclonal antibodies. Here, for the first time it is reported, that PML-RARa bcr1 fusion is not responsible for colorectal tumor development and also, this translocation is not predicting the lack of efficacy of anti-EGFR therapies in wild type KRAS and BRAF colorectal cancer patients. These results also suggest that PML-RARa is unlikely to be a promising target for adjuvant therapy in colorectal cancer patients.
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The expression pattern of aldehyde dehydrogenase 1 (ALDH1) is an independent prognostic marker for low survival in colorectal tumors. Exp Mol Pathol 2011; 92:111-7. [PMID: 22101256 DOI: 10.1016/j.yexmp.2011.10.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2011] [Accepted: 10/10/2011] [Indexed: 01/13/2023]
Abstract
BACKGROUND Aldehyde dehydrogenase-1 (ALDH1) is involved in the regulation of cell proliferation and differentiation. Moreover, it is a marker for cancer stem cells (CSC). As CSCs were shown to be the driving force of tumor progression and metastases we suspected that the expression of ALDH1 correlated with the prognostic 5 year survival of colorectal cancer. METHODS ALDH1 expression was analyzed in a highly stratified collective of 186 T3 N0 M0 G2 primary colorectal cancer specimens applying immunohistochemistry. For the analysis a scoring system for the expression of ALDH1 was developed that was aided by the pattern of the subcellular expression of beta-catenin which is a well known indicator for colorectal CSCs. RESULTS First, ALDH1 expression could be assigned to two groups which correlated with the absence or presence of nuclear beta-catenin expression. Second, ALDH1 group 2 expression patterning correlated highly significantly with low long term survival (p=0.010) of patients with T3 N0 M0 G2 colorectal cancer. This correlation was found univariately and when applying the multivariate Cox-model. CONCLUSION ALDH1 expression pattern is an independent prognostic marker for survival of T3 N0 M0 G2 colorectal cancer patients.
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Sun Z, Cao X, Jiang MM, Qiu Y, Zhou H, Chen L, Qin B, Wu H, Jiang F, Chen J, Liu J, Dai Y, Chen HF, Hu QY, Wu Z, Zeng JZ, Yao XS, Zhang XK. Inhibition of β-catenin signaling by nongenomic action of orphan nuclear receptor Nur77. Oncogene 2011; 31:2653-67. [PMID: 21986938 PMCID: PMC3257393 DOI: 10.1038/onc.2011.448] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Dysregulation of β-catenin turnover due to mutations of its regulatory proteins including adenomatous polyposis coli (APC) and p53 is implicated in the pathogenesis of cancer. Thus, intensive effort is being made to search for alternative approaches to reduce abnormally activated β-catenin in cancer cells. Nur77, an orphan member of the nuclear receptor superfamily, has a role in the growth and apoptosis of cancer cells. Here, we reported that Nur77 could inhibit transcriptional activity of β-catenin by inducing β-catenin degradation via proteasomal degradation pathway that is glycogen synthase kinase 3β and Siah-1 independent. Nur77 induction of β-catenin degradation required both the N-terminal region of Nur77, which was involved in Nur77 ubiquitination, and the C-terminal region, which was responsible for β-catenin binding. Nur77/ΔDBD, a Nur77 mutant lacking its DNA-binding domain, resided in the cytoplasm, interacted with β-catenin, and induced β-catenin degradation, demonstrating that Nur77-mediated β-catenin degradation was independent of its DNA binding and transactivation, and might occur in the cytoplasm. In addition, we reported our identification of two digitalis-like compounds (DLCs), H-9 and ATE-i2-b4, which potently induced Nur77 expression and β-catenin degradation in SW620 colon cancer cells expressing mutant APC protein in vitro and in animals. DLC-induced Nur77 protein was mainly found in the cytoplasm, and inhibition of Nur77 nuclear export by the CRM1-dependent nuclear export inhibitor leptomycin B or Jun N-terminal kinase inhibitor prevented the effect of DLC on inducing β-catenin degradation. Together, our results demonstrate that β-catenin can be degraded by cytoplasmic Nur77 through their interaction and identify H-9 and ATE-i2-b4 as potent activators of the Nur77-mediated pathway for β-catenin degradation.
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Affiliation(s)
- Z Sun
- School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
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Zhang F, Meng F, Li H, Dong Y, Yang W, Han A. Suppression of retinoid X receptor alpha and aberrant β-catenin expression significantly associates with progression of colorectal carcinoma. Eur J Cancer 2011; 47:2060-7. [PMID: 21561764 DOI: 10.1016/j.ejca.2011.04.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2011] [Revised: 04/01/2011] [Accepted: 04/05/2011] [Indexed: 01/27/2023]
Abstract
To investigate retinoid X receptor alpha (RXRα) and β-catenin expression and their relationship with the clinicopathological features of colorectal carcinoma (CRC). Real-time PCR and western blot analyses revealed that β-catenin and RXRα expression at both mRNA and protein levels in four pairs of fresh CRC and adjacent non-tumour tissues (ANT) dramatically was increased and decreased in CRC compared with ANT, respectively. Furthermore, RXRα expression at both mRNA and protein levels was downregulated in higher histological grade CRC. Immunohistochemistry staining in 120 cases of CRC and 60 cases of lymph node metastatic carcinoma of CRC showed that RXRα expression was significantly suppressed in CRC compared with ANT (P<0.001) and low expression of RXRα in CRC was significantly associated with histological grade (P<0.001), TNM stage (P=0.022) and N classification (P=0.002). The aberrant (accumulated cytoplasm or/and nuclei) expression of β-catenin was higher in CRC than that in ANT (P<0.001) and associated with histological grade (P=0.001) and N classification (P=0.002). Moreover, there was a close relationship between low RXRα expression and aberrant β-catenin expression in CRC (P=0.032). Taken together with our previous study, aberrant β-catenin expression upregulated by suppression of RXRα may play a crucial role in pathogenesis and progression of CRC.
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Affiliation(s)
- Fenfen Zhang
- Department of Pathology, The First Affiliated Hospital and Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
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29
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Beildeck ME, Gelmann EP, Byers SW. Cross-regulation of signaling pathways: an example of nuclear hormone receptors and the canonical Wnt pathway. Exp Cell Res 2010; 316:1763-72. [PMID: 20138864 PMCID: PMC2878914 DOI: 10.1016/j.yexcr.2010.02.001] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2009] [Revised: 01/28/2010] [Accepted: 02/01/2010] [Indexed: 12/24/2022]
Abstract
Predicting the potential physiological outcome(s) of any given molecular pathway is complex because of cross-talk with other pathways. This is particularly evident in the case of the nuclear hormone receptor and canonical Wnt pathways, which regulate cell growth and proliferation, differentiation, apoptosis, and metastatic potential in numerous tissues. These pathways are known to intersect at many levels: in the intracellular space, at the membrane, in the cytoplasm, and within the nucleus. The outcomes of these interactions are important in the control of stem cell differentiation and maintenance, feedback loops, and regulating oncogenic potential. The aim of this review is to demonstrate the importance of considering pathway cross-talk when predicting functional outcomes of signaling, using nuclear hormone receptor/canonical Wnt pathway cross-talk as an example.
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30
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Kaur M, Velmurugan B, Tyagi A, Agarwal C, Singh RP, Agarwal R. Silibinin suppresses growth of human colorectal carcinoma SW480 cells in culture and xenograft through down-regulation of beta-catenin-dependent signaling. Neoplasia 2010; 12:415-24. [PMID: 20454513 PMCID: PMC2864479 DOI: 10.1593/neo.10188] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2010] [Revised: 02/17/2010] [Accepted: 02/17/2010] [Indexed: 12/18/2022]
Abstract
Mutations in APC/beta-catenin resulting in an aberrant activation of Wnt/beta-catenin pathway are common in colorectal cancer (CRC), suggesting that targeting the beta-catenin pathway with chemopreventive/anticancer agents could be a potential translational approach to control CRC. Using human CRC cell lines harboring mutant (SW480) versus wildtype (HCT116) APC gene and alteration in beta-catenin pathway, herein we performed both in vitro and in vivo studies to examine for the first time whether silibinin targets beta-catenin pathway in its efficacy against CRC. Silibinin treatment inhibited cell growth, induced cell death, and decreased nuclear and cytoplasmic levels of beta-catenin in SW480 but not in HCT116 cells, suggesting its selective effect on the beta-catenin pathway and associated biologic responses. Other studies, therefore, were performed only in SW480 cells where silibinin significantly decreased beta-catenin-dependent T-cell factor-4 (TCF-4) transcriptional activity and protein expression of beta-catenin target genes such as c-Myc and cyclin D1. Silibinin also decreased cyclin-dependent kinase 8 (CDK8), a CRC oncoprotein that positively regulates beta-catenin activity, and cyclin C expression. In a SW480 tumor xenograft study, 100- and 200-mg/kg doses of silibinin feeding for 6 weeks inhibited tumor growth by 26% to 46% (P < .001). Analyses of xenografts showed that similar to cell culture findings, silibinin decreases proliferation and expression of beta-catenin, cyclin D1, c-Myc, and CDK8 but induces apoptosis in vivo. Together, these findings suggest that silibinin inhibits the growth of SW480 tumors carrying the mutant APC gene by down-regulating CDK8 and beta-catenin signaling and, therefore, could be an effective agent against CRC.
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Affiliation(s)
- Manjinder Kaur
- Department of Pharmaceutical Sciences, School of Pharmacy, Aurora, CO, USA
| | - Balaiya Velmurugan
- Department of Pharmaceutical Sciences, School of Pharmacy, Aurora, CO, USA
| | - Alpna Tyagi
- Department of Pharmaceutical Sciences, School of Pharmacy, Aurora, CO, USA
| | - Chapla Agarwal
- Department of Pharmaceutical Sciences, School of Pharmacy, Aurora, CO, USA
- University of Colorado Cancer Center, University of Colorado Denver, Aurora, CO, USA
| | - Rana P Singh
- Department of Pharmaceutical Sciences, School of Pharmacy, Aurora, CO, USA
- Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Rajesh Agarwal
- Department of Pharmaceutical Sciences, School of Pharmacy, Aurora, CO, USA
- University of Colorado Cancer Center, University of Colorado Denver, Aurora, CO, USA
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31
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Day RM, Matus IA, Suzuki YJ, Yeum KJ, Qin J, Park AM, Jain V, Kuru T, Tang G. Plasma levels of retinoids, carotenoids and tocopherols in patients with mild obstructive sleep apnoea. Respirology 2009; 14:1134-42. [PMID: 19761534 DOI: 10.1111/j.1440-1843.2009.01623.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND OBJECTIVE OSA is associated with increased incidence of cardiovascular diseases. Pathogenic mechanisms of vascular diseases include thickened vascular walls due to the increased number of smooth muscle cells (SMC). Retinoic acid (RA) suppresses the growth of SMC, and reduced retinoid levels are associated with vascular diseases. Oxidant signalling promotes SMC growth, thus antioxidant levels may also influence the development of cardiovascular diseases. The present study tested the hypothesis that plasmas from OSA patients contain altered levels of retinoids, carotenoids and tocopherols. METHODS Plasma samples were taken before and after sleep from patients with OSA (mostly mild) without known cardiovascular diseases and from control subjects. Levels of retinoids, carotenoids and tocopherols were measured using sensitive gas chromatograph-mass spectrometry and high pressure liquid chromatography methods and total antioxidant capacity was assessed fluorometrically. RESULTS Results showed that plasmas from patients with OSA had significantly lower retinyl palmitate and 9-cis RA compared with control subjects, while levels of retinol, all-trans RA and 13-cis RA were indifferent. All-transbeta-carotene and 9-cisbeta-carotene were also lower in OSA patients. Levels of all-trans RA and 13-cis RA in OSA patients were reduced after sleep compared with before sleep. OSA patients showed significantly higher delta-tocopherol compared with controls. Treatment of cultured human vascular SMC with post-sleep OSA patient plasmas promoted cell growth, but not in controls. CONCLUSIONS Mild OSA exhibits altered levels of specific retinoids, carotenoids and tocopherols, which may be markers and/or mediators for the increased susceptibility of patients to vascular diseases.
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Affiliation(s)
- Regina M Day
- Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799, USA.
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Leung EYL, Crozier JEM, Talwar D, O'Reilly DSJ, McKee RF, Horgan PG, McMillan DC. Vitamin antioxidants, lipid peroxidation, tumour stage, the systemic inflammatory response and survival in patients with colorectal cancer. Int J Cancer 2008; 123:2460-4. [PMID: 18729200 DOI: 10.1002/ijc.23811] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Both the tumour growth and progression and the systemic inflammatory response have the potential to increase oxidative stress. We therefore examined the relationship between lipid-soluble antioxidant vitamins, lipid peroxidation, the systemic inflammatory response and survival in patients with primary operable (n = 53) and advanced inoperable (n = 53) colorectal cancer. Compared with those patients with primary operable colorectal cancer, patients with unresectable liver disease had significantly lower median concentrations of alpha-tocopherol (p < 0.001), lutein (p < 0.001), lycopene (p < 0.001), alpha-carotene (p < 0.01) and beta-carotene (p < 0.001) and higher malondialdehyde concentrations. An elevated systemic inflammatory response (Glasgow prognostic score, mGPS) was associated with a greater proportion of females (p < 0.05) and more advanced tumour stage (p < 0.05), lower circulating levels of retinol (p < 0.01), lutein (p < 0.01), lycopene (p < 0.01) and alpha- (p < 0.01) and beta-carotene but not MDA (p = 0.633). In the liver metastases group 41 patients died of their cancer and a further 1 patient died of intercurrent disease on follow-up. On univariate survival analysis, mGPS (p < 0.01), retinol (p < 0.001), alpha-tocopherol (p < 0.05) and alpha-carotene (p < 0.05) were associated significantly with cancer-specific survival. On multivariate survival analysis of these significant variables, only mGPS (p < 0.01) and retinol (p < 0.001) were independently associated with cancer-specific survival. The results of the present study showed that the systemic inflammatory response was associated with a reduction of lipid-soluble antioxidant vitamins, whereas advanced tumour stage was associated with increased lipid peroxidation in patients with colorectal cancer. Of the antioxidant vitamins measured, only retinol was independently associated with cancer-specific survival.
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Affiliation(s)
- Elaine Y L Leung
- University Department of Surgery, Glasgow Royal Infirmary, Glasgow G31 2ER, United Kingdom
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33
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Dillard AC, Lane MA. Retinol Increases beta-catenin-RXRalpha binding leading to the increased proteasomal degradation of beta-catenin and RXRalpha. Nutr Cancer 2008; 60:97-108. [PMID: 18444141 DOI: 10.1080/01635580701586754] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Retinol utilizes a retinoid X receptor (RXR)-mediated degradation pathway to decrease beta-catenin protein in all-trans retinoic acid (ATRA)-resistant human colon cancer cells. In this study, we examined interactions between RXRalpha and beta-catenin in ATRA-resistant human colon cancer cells treated with retinol. Retinol treatment triggers relocation of beta-catenin and RXRalpha proteins. Cells treated with retinol for 8 and 24 h displayed increased cytosolic but decreased nuclear beta-catenin and RXRalpha. Retinol treatment increased beta-catenin and RXRalpha protein interaction. Previously, we showed that 24 h of retinol treatment increased RXRalpha protein. Here we show this increase in RXRalpha levels is due to increased RXRalpha messenger RNA. Treatment with 48 h with retinol decreased RXRalpha protein levels. Last, by transfecting HCT-116 cells with a RXRalpha construct lacking the activation function-1 and DNA binding domains, we show RXRalpha and beta-catenin binding is required for proteosomal degradation of beta-catenin. These results suggest retinol induces RXRalpha and beta-catenin binding and transport to the cytosol where they are proteasomally degraded.
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Affiliation(s)
- Alice C Dillard
- Department of Human Ecology, Division of Nutritional Sciences, The University of Texas at Austin, Austin, TX 78712, USA
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Park EY, Wilder ET, Chipuk JE, Lane MA. Retinol decreases phosphatidylinositol 3-kinase activity in colon cancer cells. Mol Carcinog 2008; 47:264-74. [PMID: 17918208 DOI: 10.1002/mc.20381] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Previously, we showed that retinol inhibited all-trans-retinoic acid (ATRA)-resistant human colon cancer cell invasion via a retinoic acid receptor-independent mechanism. Because phosphatidylinositol 3-kinase (PI3K) regulates cell invasion, the objective of the current study was to determine if retinol affected PI3K activity. Following 24 h of serum starvation, the ATRA resistant human colon cancer cell lines HCT-116 and SW620 were treated with 0, 1, or 10 microM retinol. Thirty minutes of retinol treatment resulted in a significant decrease in PI3K activity in both cell lines. To determine the mechanism by which retinol reduces PI3K activity, the levels and heterodimerization of the regulatory subunit, p85, and the catalytic subunit, p110, of PI3K were examined. Retinol treatment did not alter p85 or p110 protein levels or the heterodimerization of these subunits at any time point examined. To determine if retinol affected the ability of PI3K to phosphorylate the substrate, phosphatidylinositol (PI), PI3K was immunoprecipitated from control cells and incubated with 10 microg PI and increasing concentrations of retinol or 10 microg retinol and increasing concentrations of PI. Retinol decreased PI3K activity in a dose-responsive manner and increased PI suppressed the inhibitory effect of retinol on PI3K activity. Finally, the PI3K inhibitor, LY294002, mimicked the ability of retinol to decrease cell invasion. Computational modeling revealed that retinol may inhibit PI3K activity in a manner similar to that of wortmannin. Thus, a decrease in PI3K activity due to retinol treatment may confer the ability of retinol to inhibit ATRA-resistant colon cancer cell invasion.
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Affiliation(s)
- Eun Young Park
- Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA
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O'Reilly K, Bailey SJ, Lane MA. Retinoid-mediated regulation of mood: possible cellular mechanisms. Exp Biol Med (Maywood) 2008; 233:251-8. [PMID: 18296731 DOI: 10.3181/0706-mr-158] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Vitamin A and its derivatives, the retinoids, have long been studied for their ability to alter central nervous system (CNS) development. Increasingly, it is recognized that sufficient levels of retinoids may also be required for adult CNS function. However, excess dietary vitamin A, due to the consumption of supplements or foods rich in vitamin A, has been reported to induce psychosis. In addition, 13-cis-retinoic acid (13-cis-RA, isotretinoin), the active ingredient in the acne treatment Accutane, has been reported to cause adverse psychiatric events, including depression and suicidal ideation. Nevertheless, epidemiological studies have reported no consistent link between Accutane use and clinical depression in humans. Using an animal model, we have recently shown that 13-cis-RA induces an increase in depression-related behavior. Impairments in spatial learning and memory have also been demonstrated following 13-cis-RA treatment in mice. This review focuses on the behavioral and possible cellular effects of retinoid deficiency or excess in the adult brain in relation to altered mood. Specifically, we discuss the effect of retinoids on depression-related behaviors and whether norepinephrinergic, dopaminergic, or serotonergic neurotransmitter systems may be impaired. In addition, we consider the evidence that adult neurogenesis, a process implicated in the pathophysiology of depression, is reduced by retinoid signaling. We suggest that 13-cis-RA treatment may induce depression-related behaviors by decreasing adult neurogenesis and/or altering the expression of components of serotonergic neurotransmitter system, thereby leading to impaired serotonin signaling.
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Affiliation(s)
- Kally O'Reilly
- Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA
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Han A, Tong C, Hu D, Bi X, Yang W. A direct protein-protein interaction is involved in the suppression of beta-catenin transcription by retinoid X receptor alpha in colorectal cancer cells. Cancer Biol Ther 2008; 7:454-9. [PMID: 18196974 PMCID: PMC2820390 DOI: 10.4161/cbt.7.3.5455] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Using both mammalian two-hybrid assay in vivo and immunoprecipitation in vitro we found that retinoid X receptor alpha (RXR alpha) directly interacted with beta-catenin and suppressed beta-catenin transcription activity and protein expression in colorectal cancer cells. But, reduction of RXR alpha by small interfering RNA upregulated beta-catenin transcriptional activity and protein expression. However, gain- or loss-expression of beta-catenin did not affect RXR alpha. Therefore, our data provided the first evidence tht RXR alpha directly interacted with beta-catenin and regulated beta-catenin transcription, which provides important information for developing novel strategies in colorectal cancer prevention by targeting RXR alpha-beta-catenin signaling.
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Affiliation(s)
| | - Chang Tong
- Department of Pathology; University of Illinois at Chicago; Chicago, Illinois USA
| | - Dong Hu
- Department of Pathology; University of Illinois at Chicago; Chicago, Illinois USA
| | - Xiuli Bi
- Department of Pathology; University of Illinois at Chicago; Chicago, Illinois USA
| | - Wancai Yang
- Department of Pathology; University of Illinois at Chicago; Chicago, Illinois USA
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Ooki A, Yamashita K, Kobayashi N, Katada N, Sakuramoto S, Kikuchi S, Watanabe M. Lymph node metastasis density and growth pattern as independent prognostic factors in advanced esophageal squamous cell carcinoma. World J Surg 2007; 31:2184-91. [PMID: 17721721 DOI: 10.1007/s00268-007-9198-9] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2007] [Accepted: 05/27/2007] [Indexed: 11/29/2022]
Abstract
BACKGROUND Esophageal cancer is one of the leading types of cancer, and it is a particularly deadly form of malignancy. TNM classification is the most common staging system, but it has been reported that prognosis is not reflected adequately by this classification. The purpose of this study was to clarify independent prognostic factors in esophageal squamous cell carcinoma (ESCC), a dominant type of esophageal cancer in Japan, to broaden the staging system to improve its predictive value. Thus staging could be expanded to make the prognosis a valuable clinical tool, and to improve knowledge of the biological traits of advanced ESCC. METHODS The present study included 121 patients with advanced ESCC (stage II to IVA) treated by esophagectomy between 1990 and 2003 at the Kitasato University Higashi Hospital. RESULTS Univariate prognostic analysis of the disease-specific survival revealed that TNM stage (p < 0.0001), lymph node metastasis density over 10% (ND10; p < 0.0001), R-category (p = 0.003), intramural metastasis within the esophagus (IM; p = 0.009), growth pattern (p = 0.01), and size of tumor (p = 0.02) were significantly associated with a poor outcome in advanced ESCC. Multivariate analysis confirmed that growth pattern (p = 0.02, HR = 3.1) and ND10 (p = 0.02, HR = 2.0) were finally remnant prognostic factors independent of TNM stage. Growth pattern was prominent in stage II, whereas ND10 was directly proportional to stage progression and characteristics to stage IV disease. Interestingly, ND20, the most malignant phenotype of ESCC, was the only prognostic determinant, even in stage IV disease. CONCLUSIONS From the present study, we concluded that progression of lymph node density is characteristic of a life-threatening phenotype of advanced ESCC, and it should be employed as a therapeutic target to improve patient survival. Growth pattern is an alternative target characteristic of less advanced ESCC. Both of these parameters may be applied as useful clinical tools in the management of patients with advanced esophageal cancer.
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Affiliation(s)
- Akira Ooki
- Department of Surgery, Kitasato University Higashi Hospital, Asamizodai 2-1-1, Sagamihara 228-8520 Kanagawa, Japan
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Abstract
Retinoids (retinol [vitamin A] and its biologically active metabolites) are essential signaling molecules that control various developmental pathways and influence the proliferation and differentiation of a variety of cell types. The physiological actions of retinoids are mediated primarily by the retinoic acid receptors alpha, beta, and gamma (RARs) and rexinoid receptors alpha, beta, and gamma. Although mutations in RARalpha, via the PML-RARalpha fusion proteins, result in acute promyelocytic leukemia, RARs have generally not been reported to be mutated or part of fusion proteins in carcinomas. However, the retinoid signaling pathway is often compromised in carcinomas. Altered retinol metabolism, including low levels of lecithin:retinol acyl trasferase and retinaldehyde dehydrogenase 2, and higher levels of CYP26A1, has been observed in various tumors. RARbeta(2) expression is also reduced or is absent in many types of cancer. A greater understanding of the molecular mechanisms by which retinoids induce cell differentiation, and in particular stem cell differentiation, is required in order to solve the issue of retinoid resistance in tumors, and thereby to utilize RA and synthetic retinoids more effectively in combination therapies for human cancer.
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Affiliation(s)
- Nigel P Mongan
- Department of Pharmacology, Weill Cornell Medical College, New York, NY 10021, USA
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