DOCSLIB.ORG

ALDH1A2 Is a Candidate Tumor Suppressor Gene in Ovarian Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
ALDH1A2 Is a Candidate Tumor Suppressor Gene in Ovarian Cancer cancers Article ALDH1A2 Is a Candidate Tumor Suppressor Gene in Ovarian Cancer Jung-A Choi 1, Hyunja Kwon 1, Hanbyoul Cho 1,* , Joon-Yong Chung 2 , Stephen M. Hewitt 2 and Jae-Hoon Kim 1 1 Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Korea; [email protected] (J.-A.C.); [email protected] (H.K.); [email protected] (J.-H.K.) 2 Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; [email protected] (J.-Y.C.); [email protected] (S.M.H.) * Correspondence: [email protected]; Tel.: +82-2-2019-3430; Fax: +82-2-3462-8209 Received: 11 July 2019; Accepted: 10 October 2019; Published: 14 October 2019 Abstract: Aldehyde dehydrogenase 1 family member A2 (ALDH1A2) is a rate-limiting enzyme involved in cellular retinoic acid synthesis. However, its functional role in ovarian cancer remains elusive. Here, we found that ALDH1A2 was the most prominently downregulated gene among ALDH family members in ovarian cancer cells, according to complementary DNA microarray data. Low ALDH1A2 expression was associated with unfavorable prognosis and shorter disease-free and overall survival for ovarian cancer patients. Notably, hypermethylation of ALDH1A2 was significantly higher in ovarian cancer cell lines when compared to that in immortalized human ovarian surface epithelial cell lines. ALDH1A2 expression was restored in various ovarian cancer cell lines after treatment with the DNA methylation inhibitor 5-aza-20-deoxycytidine. Furthermore, silencing DNA methyltransferase 1 (DNMT1) or 3B (DNMT3B) restored ALDH1A2 expression in ovarian cancer cell lines. Functional studies revealed that forced ALDH1A2 expression significantly impaired the proliferation of ovarian cancer cells and their invasive activity. To the best of our knowledge, this is the first study to show that ALDH1A2 expression is regulated by the epigenetic regulation of DNMTs, and subsequently that it might act as a tumor suppressor in ovarian cancer, further suggesting that enhancing ALDH1A2-linked signaling might provide new opportunities for therapeutic intervention in ovarian cancer. Keywords: ALDH1A2; methylation; DNMT; OVARIAN cancer; invasion 1. Introduction Ovarian cancer has the highest mortality rate among all gynecological cancers because most cases are not diagnosed until the disease has reached an advanced stage [1]. Although the five-year survival rate for ovarian cancer patients has substantially improved, owing to ongoing efforts to develop an effective screening strategy [1], the lack of reliable methods for early diagnosis and the absence of specific symptoms result in diagnoses at advanced stages [1]. Furthermore, approximately 80% of women with advanced ovarian cancer show tumor progression or, more commonly, recurrence [2]. Thus, understanding the pathogenesis of ovarian cancer and the molecular mechanism of its early stage is crucial for the management of this lethal, highly metastatic disease. The aldehyde dehydrogenase 1 (ALDH1) family comprises major enzymes that produce retinoic acid (RA) via the oxidation of all-trans retinal and 9-cis-retinal, which is mainly involved in biological functions related to cell differentiation, cell cycle arrest, and eventually, apoptosis [3–5]. The ALDH1A Cancers 2019, 11, 1553; doi:10.3390/cancers11101553 www.mdpi.com/journal/cancers Cancers 2019, 11, 1553 2 of 18 subfamily consists of three members, ALDH1A1, ALDH1A2, and ALDH1A3 [6]. ALDH1A1 participates in retinal oxidation, acetaldehyde metabolism, and detoxification of cyclophosphamide, whereas the ALDH1A2 and ALDH1A3 proteins are integral to the oxidation of retinal to RA [7]. Interestingly, despite similarities in the structure and function of the isoenzymes of the ALDH1A subfamily [8], several lines of evidence suggest that these molecules might perform different functions in cancer progression [7–14]. ALDH1A1 has been implicated in conferring resistance to certain anticancer agents, such as cyclophosphamide, and was shown to play a functional role in cancer stem cells [11,12]. In contrast to that of ALDH1A1, low ALDH1A2 expression has been associated with an unfavorable prognosis in prostate cancer and head and neck squamous cell carcinoma patients [13,14]. Meanwhile, ALDH1A3 plays important roles in several metabolic and physiological processes [15], which potentially suggest different roles for ALDH1A isoforms in cancer progression. However, the functions and prognostic value of ALDH1A2 in ovarian cancer progression remain unclear. The methylation of CpG sites is an epigenetic mechanism underlying the regulation of gene expression, which usually leads to gene silencing [16]. Aberrant methylation of gene promoter regions is one of the earliest molecular alterations that occurs during carcinogenesis and a key mechanism for the inactivation of tumor suppressor genes [16–18]. Therefore, methylation has emerged as a promising marker for the early detection of cancer [19]. In fact, CpG islands in tumor suppressor genes such as CDKN2B, BRACA1, RASSF1A, MLH1, RARB2, and TIMP3 undergo aberrant methylation in ovarian cancer [20]. DNA methylation patterns have been shown to be regulated by DNA methyltransferases (DNMTs), including DNMT1, DNMT3A, and DNMT3B [21]. DNMT1 is essential for maintaining DNA methylation patterns in proliferating cells [22], whereas DNMT3A and DNMT3B are required for de novo methylation during embryonic development [23]. However, there are no reports regarding the epigenetic regulation of ALDH1A2 by DNMTs in human ovarian cancer. Therefore, in this study, we evaluated the expression profiles of ALDH isozyme-encoding genes in ovarian cancer using a complementary DNA (cDNA) microarray. Additionally, we focused on the role of ALDH1A2 as one of the most prominently downregulated genes in ovarian cancer. 2. Results 2.1. Reduced Expression of ALDH1A2 in Ovarian Cancer To evaluate whether ALDH isozymes contribute to the progression of ovarian cancer, an Illumina microarray was used to identify differentially expressed ALDH genes in six ovarian cancer cell lines (YDOV-139, YDOV-157, YDOV-161, YDOV-13, YDOV-105, and YDOV-151) and four human ovarian surface epithelial (HOSE) cell lines (HOSE 198, 209, 211, and 213) [24]. RNA isolated from the cells was directly compared by hybridization with cDNA microarrays with 24,957 probe sets. The volcano plot shows that 24,957 genes were differentially expressed (p < 0.01 and fold change > 2) in the cancer cells compared to the normal cells (Figure1A). We found that 15 ALDH isoforms exhibited di fferential expression patterns in the ovarian cancer cell lines compared to the normal cells (Figure1A,B, Table S1). ALDH1A2, ALDH1B1, and ALDH9A1 were downregulated in the ovarian cancer cells compared to the expression in HOSE cells (Figure1A and Table S1), whereas ALDH3A1 was upregulated in the ovarian cancer cells. Among these isoforms, we further characterized the functional role of ALDH1A2 in ovarian cancer progression, because it was one of the most prominently downregulated genes, with approximately 50-fold lower expression levels in ovarian cancer cells than in normal cells (Figure1B, Table S1). These decreased expression levels were further validated by real-time PCR, and immunoblotting in ovarian cancer cell lines (SNU840, RMG1, OVCA433, OVCA429, and SKOV3) and IHOSE8695 cells (Figure1C,D). Taken together, these observations suggest that the expression of ALDH1A2 is strongly downregulated in ovarian cancer. Cancers 2019, 11, 1553 3 of 18 Cancers 2019, 11, x FOR PEER REVIEW 3 of 18 FigureFigure 1. 1. ComparativeComparative analysis analysis of of ALDH ALDH gene gene expression expression profiles profiles and ALDH1A2ALDH1A2 protein protein expression expression in inovarian ovarian cancer cancer cell cell lines. lines. (A )( VolcanoA) Volcano plot plot of the of distribution the distribution of diff erentiallyof differentially expressed expressed genes between genes betweenovarian ovarian cancer cell cancer lines cell (YDOV-139, lines (YDOV YDOV-157,‐139, YDOV YDOV-161,‐157, YDOV YDOV-13,‐161, YDOV YDOV-105,‐13, YDOV and YDOV-151)‐105, and YDOVand human‐151) and ovarian human surface ovarian epithelial surface (HOSE) epithelial cell (HOSE) lines (HOSE cell lines 198, (HOSE 209, 211, 198, and 209, 213) 211, using and a DNA213) usingmicroarray. a DNA Themicroarray. volcano The plot volcano shows that plot 24,957 shows genes that 24,957 were di genesfferentially were differentially expressed (p expressed< 0.01 and (p fold < change > 2). The log10 (p-value) of each gene is plotted against the log 2 ratio of cancer intensity 0.01 and fold change− > 2). The −log10 (p‐value) of each gene is plotted against the log 2 ratio of cancer intensityto normal to intensity.normal intensity. Vertical dottedVertical lines dotted in red lines and in green red and correspond green correspond to a 2.0-fold to upregulation a 2.0‐fold upregulationand 2.0-fold and downregulation 2.0‐fold downregulation of expression, of respectively.expression, respectively. Horizontal blackHorizontal dotted black lines dotted indicate lines the indicatesignificance the significance level at p = 0.01.level Plotsat p were= 0.01. generated Plots were using generated ExDEGA using v.1.6.5 ExDEGA software v.1.6.5 (Ebiogen, software Seoul, (Ebiogen,Republic Seoul, of Korea). Republic (B) Up-of Korea). and downregulation (B) Up‐ and downregulation of gene expression of gene were expression examined
Load more

Recommended publications
  • The Utility of Genetic Risk Scores in Predicting the Onset of Stroke March 2021 6
    DOT/FAA/AM-21/24 Office of Aerospace Medicine Washington, DC 20591 The Utility of Genetic Risk Scores in Predicting the Onset of Stroke Diana Judith Monroy Rios, M.D1 and Scott J. Nicholson, Ph.D.2 1. KR 30 # 45-03 University Campus, Building 471, 5th Floor, Office 510 Bogotá D.C. Colombia 2. FAA Civil Aerospace Medical Institute, 6500 S. MacArthur Blvd Rm. 354, Oklahoma City, OK 73125 March 2021 NOTICE This document is disseminated under the sponsorship of the U.S. Department of Transportation in the interest of information exchange. The United States Government assumes no liability for the contents thereof. _________________ This publication and all Office of Aerospace Medicine technical reports are available in full-text from the Civil Aerospace Medical Institute’s publications Web site: (www.faa.gov/go/oamtechreports) Technical Report Documentation Page 1. Report No. 2. Government Accession No. 3. Recipient's Catalog No. DOT/FAA/AM-21/24 4. Title and Subtitle 5. Report Date March 2021 The Utility of Genetic Risk Scores in Predicting the Onset of Stroke 6. Performing Organization Code 7. Author(s) 8. Performing Organization Report No. Diana Judith Monroy Rios M.D1, and Scott J. Nicholson, Ph.D.2 9. Performing Organization Name and Address 10. Work Unit No. (TRAIS) 1 KR 30 # 45-03 University Campus, Building 471, 5th Floor, Office 510, Bogotá D.C. Colombia 11. Contract or Grant No. 2 FAA Civil Aerospace Medical Institute, 6500 S. MacArthur Blvd Rm. 354, Oklahoma City, OK 73125 12. Sponsoring Agency name and Address 13. Type of Report and Period Covered Office of Aerospace Medicine Federal Aviation Administration 800 Independence Ave., S.W.
    [Show full text]
  • Identify Distinct Prognostic Impact of ALDH1 Family Members by TCGA Database in Acute Myeloid Leukemia
    Open Access Annals of Hematology & Oncology Research Article Identify Distinct Prognostic Impact of ALDH1 Family Members by TCGA Database in Acute Myeloid Leukemia Yi H, Deng R, Fan F, Sun H, He G, Lai S and Su Y* Department of Hematology, General Hospital of Chengdu Abstract Military Region, China Background: Acute myeloid leukemia is a heterogeneous disease. Identify *Corresponding author: Su Y, Department of the prognostic biomarker is important to guide stratification and therapeutic Hematology, General Hospital of Chengdu Military strategies. Region, Chengdu, 610083, China Method: We detected the expression level and the prognostic impact of Received: November 25, 2017; Accepted: January 18, each ALDH1 family members in AML by The Cancer Genome Atlas (TCGA) 2018; Published: February 06, 2018 database. Results: Upon 168 patients whose expression level of ALDH1 family members were available. We found that the level of ALDH1A1correlated to the prognosis of AML by the National Comprehensive Cancer Network (NCCN) stratification but not in other ALDH1 members. Moreover, we got survival data from 160 AML patients in TCGA database. We found that high ALDH1A1 expression correlated to poor Overall Survival (OS), mostly in Fms-like Tyrosine Kinase-3 (FLT3) mutated group. HighALDH1A2 expression significantly correlated to poor OS in FLT3 wild type population but not in FLT3 mutated group. High ALDH1A3 expression significantly correlated to poor OS in FLT3 mutated group but not in FLT3 wild type group. There was no relationship between the OS of AML with the level of ALDH1B1, ALDH1L1 and ALDH1L2. Conclusion: The prognostic impacts were different in each ALDH1 family members, which needs further investigation.
    [Show full text]
  • A Missense Mutation in ALDH1A3 Causes Isolated Microphthalmia/Anophthalmia in Nine Individuals from an Inbred Muslim Kindred
    European Journal of Human Genetics (2014) 22, 419–422 & 2014 Macmillan Publishers Limited All rights reserved 1018-4813/14 www.nature.com/ejhg SHORT REPORT A missense mutation in ALDH1A3 causes isolated microphthalmia/anophthalmia in nine individuals from an inbred Muslim kindred Adi Mory1,2, Francesc X Ruiz3, Efrat Dagan2,4, Evgenia A Yakovtseva3, Alina Kurolap1, Xavier Pare´s3, Jaume Farre´s3 and Ruth Gershoni-Baruch*,1,2 Nine affected individuals with isolated anophthalmia/microphthalmia from a large Muslim-inbred kindred were investigated. Assuming autosomal-recessive mode of inheritance, whole-genome linkage analysis, on DNA samples from four affected individuals, was undertaken. Homozygosity mapping techniques were employed and a 1.5-Mbp region, homozygous in all affected individuals, was delineated. The region contained nine genes, one of which, aldehyde dehydrogenase 1 (ALDH1A3), was a clear candidate. This gene seems to encode a key enzyme in the formation of a retinoic-acid gradient along the dorsoventral axis during an early eye development and the development of the olfactory system. Sanger sequence analysis revealed a missense mutation, causing a substitution of valine (Val) to methionine (Met) at position 71. Analyzing the p.Val71Met missense mutation using standard open access software (MutationTaster online, PolyPhen, SIFT/PROVEAN) predicts this variant to be damaging. Enzymatic activity, studied in vitro, showed no changes between the mutated and the wild-type ALDH1A3 protein. European Journal of Human Genetics (2014) 22, 419–422; doi:10.1038/ejhg.2013.157; published online 24 July 2013 Keywords: ALDH1A3 gene; anophthalmia/microphthalmia; homozogosity mapping INTRODUCTION METHODS Anophthalmia and microphthalmia (A/M) are rare developmental Patients and families anomalies resulting in absent or small ocular globes, respectively.
    [Show full text]
  • Acquire a High Level of Retinoic Acid− Producing Capacity in Response to Vitamin D 3 This Information Is Current As of September 28, 2021
    Human CD1c+ Myeloid Dendritic Cells Acquire a High Level of Retinoic Acid− Producing Capacity in Response to Vitamin D 3 This information is current as of September 28, 2021. Takayuki Sato, Toshio Kitawaki, Haruyuki Fujita, Makoto Iwata, Tomonori Iyoda, Kayo Inaba, Toshiaki Ohteki, Suguru Hasegawa, Kenji Kawada, Yoshiharu Sakai, Hiroki Ikeuchi, Hiroshi Nakase, Akira Niwa, Akifumi Takaori-Kondo and Norimitsu Kadowaki Downloaded from J Immunol 2013; 191:3152-3160; Prepublished online 21 August 2013; doi: 10.4049/jimmunol.1203517 http://www.jimmunol.org/content/191/6/3152 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2013/08/21/jimmunol.120351 Material 7.DC1 References This article cites 41 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/191/6/3152.full#ref-list-1 by guest on September 28, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606.
    [Show full text]
  • ALDH2 Antibody (Center)
    BioVision 05/14 For research use only ALDH2 Antibody (Center) ALTERNATE NAMES: ALDH2; ALDM; Aldehyde dehydrogenase, mitochondrial; ALDH class 2; ALDH-E2; ALDHI. CATALOG #: 6748-100 AMOUNT: 100 µl HOST/ISOTYPE: Rabbit IgG Western blot analysis in A549 cell lysates and mouse liver and lung and rat liver IMMUNOGEN: This ALDH2 antibody is generated from rabbits immunized with tissue lysates (35 µg/lane). a KLH conjugated synthetic peptide between 318-347 amino acids from the Central region of human ALDH2. PURIFICATION: This antibody is purified through a protein A column, followed by peptide affinity purification. MOLECULAR WEIGHT: ~56.38 kDa FORM: Liquid FORMULATION: Supplied in PBS with 0.09% (W/V) sodium azide. SPECIES REACTIVITY: Human. Predicted cross reactivity with mouse and rat samples. STORAGE CONDITIONS: Maintain refrigerated at 2-8°C for up to 6 months. For long term storage, store at -20°C in small aliquots to prevent freeze-thaw cycles. Formalin-fixed and paraffin-embedded human hepatocarcinoma reacted with ALDH2 antibody, DESCRIPTION: ALDH2 (Aldehyde dehydrogenase 2 family) belongs to the aldehyde which was peroxidase-conjugated to the dehydrogenase family which catalyze the chemical transformation from acetaldehyde to secondary antibody, followed by DAB staining. acetic acid and is the second enzyme of the major oxidative pathway of alcohol metabolism. Aldehyde dehydrogenases (ALDHs) mediate NADP+-dependent oxidation of aldehydes into acids during detoxification of alcohol-derived acetaldehyde; lipid peroxidation; and metabolism of corticosteroids, biogenic amines and neurotransmitters. ALDH1A1, also designated retinal dehydrogenase 1 (RalDH1 or RALDH1); aldehyde dehydrogenase family 1 member A1; aldehyde dehydrogenase cytosolic; ALDHII; ALDH-E1 or ALDH E1, is a retinal dehydrogenase that participates in the biosynthesis of retinoic acid (RA).
    [Show full text]
  • Severe Osteoarthritis of the Hand Associates with Common Variants Within the ALDH1A2 Gene and with Rare Variants at 1P31
    Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31. Styrkarsdottir, Unnur; Thorleifsson, Gudmar; Helgadottir, Hafdis T; Bomer, Nils; Metrustry, Sarah; Bierma-Zeinstra, S; Strijbosch, Annelieke M; Evangelou, Evangelos; Hart, Deborah; Beekman, Marian; Jonasdottir, Aslaug; Sigurdsson, Asgeir; Eiriksson, Finnur F; Thorsteinsdottir, Margret; Frigge, Michael L; Kong, Augustine; Gudjonsson, Sigurjon A; Magnusson, Olafur T; Masson, Gisli; Hofman, Albert; Arden, Nigel K; Ingvarsson, Thorvaldur; Lohmander, Stefan; Kloppenburg, Margreet; Rivadeneira, Fernando; Nelissen, Rob G H H; Spector, Tim; Uitterlinden, Andre; Slagboom, P Eline; Thorsteinsdottir, Unnur; Jonsdottir, Ingileif; Valdes, Ana M; Meulenbelt, Ingrid; van Meurs, Joyce; Jonsson, Helgi; Stefansson, Kari Published in: Nature Genetics DOI: 10.1038/ng.2957 2014 Link to publication Citation for published version (APA): Styrkarsdottir, U., Thorleifsson, G., Helgadottir, H. T., Bomer, N., Metrustry, S., Bierma-Zeinstra, S., Strijbosch, A. M., Evangelou, E., Hart, D., Beekman, M., Jonasdottir, A., Sigurdsson, A., Eiriksson, F. F., Thorsteinsdottir, M., Frigge, M. L., Kong, A., Gudjonsson, S. A., Magnusson, O. T., Masson, G., ... Stefansson, K. (2014). Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31. Nature Genetics, 46(5), 498-502. https://doi.org/10.1038/ng.2957 Total number of authors: 36 General rights Unless other specific re-use rights are stated the following general rights apply: Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.
    [Show full text]
  • Transcriptional Silencing of ALDH2 Confers a Dependency on Fanconi Anemia Proteins in Acute Myeloid Leukemia
    Author Manuscript Published OnlineFirst on April 23, 2021; DOI: 10.1158/2159-8290.CD-20-1542 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Transcriptional silencing of ALDH2 confers a dependency on Fanconi anemia proteins in acute myeloid leukemia Zhaolin Yang1, Xiaoli S. Wu1,2, Yiliang Wei1, Sofya A. Polyanskaya1, Shruti V. Iyer1,2, Moonjung Jung3, Francis P. Lach3, Emmalee R. Adelman4, Olaf Klingbeil1, Joseph P. Milazzo1, Melissa Kramer1, Osama E. Demerdash1, Kenneth Chang1, Sara Goodwin1, Emily Hodges5, W. Richard McCombie1, Maria E. Figueroa4, Agata Smogorzewska3, and Christopher R. Vakoc1,6* 1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA 2Genetics Program, Stony Brook University, Stony Brook, New York 11794, USA 3Laboratory of Genome Maintenance, The Rockefeller University, New York 10065, USA 4Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA 5Department of Biochemistry and Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA 6Lead contact *Correspondence: [email protected]; Christopher R. Vakoc, 1 Bungtown Rd, Cold Spring Harbor, NY 11724. 516-367-5030 Running title: Fanconi anemia pathway dependency in AML Category: Myeloid Neoplasia Keywords: CONFLICT OF INTEREST DISCLOSURES C.R.V. has received consulting fees from Flare Therapeutics, Roivant Sciences, and C4 Therapeutics, has served on the scientific advisory board of KSQ Therapeutics and Syros Pharmaceuticals, and has received research funding from Boehringer-Ingelheim. W.R.M. is a founder and shareholder of Orion Genomics and has received research support from Pacific Biosciences and support for attending meetings from Oxford Nanopore.
    [Show full text]
  • A Novel ALDH1A1 Inhibitor Targets Cells with Stem Cell Characteristics in Ovarian Cancer
    cancers Article A Novel ALDH1A1 Inhibitor Targets Cells with Stem Cell Characteristics in Ovarian Cancer Nkechiyere G. Nwani 1, Salvatore Condello 2 , Yinu Wang 1, Wendy M. Swetzig 1, Emma Barber 1, Thomas Hurley 3,4 and Daniela Matei 1,5,6,* 1 Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60611, USA; [email protected] (N.G.N.); [email protected] (Y.W.); [email protected] (W.M.S.); [email protected] (E.B.) 2 Department of Obstetrics and Gynecology, Indiana University, Indianapolis, IN 46202, USA; [email protected] 3 Department of Biochemistry and molecular Biology, Indiana University, Indianapolis, IN 46202, USA; [email protected] 4 Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA 5 Robert H Lurie Comprehensive Cancer Center, Chicago, IL 60611, USA 6 Jesse Brown VA Medical Center, Chicago, IL 60612, USA * Correspondence: [email protected] Received: 8 February 2019; Accepted: 3 April 2019; Published: 8 April 2019 Abstract: A small of population of slow cycling and chemo-resistant cells referred to as cancer stem cells (CSC) have been implicated in cancer recurrence. There is emerging interest in developing targeted therapeutics to eradicate CSCs. Aldehyde-dehydrogenase (ALDH) activity was shown to be a functional marker of CSCs in ovarian cancer (OC). ALDH activity is increased in cells grown as spheres versus monolayer cultures under differentiating conditions and in OC cells after treatment with platinum. Here, we describe the activity of CM37, a newly identified small molecule with inhibitory activity against ALDH1A1, in OC models enriched in CSCs. Treatment with CM37 reduced OC cells’ proliferation as spheroids under low attachment growth conditions and the expression of stemness-associated markers (OCT4 and SOX2) in ALDH+ cells fluorescence-activated cell sorting (FACS)-sorted from cell lines and malignant OC ascites.
    [Show full text]
  • Isoenzymes in Gastric Cancer
    www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 18 Mining distinct aldehyde dehydrogenase 1 (ALDH1) isoenzymes in gastric cancer Jia-Xin Shen1,*, Jing Liu2,3,*, Guan-Wu Li4, Yi-Teng Huang5, Hua-Tao Wu1 1Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, PR China 2Chang Jiang Scholar’s Laboratory, Shantou University Medical College, Shantou, PR China 3Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou, PR China 4Open Laboratory for Tumor Molecular Biology/Department of Biochemistry, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, PR China 5Health Care Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, PR China *These authors contributed equally to this work Correspondence to: Hua-Tao Wu, email: [email protected] Keywords: ALDH1, gastric cancer, prognosis, KM plotter, hazard ratio (HR) Received: October 27, 2015 Accepted: March 10, 2016 Published: March 23, 2016 ABSTRACT Aldehyde dehydrogenase 1 (ALDH1) consists of a family of intracellular enzymes, highly expressed in stem cells populations of leukemia and some solid tumors. Up to now, 6 isoforms of ALDH1 have been reported. However, the expression patterns and the identity of ALDH1 isoenzymes contributing to ALDH1 activity, as well as the prognostic values of ALDH1 isoenzymes in cancers all remain to be elucidated. Here, we studied the expressions of ALDH1 transcripts in gastric cancer (GC) compared with the normal controls using the ONCOMINE database. Through the Kaplan-Meier plotter database, which contains updated gene expression data and survival information of 876 GC patients, we also investigated the prognostic values of ALDH1 isoenzymes in GC patients.
    [Show full text]
  • Phylogeny and Evolution of Aldehyde Dehydrogenase-Homologous Folate Enzymes
    Chemico-Biological Interactions 191 (2011) 122–128 Contents lists available at ScienceDirect Chemico-Biological Interactions journal homepage: www.elsevier.com/locate/chembioint Phylogeny and evolution of aldehyde dehydrogenase-homologous folate enzymes Kyle C. Strickland a, Roger S. Holmes b, Natalia V. Oleinik a, Natalia I. Krupenko a, Sergey A. Krupenko a,∗ a Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425 USA b School of Biomolecular and Physical Sciences, Griffith University, Nathan 4111 Brisbane, Queensland, Australia article info abstract Article history: Folate coenzymes function as one-carbon group carriers in intracellular metabolic pathways. Folate- Available online 6 January 2011 dependent reactions are compartmentalized within the cell and are catalyzed by two distinct groups of enzymes, cytosolic and mitochondrial. Some folate enzymes are present in both compartments Keywords: and are likely the products of gene duplications. A well-characterized cytosolic folate enzyme, FDH Folate metabolism (10-formyltetrahydro-folate dehydrogenase, ALDH1L1), contains a domain with significant sequence Mitochondria similarity to aldehyde dehydrogenases. This domain enables FDH to catalyze the NADP+-dependent 10-Formyltetrahydrofolate dehydrogenase conversion of short-chain aldehydes to corresponding acids in vitro. The aldehyde dehydrogenase-like Aldehyde dehydrogenase Domain structure reaction is the final step in the overall FDH mechanism, by which a tetrahydrofolate-bound formyl group + Evolution is oxidized to CO2 in an NADP -dependent fashion. We have recently cloned and characterized another folate enzyme containing an ALDH domain, a mitochondrial FDH. Here the biological roles of the two enzymes, a comparison of the respective genes, and some potential evolutionary implications are dis- cussed.
    [Show full text]
  • Aldehyde Dehydrogenase, Liver Disease and Cancer Wenjun Wang1, Chunguang Wang2, Hongxin Xu1, Yanhang Gao1
    Int. J. Biol. Sci. 2020, Vol. 16 921 Ivyspring International Publisher International Journal of Biological Sciences 2020; 16(6): 921-934. doi: 10.7150/ijbs.42300 Review Aldehyde Dehydrogenase, Liver Disease and Cancer Wenjun Wang1, Chunguang Wang2, Hongxin Xu1, Yanhang Gao1 1. Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin, 130021, China. 2. Department of Thoracic & Cardiovascular Surgery, Second Clinical College, Jilin University, Changchun, 130041, China. Corresponding author: Yanhang Gao, MD., PhD., Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin, 130021, China. Email: [email protected]. Tel: +86 15804303019; +86 431 81875121; +86 431 81875106; Fax number: 0431-81875106. © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2019.11.20; Accepted: 2020.01.03; Published: 2020.01.22 Abstract Acetaldehyde dehydrogenase 2 (ALDH2) is the key enzyme responsible for metabolism of the alcohol metabolite acetaldehyde in the liver. In addition to conversion of the acetaldehyde molecule, ALDH is also involved in other cellular functions. Recently, many studies have investigated the involvement of ALDH expression in viral hepatitis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, and liver cancer. Notably, ALDH2 expression has been linked with liver cancer risk, as well as pathogenesis and prognosis, and has emerged as a promising therapeutic target. Of note, approximately 8% of the world’s population, and approximately 30-40% of the population in East Asia carry an inactive ALDH2 gene.
    [Show full text]
  • ALDH1A2 Is a Candidate Tumor Suppressor Gene in Ovarian Cancer
    Supplementary Materials ALDH1A2 is a Candidate Tumor Suppressor Gene in Ovarian Cancer Jung-A Choi, Hyunja Kwon, Hanbyoul Cho*, Joon-Yong Chung, Stephen M. Hewitt and Jae-Hoon Kim Figure S1. Transfection efficiency after pCMV-tagB-Flag-ALDH1A2 transfection in RMG-I, SKOV3, and OVCA433 cells. Cells were grown on coverslips and transfected with pCMV-tagB-Flag- ALDH1A2 using Lipofectamine® 2000. Cells were then immunostained with primary antibodies for Flag and visualized by confocal microscopy (A). Transfection efficiency (%) was evaluated by counting cells expressing Flag. Figure S2. Effect of ALDH1A2 overexpression on cell cycle distribution and cell death in ovarian cancer. (A-B) Cells were transfected with pCMV-tagB-Flag-ALDH1A2 using Lipofectamine® 2000. After 24 h, the cells were harvested, fixed in ice-cold 70% ethanol, and stained with propidium iodide. Cell-cycle distribution (A) and cell death (B) were analyzed by fluorescence-activated cell sorting (FACS). Apoptotic cells were quantified for DNA content after propidium iodide staining; the sub- G 1 fraction (%) represents the proportion of apoptotic cells. Statistical significance was assessed using an unpaired t test. **p < 0.05, ***p < 0.005 . 1 Figure S3. Annexin V/PI staining in RMG-I, SKOV3, and OVCA433 cells overexpressing ALDH1A2. (A-B) Cells were transfected with pCMV-tagB-Flag-ALDH1A2 using Lipofectamine® 2000. After the indicated time, cells were immediately stained with Annexin V-FITC and PI, subjected to flow cytometry analyses (A). Quantitative results of cell death were determined using Annexin V/PI (B). 2 Figure S4. Methylation status of ALDH1A2 genes in public datasets, Methylation and Expression Database of Normal and Tumor Tissues (MENT; http://mgrc.kribb.re.kr:8080/MENT/).
    [Show full text]