Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783455382741450752 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6770059 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT dattakeshavak chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT patilshankargouda chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT patelkrishna chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT babuniraj chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT rajaremya chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT nanjappavishalakshi chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT mangalaparthikirankumar chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT dhakabharti chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT rajagopalanpavithra chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT deolankarsayalichandrashekhar chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT kannanramakrishnan chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT kumarprashant chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT prasadtskeshava chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT mathurpremendup chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT kumarianjali chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT manoharanmalini chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT coralkarunakaran chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT murugansaktivel chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT sidranskydavid chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT guptaravi chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT guptarohit chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT khannaguptaarati chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT chatterjeeaditi chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT gowdaharsha chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells |