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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2019-08-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/8/9/949 |
| _version_ | 1797717388141002752 |
|---|---|
| author | Keshava K. Datta Shankargouda Patil Krishna Patel Niraj Babu Remya Raja Vishalakshi Nanjappa Kiran Kumar Mangalaparthi Bharti Dhaka Pavithra Rajagopalan Sayali Chandrashekhar Deolankar Ramakrishnan Kannan Prashant Kumar T. S. Keshava Prasad Premendu P. Mathur Anjali Kumari Malini Manoharan Karunakaran Coral Saktivel Murugan David Sidransky Ravi Gupta Rohit Gupta Arati Khanna-Gupta Aditi Chatterjee Harsha Gowda |
| author_facet | Keshava K. Datta Shankargouda Patil Krishna Patel Niraj Babu Remya Raja Vishalakshi Nanjappa Kiran Kumar Mangalaparthi Bharti Dhaka Pavithra Rajagopalan Sayali Chandrashekhar Deolankar Ramakrishnan Kannan Prashant Kumar T. S. Keshava Prasad Premendu P. Mathur Anjali Kumari Malini Manoharan Karunakaran Coral Saktivel Murugan David Sidransky Ravi Gupta Rohit Gupta Arati Khanna-Gupta Aditi Chatterjee Harsha Gowda |
| author_sort | Keshava K. Datta |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-12T08:35:37Z |
| format | Article |
| id | doaj.art-3af770fd8bcb47608756a51e2b8659d8 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T08:35:37Z |
| publishDate | 2019-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-3af770fd8bcb47608756a51e2b8659d82023-09-02T17:17:13ZengMDPI AGCells2073-44092019-08-018994910.3390/cells8090949cells8090949Chronic Exposure to Chewing Tobacco Induces Metabolic Reprogramming and Cancer Stem Cell-Like Properties in Esophageal Epithelial CellsKeshava K. Datta0Shankargouda Patil1Krishna Patel2Niraj Babu3Remya Raja4Vishalakshi Nanjappa5Kiran Kumar Mangalaparthi6Bharti Dhaka7Pavithra Rajagopalan8Sayali Chandrashekhar Deolankar9Ramakrishnan Kannan10Prashant Kumar11T. S. Keshava Prasad12Premendu P. Mathur13Anjali Kumari14Malini Manoharan15Karunakaran Coral16Saktivel Murugan17David Sidransky18Ravi Gupta19Rohit Gupta20Arati Khanna-Gupta21Aditi Chatterjee22Harsha Gowda23Institute of Bioinformatics, International Tech Park, Bangalore 560066, IndiaDepartment of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Jazan 45142, Saudi ArabiaInstitute of Bioinformatics, International Tech Park, Bangalore 560066, IndiaInstitute of Bioinformatics, International Tech Park, Bangalore 560066, IndiaInstitute of Bioinformatics, International Tech Park, Bangalore 560066, IndiaInstitute of Bioinformatics, International Tech Park, Bangalore 560066, IndiaInstitute of Bioinformatics, International Tech Park, Bangalore 560066, IndiaInstitute of Bioinformatics, International Tech Park, Bangalore 560066, IndiaInstitute of Bioinformatics, International Tech Park, Bangalore 560066, IndiaCenter for Systems Biology and Molecular Medicine, Yenepoya (Deemed to be University), Mangalore 575018, IndiaNational Institute of Mental Health and Neuro Sciences (NIMHANS), Hosur Road, Bangalore 560029, IndiaInstitute of Bioinformatics, International Tech Park, Bangalore 560066, IndiaCenter for Systems Biology and Molecular Medicine, Yenepoya (Deemed to be University), Mangalore 575018, IndiaSchool of Biotechnology, KIIT (Deemed to be University), Bhubaneswar 751024, IndiaMedgenome Labs Pvt. Ltd., Bangalore 560099, IndiaMedgenome Labs Pvt. Ltd., Bangalore 560099, IndiaMedgenome Labs Pvt. Ltd., Bangalore 560099, IndiaMedgenome Labs Pvt. Ltd., Bangalore 560099, IndiaDepartment of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USAMedgenome Labs Pvt. Ltd., Bangalore 560099, IndiaMedgenome Labs Pvt. Ltd., Bangalore 560099, IndiaMedgenome Labs Pvt. Ltd., Bangalore 560099, IndiaInstitute of Bioinformatics, International Tech Park, Bangalore 560066, IndiaInstitute of Bioinformatics, International Tech Park, Bangalore 560066, IndiaTobacco 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.https://www.mdpi.com/2073-4409/8/9/949mitochondriacancer metabolismtobaccoproteomicsexome sequencingelectron microscopy |
| spellingShingle | Keshava K. Datta Shankargouda Patil Krishna Patel Niraj Babu Remya Raja Vishalakshi Nanjappa Kiran Kumar Mangalaparthi Bharti Dhaka Pavithra Rajagopalan Sayali Chandrashekhar Deolankar Ramakrishnan Kannan Prashant Kumar T. S. Keshava Prasad Premendu P. Mathur Anjali Kumari Malini Manoharan Karunakaran Coral Saktivel Murugan David Sidransky Ravi Gupta Rohit Gupta Arati Khanna-Gupta Aditi Chatterjee Harsha Gowda Chronic Exposure to Chewing Tobacco Induces Metabolic Reprogramming and Cancer Stem Cell-Like Properties in Esophageal Epithelial Cells Cells mitochondria cancer metabolism tobacco proteomics exome sequencing electron microscopy |
| 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 | mitochondria cancer metabolism tobacco proteomics exome sequencing electron microscopy |
| url | https://www.mdpi.com/2073-4409/8/9/949 |
| work_keys_str_mv | AT keshavakdatta chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT shankargoudapatil chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT krishnapatel chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT nirajbabu chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT remyaraja chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT vishalakshinanjappa chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT kirankumarmangalaparthi chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT bhartidhaka chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT pavithrarajagopalan chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT sayalichandrashekhardeolankar chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT ramakrishnankannan chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT prashantkumar chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT tskeshavaprasad chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT premendupmathur chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT anjalikumari chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT malinimanoharan chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT karunakarancoral chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT saktivelmurugan chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT davidsidransky chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT ravigupta chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT rohitgupta chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT aratikhannagupta chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT aditichatterjee chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells AT harshagowda chronicexposuretochewingtobaccoinducesmetabolicreprogrammingandcancerstemcelllikepropertiesinesophagealepithelialcells |