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

被引:24
作者
Datta, Keshava K. [1 ,12 ]
Patil, Shankargouda [2 ,3 ]
Patel, Krishna [1 ,4 ]
Babu, Niraj [1 ,5 ]
Raja, Remya [1 ]
Nanjappa, Vishalakshi [1 ]
Mangalaparthi, Kiran Kumar [1 ,4 ]
Dhaka, Bharti [1 ]
Rajagopalan, Pavithra [1 ]
Deolankar, Sayali Chandrashekhar [6 ,7 ]
Kannan, Ramakrishnan [7 ]
Kumar, Prashant [1 ]
Prasad, T. S. Keshava [6 ]
Mathur, Premendu P. [8 ,9 ]
Kumari, Anjali [10 ]
Manoharan, Malini [10 ]
Coral, Karunakaran [10 ]
Murugan, Saktivel [10 ]
Sidransky, David [11 ]
Gupta, Ravi [10 ]
Gupta, Rohit [10 ]
Khanna-Gupta, Arati [10 ]
Chatterjee, Aditi [1 ,5 ]
Gowda, Harsha [1 ,5 ]
机构
[1] Inst Bioinformat, Int Tech Pk, Bangalore 560066, Karnataka, India
[2] Jazan Univ, Coll Dent, Dept Maxillofacial Surg & Diagnost Sci, Div Oral Pathol, Jazan 45142, Saudi Arabia
[3] Univ Siena, Sch Dent Med, Dept Med Biotechnol, I-53100 Siena, Italy
[4] Amrita Vishwa Vidyapeetham, Amrita Sch Biotechnol, Kollam 690525, India
[5] Manipal Acad Higher Educ, Manipal 576104, Karnataka, India
[6] Yenepoya Deemed Univ, Ctr Syst Biol & Mol Med, Mangalore 575018, India
[7] NIMHANS, Hosur Rd, Bangalore 560029, Karnataka, India
[8] KIIT Deemed Univ, Sch Biotechnol, Bhubaneswar 751024, India
[9] Pondicherry Univ, Sch Life Sci, Dept Biochem & Mol Biol, Pondicherry 605014, India
[10] Medgenome Labs Pvt Ltd, Bangalore 560099, Karnataka, India
[11] Johns Hopkins Univ, Dept Otolaryngol Head & Neck Surg, Sch Med, Baltimore, MD 21231 USA
[12] QIMR Berghofer Med Res Inst, Dept Genet & Computat Biol, Brisbane, Qld 4006, Australia
关键词
mitochondria; cancer metabolism; tobacco; proteomics; exome sequencing; electron microscopy; OXIDATIVE-PHOSPHORYLATION; MITOCHONDRIAL MASS; IDENTIFICATION; CARCINOMA; ABERRATIONS; EXPRESSION; HALLMARKS; PROTEINS; TARGET; TUMORS;
D O I
10.3390/cells8090949
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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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页数:15
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