Tobacco-Specific Carcinogens Induce Hypermethylation, DNA Adducts, and DNA Damage in Bladder Cancer
Abstract
Smoking is a major risk factor for the development of bladder cancer; however, the functional consequences of the carcinogens in tobacco smoke and bladder cancer–associated metabolic alterations remain poorly defined. We assessed the metabolic profiles in bladder cancer smokers and non-smokers and identified the key alterations in their metabolism. LC/MS and bioinformatic analysis were performed to determine the metabolome associated with bladder cancer smokers and were further validated in cell line models. Smokers with bladder cancer were found to have elevated levels of methylated metabolites, polycyclic aromatic hydrocarbons, DNA adducts, and DNA damage. DNA methyltransferase 1 (DNMT1) expression was significantly higher in smokers than non-smokers with bladder cancer. An integromics approach, using multiple patient cohorts, revealed strong associations between smokers and high-grade bladder cancer. In vitro exposure to the tobacco smoke carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene (BaP) led to increase in levels of methylated metabolites, DNA adducts, and extensive DNA damage in bladder cancer cells. Cotreatment of bladder cancer cells with these carcinogens and the methylation inhibitor 5-aza-2'-deoxycytidine rewired the methylated metabolites, DNA adducts, and DNA damage. These findings were confirmed through the isotopic-labeled metabolic flux analysis. Screens using smoke-associated metabolites and DNA adducts could provide robust biomarkers and improve individual risk prediction in bladder cancer smokers. Noninvasive predictive biomarkers that can stratify the risk of developing bladder cancer in smokers could aid in early detection and treatment. Cancer Prev Res; 10(10); 588–97. ©2017 AACR.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 01, 2017
- Source ID
- 10.1158/1940-6207.capr-17-0198
Entities
People
- Arun Sreekumar
- Balasubramanyam Karanam
- Benny Abraham Kaipparettu
- Chandrashekar R. Ambati
- Cristian Coarfa
- Daniel Gödde
- Danthasinghe Waduge Badrajee Piyarathna
- Farrah Kheradmand
- Feng Jin
- Florian Roghmann
- Franklin Gu
- Friedrich-carl Von Rundstedt
- George Michailidis
- Joachim Noldus
- Jose Thaiparambil
- Kimal Rajapakshe
- Martha K. Terris
- Nagireddy Putluri
- Preeti Purwaha
- Randa El-zein
- Rashmi Krishnapuram
- Salil Kumar Bhowmik
- Sebastian Berg
- Seth P. Lerner
- Shyam M. Kavuri
- Sri Ramya Donepudi
- Stephan Degener
- Stephan Roth
- Stephan Störkel
- Suman Maity
- Vasanta Putluri
- Venkatrao Vantaku
- Yair Lotan
Organizations
- American Cancer Society
- Baylor College of Medicine
- Cancer Prevention and Research Institute of Texas
- Friedrich Schiller University Jena
- Houston Methodist Hospital
- National Institutes of Health
- National Science Foundation
- Ruhr University Bochum
- Tuskegee University
- United States Department of Defense
- United States Department of Veterans Affairs
- University of Florida
- University of Texas Southwestern Medical Center
- Witten/Herdecke University