Tobacco-Specific Carcinogens Induce Hypermethylation, DNA Adducts, and DNA Damage in Bladder Cancer

Feng Jin, Jose Thaiparambil, Sri Ramya Donepudi, Venkatrao Vantaku, Danthasinghe Waduge Badrajee Piyarathna, Suman Maity, Rashmi Krishnapuram, Vasanta Putluri, Franklin Gu, Preeti Purwaha, Salil Kumar Bhowmik, Chandrashekar R Ambati, Friedrich-Carl von Rundstedt, Florian Roghmann, Sebastian Berg, Joachim Noldus, Kimal Rajapakshe, Daniel Gödde, Stephan Roth, Stephan StörkelStephan Degener, George Michailidis, Benny Abraham Kaipparettu, Balasubramanyam Karanam, Martha K Terris, Shyam M Kavuri, Seth P Lerner, Farrah Kheradmand, Cristian Coarfa, Arun Sreekumar, Yair Lotan, Randa El-Zein, Nagireddy Putluri

Research output: Contribution to journalArticlepeer-review

43 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)588-597
Number of pages10
JournalCancer Prevention Research
Issue number10
StatePublished - Oct 2017


  • Journal Article


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