Cancer and Ageing: Rival Demons?
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The Interactions of DNA Repair, Telomere Homeostasis, and P53 Mutational Status in Solid Cancers: Risk, Prognosis, and Prediction
cancers Review The Interactions of DNA Repair, Telomere Homeostasis, and p53 Mutational Status in Solid Cancers: Risk, Prognosis, and Prediction Pavel Vodicka 1,2,3, Ladislav Andera 4,5, Alena Opattova 1,2,3,† and Ludmila Vodickova 1,2,3,*,† 1 Institute of Experimental Medicine, AS CR, 142 20 Prague, Czech Republic; [email protected] (P.V.); [email protected] (A.O.) 2 First Medical Faculty, Charles University, 121 08 Prague, Czech Republic 3 Biomedical Center, Faculty of Medicine in Pilsen, Charles University, 301 00 Pilsen, Czech Republic 4 Institute of Biotechnology, AS CR, 252 50 Vestec, Czech Republic; [email protected] 5 Institute of Molecular Genetics, AS CR, 142 20 Prague, Czech Republic * Correspondence: [email protected] † These authors contribured eaqually to this paper. Simple Summary: p53 is a nuclear transcription factor with a pro-apoptotic function. Somatic mutations in this gene represent one of the most critical events in human carcinogenesis. The disruption of genomic integrity due to the accumulation of various kinds of DNA damage, deficient DNA repair capacity, and alteration of telomere homeostasis constitute the hallmarks of malignant diseases. The main aim of our review was to accentuate a complex comprehension of the interactions between fundamental players in carcinogenesis of solid malignancies such as DNA damage response, telomere homeostasis and TP53. Abstract: The disruption of genomic integrity due to the accumulation of various kinds of DNA Citation: Vodicka, P.; Andera, L.; Opattova, A.; Vodickova, L. The damage, deficient DNA repair capacity, and telomere shortening constitute the hallmarks of malig- Interactions of DNA Repair, Telomere nant diseases. -
Cadmium Induced Cell Apoptosis, DNA Damage, De
Int. J. Med. Sci. 2013, Vol. 10 1485 Ivyspring International Publisher International Journal of Medical Sciences 2013; 10(11):1485-1496. doi: 10.7150/ijms.6308 Research Paper Cadmium Induced Cell Apoptosis, DNA Damage, De- creased DNA Repair Capacity, and Genomic Instability during Malignant Transformation of Human Bronchial Epithelial Cells Zhiheng Zhou1*, Caixia Wang2*, Haibai Liu1, Qinhai Huang1, Min Wang1 , Yixiong Lei1 1. School of public health, Guangzhou Medical University, Guangzhou 510182, People’s Republic of China 2. Department of internal medicine of Guangzhou First People’s Hospital affiliated to Guangzhou Medical University, Guangzhou 510180, People’s Republic of China * These authors contributed equally to this work. Corresponding author: Yixiong Lei, School of public health, Guangzhou Medical University, 195 Dongfengxi Road, Guangzhou 510182, People’s Republic of China. Fax: +86-20-81340196. E-mail: [email protected] © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/ licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. Received: 2013.03.23; Accepted: 2013.08.12; Published: 2013.08.30 Abstract Cadmium and its compounds are well-known human carcinogens, but the mechanisms underlying the carcinogenesis are not entirely understood. Our study was designed to elucidate the mech- anisms of DNA damage in cadmium-induced malignant transformation of human bronchial epi- thelial cells. We analyzed cell cycle, apoptosis, DNA damage, gene expression, genomic instability, and the sequence of exons in DNA repair genes in several kinds of cells. -
Cellular Senescence Promotes Skin Carcinogenesis Through P38mapk and P44/P42mapk Signaling
Author Manuscript Published OnlineFirst on July 8, 2020; DOI: 10.1158/0008-5472.CAN-20-0108 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Cellular senescence promotes skin carcinogenesis through p38MAPK and p44/p42 MAPK signaling Fatouma Alimirah1, Tanya Pulido1, Alexis Valdovinos1, Sena Alptekin1,2, Emily Chang1, Elijah Jones1, Diego A. Diaz1, Jose Flores1, Michael C. Velarde1,3, Marco Demaria1,4, Albert R. Davalos1, Christopher D. Wiley1, Chandani Limbad1, Pierre-Yves Desprez1, and Judith Campisi1,5* 1Buck Institute for Research on Aging, Novato, CA 94945, USA 2Dokuz Eylul University School of Medicine, Izmir 35340, Turkey 3Institute of Biology, University of the Philippines Diliman, College of Science, Quezon City 1101, Philippines 4European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, the Netherlands 5Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA *Lead Contact: Judith Campisi, Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA; Email: [email protected] or [email protected]. Telephone: 1-415-209-2066; Fax: 1-415-493-3640 Running title: Senescence and skin carcinogenesis Key words: doxorubicin, senescence-associated secretory phenotype, squamous cell carcinoma, microenvironment, inflammation, transgenic mice, tumorspheres Conflict of Interests JC is a co-founder of Unity Biotechnology and MD owns equity in Unity Biotechnology. All other authors declare no competing financial interests. Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 8, 2020; DOI: 10.1158/0008-5472.CAN-20-0108 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. -
Herpes Simplex Virus Type 2: Bystander Or Active Player in Cervical Carcinogenesis?
Journal of Gynecology and Women’s Health ISSN 2474-7602 Mini Review J Gynecol Women’s Health Volume 12 Issue 2 - October 2018 Copyright © All rights are reserved by Jude Ogechukwu Okoye DOI: 10.19080/JGWH.2018.12.555832 Herpes Simplex Virus Type 2: Bystander or Active Player in Cervical Carcinogenesis? Jude Ogechukwu Okoye* Department of Medical Laboratory Science, Babcock University, Nigeria Submission: September 19, 2018 ; Published: October 05, 2018 *Corresponding author: Jude Ogechukwu Okoye, Department of Medical Laboratory Science, Babcock University, Nigeria, Tel: ; Email: Abstract More emphasis have been placed on producing vaccines that prevent host cell entry by Human Papillomavirus (HPV) while less attention andhas beenits potential given to to Herpes up-modulate Simplex both virus HPV type regulatory 2 (HSV-2) andwhich oncogenic potentially gene promotes and downregulate acquisition hostand co-habitationtumour suppressor of human suggest immunodeficiency that it is not a virus (HIV), HPV and Epstein-Barr virus (EBV). The tendency for HSV-2 to induce ulcerations and chronic inflammation following reactivation, to reduce cervical cancer related mortality. bystander in cervical carcinogenesis. Thus, efforts geared towards finding HSV-2 effective microbicide and vaccine should be intensified so as Keywords: Herpes Simplex virus type 2; Human papillomavirus; Epstein-Barr virus; Cervical cancer Abbreviations: HPV: Human Papillomavirus; HIV: Human Immune virus; SSC: Squamous Cell Carcinoma; LMP1: Latent Membrane Protein 1; EBV: Epstein-Barr virus; CIN: Cervical Intraepithelial Neoplasia Introduction Cervical cancer is the second most common type of cancer in a woman’s lifetime and may also facilitate EBV infection, a (9.8%) affecting women worldwide [1-3]. -
Malignant Transformation of Human Fibroblasts Caused by Expression Of
Proc. Nati. Acad. Sci. USA Vol. 86, pp. 187-191, January 1989 Cell Biology Malignant transformation of human fibroblasts caused by expression of a transfected T24 HRAS oncogene (human cell transformation/infinite life-span human flbroblasts/pHO6T1/T24 HRAS expression/malignant fibrosarcoma) PETER J. HURLIN*, VERONICA M. MAHER, AND J. JUSTIN MCCORMICKt Carcinogenesis Laboratory, Fee Hall, Department of Microbiology and Department of Biochemistry, Michigan State University, East Lansing, MI 48824-1316 Communicated by G. N. Wogan, September 19, 1988 ABSTRACT We showed previously that diploid human passage rodent cells were transfected with an HRAS onco- fibroblasts that express a transfected HRAS oncogene from the gene and any one of a number of genes considered to be human bladder carcinoma cell line T24 exhibit several char- involved in causing cellular immortalization, malignant trans- acteristics of transformed cells but do not acquire an infinite formation resulted (5-7). Not surprisingly, transfection of life-span and are not tumorigenic. To extend these studies ofthe HRAS oncogenes into infinite life-span rodent fibroblast cell T24 HRAS in human cells, we have utilized an infinite life-span, lines resulted in malignant transformation (5, 8) in the but otherwise phenotypically normal, human fibroblast cell majority of the studies (9). strain, MSU-1.1, developed in this laboratory after transfec- To test models proposed for ras transformation generated tion of diploid fibroblasts with a viral v-myc oncogene. Trans- from experiments with rodent fibroblasts for their relevance fection of MSU-1.1 cells with the T24 HRAS flanked by two to human cell transformation, we and our colleagues (10-12) transcriptional enhancer elements (pHO6T1) yielded foci of and several other groups (13-21) have used human fibroblasts morphologically transformed cells. -
The RNA Helicase a in Malignant Transformation
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 19 The RNA helicase A in malignant transformation Marco Fidaleo1,2, Elisa De Paola1,2 and Maria Paola Paronetto1,2 1 Department of Movement, Human and Health Sciences, University of Rome “Foro Italico”, Rome, Italy 2 Laboratory of Cellular and Molecular Neurobiology, CERC, Fondazione Santa Lucia, Rome, Italy Correspondence to: Maria Paola Paronetto, email: [email protected] Keywords: RHA helicase, genomic stability, cancer Received: October 02, 2015 Accepted: January 29, 2016 Published: February 14, 2016 ABSTRACT The RNA helicase A (RHA) is involved in several steps of RNA metabolism, such as RNA processing, cellular transit of viral molecules, ribosome assembly, regulation of transcription and translation of specific mRNAs. RHA is a multifunctional protein whose roles depend on the specific interaction with different molecular partners, which have been extensively characterized in physiological situations. More recently, the functional implication of RHA in human cancer has emerged. Interestingly, RHA was shown to cooperate with both tumor suppressors and oncoproteins in different tumours, indicating that its specific role in cancer is strongly influenced by the cellular context. For instance, silencing of RHA and/or disruption of its interaction with the oncoprotein EWS-FLI1 rendered Ewing sarcoma cells more sensitive to genotoxic stresses and affected tumor growth and maintenance, suggesting possible therapeutic implications. Herein, we review the recent advances in the cellular functions of RHA and discuss its implication in oncogenesis, providing a perspective for future studies and potential translational opportunities in human cancer. INTRODUCTION females, which contain two X chromosomes [8]. The C. elegans RHA-1 displays about 60% of similarity with both RNA helicase A (RHA) is a DNA/RNA helicase human RHA and Drosophila MLE and is involved in gene involved in all the essential steps of RNA metabolism, silencing. -
Origin of Genome Instability and Determinants of Mutational Landscape in Cancer Cells
G C A T T A C G G C A T genes Review Origin of Genome Instability and Determinants of Mutational Landscape in Cancer Cells Sonam Mehrotra * and Indraneel Mittra Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India; [email protected] * Correspondence: [email protected]; Tel.: +91-22-27405143 Received: 15 August 2020; Accepted: 18 September 2020; Published: 21 September 2020 Abstract: Genome instability is a crucial and early event associated with an increased predisposition to tumor formation. In the absence of any exogenous agent, a single human cell is subjected to about 70,000 DNA lesions each day. It has now been shown that physiological cellular processes including DNA transactions during DNA replication and transcription contribute to DNA damage and induce DNA damage responses in the cell. These processes are also influenced by the three dimensional-chromatin architecture and epigenetic regulation which are altered during the malignant transformation of cells. In this review, we have discussed recent insights about how replication stress, oncogene activation, chromatin dynamics, and the illegitimate recombination of cell-free chromatin particles deregulate cellular processes in cancer cells and contribute to their evolution. The characterization of such endogenous sources of genome instability in cancer cells can be exploited for the development of new biomarkers and more effective therapies for cancer treatment. Keywords: genome instability; replication stress; replication-transcription conflict; cell free chromatin; cancer 1. Introduction Genome instability is a characteristic feature observed in most human cancers. The accumulation of genetic alterations ranging from single nucleotide mutations to chromosome rearrangements can predispose cells towards malignancy. -
Hyper Telomere Recombination Accelerates Replicative Senescence and May Promote Premature Aging
Hyper telomere recombination accelerates replicative senescence and may promote premature aging R. Tanner Hagelstroma,b, Krastan B. Blagoevc,d, Laura J. Niedernhofere, Edwin H. Goodwinf, and Susan M. Baileya,1 aDepartment of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523-1618; bPharmaceutical Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004; cNational Science Foundation, Arlington, VA 22230; dDepartment of Physics Cavendish Laboratory, Cambridge University, Cambridge CB3 0HE, United Kingdom; eDepartment of Microbiology and Molecular Genetics, University of Pittsburgh, School of Medicine and Cancer Institute, Pittsburgh, PA 15261; and fKromaTiD Inc., Fort Collins, CO 80524 Edited* by José N. Onuchic, University of California San Diego, La Jolla, CA, and approved August 3, 2010 (received for review May 7, 2010) Werner syndrome and Bloom syndrome result from defects in the cell-cycle arrest known as senescence (12). Most human tissues lack RecQ helicases Werner (WRN) and Bloom (BLM), respectively, and sufficient telomerase activity to maintain telomere length through- display premature aging phenotypes. Similarly, XFE progeroid out life, limiting cell division potential. The majority of cancers syndrome results from defects in the ERCC1-XPF DNA repair endo- circumvent this tumor-suppressor mechanism by reactivating telo- nuclease. To gain insight into the origin of cellular senescence and merase (13), thus removing telomere shortening as a barrier to human aging, we analyzed the dependence of sister chromatid continuous proliferation. In some situations, a recombination- exchange (SCE) frequencies on location [i.e., genomic (G-SCE) vs. telo- based mechanism known as “alternative lengthening of telomeres” meric (T-SCE) DNA] in primary human fibroblasts deficient in WRN, (ALT) maintains telomere length in the absence of telomerase (14). -
Cellular Senescence and Apoptosis: How Cellular Responses Might Influence Aging Phenotypes
Experimental Gerontology 38 (2003) 5–11 www.elsevier.com/locate/expgero Cellular senescence and apoptosis: how cellular responses might influence aging phenotypes Judith Campisia,b,* aLife Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720, USA bBuck Institute for Age Research, 8001 Redwood Blvd., Novato, CA 94945, USA Received 20 May 2002; accepted 28 May 2002 Abstract Aging in complex multi-cellular organisms such as mammals entails distinctive changes in cells and molecules that ultimately compromise the fitness of adult organisms. These cellular and molecular changes lead to the phenotypes we recognize as aging. This review discusses some of the cellular and molecular changes that occur with age, specifically changes that occur as a result of cellular responses that evolved to ameliorate the inevitable damage that is caused by endogenous and environmental insults. Because the force of natural selection declines with age, it is likely that these processes were never optimized during their evolution to benefit old organisms. That is, some age- related changes may be the result of gene activities that were selected for their beneficial effects in young organisms, but the same gene activities may have unselected, deleterious effects in old organisms, a phenomenon termed antagonistic pleiotropy. Two cellular processes, apoptosis and cellular senescence, may be examples of antagonistic pleiotropy. Both processes are essential for the viability and fitness of young organisms, but may contribute to aging phenotypes, including certain age-related diseases. q 2002 Elsevier Science Inc. All rights reserved. Keywords: Antagonistic pleiotropy; Apoptosis; Cancer; Cellular senescence; DNA damage response; Neurodegeneration; p53; Telomeres 1. -
Cancer Patients Have a Higher Risk Regarding COVID-19–And Vice Versa?
pharmaceuticals Opinion Cancer Patients Have a Higher Risk Regarding COVID-19–and Vice Versa? Franz Geisslinger, Angelika M. Vollmar and Karin Bartel * Pharmaceutical Biology, Department Pharmacy, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany; [email protected] (F.G.); [email protected] (A.M.V.) * Correspondence: [email protected] Received: 29 May 2020; Accepted: 3 July 2020; Published: 6 July 2020 Abstract: The world is currently suffering from a pandemic which has claimed the lives of over 230,000 people to date. The responsible virus is called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and causes the coronavirus disease 2019 (COVID-19), which is mainly characterized by fever, cough and shortness of breath. In severe cases, the disease can lead to respiratory distress syndrome and septic shock, which are mostly fatal for the patient. The severity of disease progression was hypothesized to be related to an overshooting immune response and was correlated with age and comorbidities, including cancer. A lot of research has lately been focused on the pathogenesis and acute consequences of COVID-19. However, the possibility of long-term consequences caused by viral infections which has been shown for other viruses are not to be neglected. In this regard, this opinion discusses the interplay of SARS-CoV-2 infection and cancer with special focus on the inflammatory immune response and tissue damage caused by infection. We summarize the available literature on COVID-19 suggesting an increased risk for severe disease progression in cancer patients, and we discuss the possibility that SARS-CoV-2 could contribute to cancer development. -
Cellular Senescence and the Senescent Secretory Phenotype: Therapeutic Opportunities
Cellular senescence and the senescent secretory phenotype: therapeutic opportunities Tamara Tchkonia, … , Judith Campisi, James L. Kirkland J Clin Invest. 2013;123(3):966-972. https://doi.org/10.1172/JCI64098. Review Series Aging is the largest risk factor for most chronic diseases, which account for the majority of morbidity and health care expenditures in developed nations. New findings suggest that aging is a modifiable risk factor, and it may be feasible to delay age-related diseases as a group by modulating fundamental aging mechanisms. One such mechanism is cellular senescence, which can cause chronic inflammation through the senescence-associated secretory phenotype (SASP). We review the mechanisms that induce senescence and the SASP, their associations with chronic disease and frailty, therapeutic opportunities based on targeting senescent cells and the SASP, and potential paths to developing clinical interventions. Find the latest version: https://jci.me/64098/pdf Review series Cellular senescence and the senescent secretory phenotype: therapeutic opportunities Tamara Tchkonia,1 Yi Zhu,1 Jan van Deursen,1 Judith Campisi,2 and James L. Kirkland1 1Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA. 2Buck Institute for Research on Aging, Novato, California, USA. Aging is the largest risk factor for most chronic diseases, which account for the majority of morbidity and health care expenditures in developed nations. New findings suggest that aging is a modifiable risk factor, and it may be feasible to delay age-related diseases as a group by modulating fundamental aging mechanisms. One such mech- anism is cellular senescence, which can cause chronic inflammation through the senescence-associated secretory phenotype (SASP). -
Genetics, Epigenetics and Cancer. Cancer Therapy
Cancer Therapy & Oncology International Journal ISSN: 2473-554X Research Article Canc Therapy & Oncol Int J Volume 4 Issue 2 - April 2017 Copyright © All rights are reserved by Alain L. Fymat DOI: 10.19080/CTOIJ.2017.04.555634 Genetics, Epigenetics and Cancer Alain L. Fymat* International Institute of Medicine and Science, USA Submission: March 27, 2017; Published: April 07, 2017 *Correspondence Address: Alain L. Fymat, International Institute of Medicine and Science, USA, Tel: ; Email: Abstract With deeper understanding of cell biology and genetics, it now appears that cancer is less an organ disease and more a disease of the genes that regulate cell growth and differentiation are altered. Most cancers have multiple possible concurring causes, and it is not possiblemolecular to mechanisms prevent all such caused causes. by mutations However, ofonly specific a small genes. minority Cancer of cancersis fundamentally (5-10%) are a disease due to ofinherited tissue growth genetic regulation mutations failurewhereas when the vast majority (90-95%) are non-hereditary epigenetic mutations that are caused by various agents (environmental factors, physical factors, and hormones). Thus, although there are some genetic predispositions in a small fraction of cancers, the major fraction is due to a set of new genetic mutations (called “epigenetic” mutations). After a brief primer on cancer and its genetics, this article focuses on the epigenetics of cancer. Epigenetics is the study of cellular and physiological traits inherited by daughter cells, but not caused by changes in the DNA sequence. imprintingImportant examplesand trans-generational of epigenetic mechanisms inheritance. (DNAEpigenetic methylation, carcinogens histone and modification, cancer treatment chromatin are also remodeling) treated.