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Chronic Exposure to Chewing Tobacco Induces Metabolic Reprogramming and Cancer Stem Cell-Like Properties in Esophageal Epithelial Cells

Tobacco in its smoke and smokeless form are major risk factors for esophageal squamous cell carcinoma (ESCC). However, molecular alterations associated with smokeless tobacco exposure are poorly understood. In the Indian subcontinent, tobacco is predominantly consumed in chewing form. An understandi...

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Autores principales: Datta, Keshava K., Patil, Shankargouda, Patel, Krishna, Babu, Niraj, Raja, Remya, Nanjappa, Vishalakshi, Mangalaparthi, Kiran Kumar, Dhaka, Bharti, Rajagopalan, Pavithra, Deolankar, Sayali Chandrashekhar, Kannan, Ramakrishnan, Kumar, Prashant, Prasad, T. S. Keshava, Mathur, Premendu P., Kumari, Anjali, Manoharan, Malini, Coral, Karunakaran, Murugan, Saktivel, Sidransky, David, Gupta, Ravi, Gupta, Rohit, Khanna-Gupta, Arati, Chatterjee, Aditi, Gowda, Harsha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770059/
https://www.ncbi.nlm.nih.gov/pubmed/31438645
http://dx.doi.org/10.3390/cells8090949
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author Datta, Keshava K.
Patil, Shankargouda
Patel, Krishna
Babu, Niraj
Raja, Remya
Nanjappa, Vishalakshi
Mangalaparthi, Kiran Kumar
Dhaka, Bharti
Rajagopalan, Pavithra
Deolankar, Sayali Chandrashekhar
Kannan, Ramakrishnan
Kumar, Prashant
Prasad, T. S. Keshava
Mathur, Premendu P.
Kumari, Anjali
Manoharan, Malini
Coral, Karunakaran
Murugan, Saktivel
Sidransky, David
Gupta, Ravi
Gupta, Rohit
Khanna-Gupta, Arati
Chatterjee, Aditi
Gowda, Harsha
author_facet Datta, Keshava K.
Patil, Shankargouda
Patel, Krishna
Babu, Niraj
Raja, Remya
Nanjappa, Vishalakshi
Mangalaparthi, Kiran Kumar
Dhaka, Bharti
Rajagopalan, Pavithra
Deolankar, Sayali Chandrashekhar
Kannan, Ramakrishnan
Kumar, Prashant
Prasad, T. S. Keshava
Mathur, Premendu P.
Kumari, Anjali
Manoharan, Malini
Coral, Karunakaran
Murugan, Saktivel
Sidransky, David
Gupta, Ravi
Gupta, Rohit
Khanna-Gupta, Arati
Chatterjee, Aditi
Gowda, Harsha
author_sort Datta, Keshava K.
collection PubMed
description Tobacco in its smoke and smokeless form are major risk factors for esophageal squamous cell carcinoma (ESCC). However, molecular alterations associated with smokeless tobacco exposure are poorly understood. In the Indian subcontinent, tobacco is predominantly consumed in chewing form. An understanding of molecular alterations associated with chewing tobacco exposure is vital for identifying molecular markers and potential targets. We developed an in vitro cellular model by exposing non-transformed esophageal epithelial cells to chewing tobacco over an eight-month period. Chronic exposure to chewing tobacco led to increase in cell proliferation, invasive ability and anchorage independent growth, indicating cell transformation. Molecular alterations associated with chewing tobacco exposure were characterized by carrying out exome sequencing and quantitative proteomic profiling of parental cells and chewing tobacco exposed cells. Quantitative proteomic analysis revealed increased expression of cancer stem cell markers in tobacco treated cells. In addition, tobacco exposed cells showed the Oxidative Phosphorylation (OXPHOS) phenotype with decreased expression of enzymes associated with glycolytic pathway and increased expression of a large number of mitochondrial proteins involved in electron transport chain as well as enzymes of the tricarboxylic acid (TCA) cycle. Electron micrographs revealed increase in number and size of mitochondria. Based on these observations, we propose that chronic exposure of esophageal epithelial cells to tobacco leads to cancer stem cell-like phenotype. These cells show the characteristic OXPHOS phenotype, which can be potentially targeted as a therapeutic strategy.
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spelling pubmed-67700592019-10-30 Chronic Exposure to Chewing Tobacco Induces Metabolic Reprogramming and Cancer Stem Cell-Like Properties in Esophageal Epithelial Cells Datta, Keshava K. Patil, Shankargouda Patel, Krishna Babu, Niraj Raja, Remya Nanjappa, Vishalakshi Mangalaparthi, Kiran Kumar Dhaka, Bharti Rajagopalan, Pavithra Deolankar, Sayali Chandrashekhar Kannan, Ramakrishnan Kumar, Prashant Prasad, T. S. Keshava Mathur, Premendu P. Kumari, Anjali Manoharan, Malini Coral, Karunakaran Murugan, Saktivel Sidransky, David Gupta, Ravi Gupta, Rohit Khanna-Gupta, Arati Chatterjee, Aditi Gowda, Harsha Cells Article Tobacco in its smoke and smokeless form are major risk factors for esophageal squamous cell carcinoma (ESCC). However, molecular alterations associated with smokeless tobacco exposure are poorly understood. In the Indian subcontinent, tobacco is predominantly consumed in chewing form. An understanding of molecular alterations associated with chewing tobacco exposure is vital for identifying molecular markers and potential targets. We developed an in vitro cellular model by exposing non-transformed esophageal epithelial cells to chewing tobacco over an eight-month period. Chronic exposure to chewing tobacco led to increase in cell proliferation, invasive ability and anchorage independent growth, indicating cell transformation. Molecular alterations associated with chewing tobacco exposure were characterized by carrying out exome sequencing and quantitative proteomic profiling of parental cells and chewing tobacco exposed cells. Quantitative proteomic analysis revealed increased expression of cancer stem cell markers in tobacco treated cells. In addition, tobacco exposed cells showed the Oxidative Phosphorylation (OXPHOS) phenotype with decreased expression of enzymes associated with glycolytic pathway and increased expression of a large number of mitochondrial proteins involved in electron transport chain as well as enzymes of the tricarboxylic acid (TCA) cycle. Electron micrographs revealed increase in number and size of mitochondria. Based on these observations, we propose that chronic exposure of esophageal epithelial cells to tobacco leads to cancer stem cell-like phenotype. These cells show the characteristic OXPHOS phenotype, which can be potentially targeted as a therapeutic strategy. MDPI 2019-08-21 /pmc/articles/PMC6770059/ /pubmed/31438645 http://dx.doi.org/10.3390/cells8090949 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Datta, Keshava K.
Patil, Shankargouda
Patel, Krishna
Babu, Niraj
Raja, Remya
Nanjappa, Vishalakshi
Mangalaparthi, Kiran Kumar
Dhaka, Bharti
Rajagopalan, Pavithra
Deolankar, Sayali Chandrashekhar
Kannan, Ramakrishnan
Kumar, Prashant
Prasad, T. S. Keshava
Mathur, Premendu P.
Kumari, Anjali
Manoharan, Malini
Coral, Karunakaran
Murugan, Saktivel
Sidransky, David
Gupta, Ravi
Gupta, Rohit
Khanna-Gupta, Arati
Chatterjee, Aditi
Gowda, Harsha
Chronic Exposure to Chewing Tobacco Induces Metabolic Reprogramming and Cancer Stem Cell-Like Properties in Esophageal Epithelial Cells
title Chronic Exposure to Chewing Tobacco Induces Metabolic Reprogramming and Cancer Stem Cell-Like Properties in Esophageal Epithelial Cells
title_full Chronic Exposure to Chewing Tobacco Induces Metabolic Reprogramming and Cancer Stem Cell-Like Properties in Esophageal Epithelial Cells
title_fullStr Chronic Exposure to Chewing Tobacco Induces Metabolic Reprogramming and Cancer Stem Cell-Like Properties in Esophageal Epithelial Cells
title_full_unstemmed Chronic Exposure to Chewing Tobacco Induces Metabolic Reprogramming and Cancer Stem Cell-Like Properties in Esophageal Epithelial Cells
title_short Chronic Exposure to Chewing Tobacco Induces Metabolic Reprogramming and Cancer Stem Cell-Like Properties in Esophageal Epithelial Cells
title_sort chronic exposure to chewing tobacco induces metabolic reprogramming and cancer stem cell-like properties in esophageal epithelial cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770059/
https://www.ncbi.nlm.nih.gov/pubmed/31438645
http://dx.doi.org/10.3390/cells8090949
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