title: Global proteomic profiling identifies etoposide chemoresistance markers in non-small cell lung carcinoma.
abstract: Chemoresistance is one of the leading health concerns in cancer treatment. Understanding the mechanism of chemoresistance is the best way to improve the survival of the patient. Etoposide and its analogues are widely used as antitumor drugs in lung cancer but many etoposide resistant lung cancer cases has been identified in recent years. The present study aims to explore the cellular response of lung cancer cell lines to etoposide and finding the potential chemoresistant marker proteins. Multiple proteomic platforms like 2-DE, DIGE and iTRAQ have been used to study the global proteome profile of NCI-H460 and etoposide resistant NCI-H460R cell lines. Our study revealed that etoposide treatment leads to alteration of 83 proteins in NCI-H460R cell lines. The functional analysis highlighted the role of the differential expressed proteins in cellular signaling, apoptosis, and cytoskeleton reorganization. Our study has identified several new proteins like RHOC, DLG5, UGDH, TMOD3 in addition to known chemoresistance associated proteins. In silico prediction of the important selected candidates are further validated at protein and mRNA level. Further, functional studies of newly identified candidate genes RHOC and DLG5 revealed that chemotherapeutic resistance is associated with their elevated level and may serve as novel targets for therapeutic intervention.
  
  
  CONCLUSIONS
  Etoposide and its analogues have been used for lung cancer treatment for a while and it was reported that many non small cell lung carcinoma patients are resistant to etoposide. Although etoposide show drug resistance, the exact mechanism was not well understood. The present study focused on the global proteome analysis of NCI-H460 and NCI-H460R cell lines using multiple proteomic platforms to understand the potential chemoresistant markers for etoposide. Our multi-proteomic analysis has showed differential expression of 83 proteins involved in oxidative phosphorylation, metabolic, protein folding, cytoskeleton associated protein along with apoptotic pathway has been identified. In addition, quite a few interesting proteins such as RHOC, DLG5, HSP90, citrate synthase, UDP-glucose-6-dehydrogenase, Tropomodulin-3 are involved in chemoresistance has been observed. Overall, this is the first comprehensive proteomic study on etoposide resistant cell line NCI-H460 to explore the mechanism of chemoresistance in lung cancer.
authors.affiliation: National Centre for Cell Science, Ganeshkhind, Pune 411007, Maharashtra, India.
authors.forename: Debasish
authors.initials: D
authors.lastname: Paul
authors.affiliation: National Centre for Cell Science, Ganeshkhind, Pune 411007, Maharashtra, India.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Chanukuppa
authors.affiliation: Department of Biosciences and Bioengineering, Indian institute of Technology Bombay, Powai, Mumbai 400076, Maharashtra, India.
authors.forename: Panga Jaipal
authors.initials: PJ
authors.lastname: Reddy
authors.affiliation: National Centre for Cell Science, Ganeshkhind, Pune 411007, Maharashtra, India.
authors.forename: Khushman
authors.initials: K
authors.lastname: Taunk
authors.affiliation: National Centre for Cell Science, Ganeshkhind, Pune 411007, Maharashtra, India.
authors.forename: Ragini
authors.initials: R
authors.lastname: Adhav
authors.affiliation: Department of Biosciences and Bioengineering, Indian institute of Technology Bombay, Powai, Mumbai 400076, Maharashtra, India.
authors.forename: Sanjeeva
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: National Centre for Cell Science, Ganeshkhind, Pune 411007, Maharashtra, India. Electronic address: manas@nccs.res.in.
authors.forename: Manas Kumar
authors.initials: MK
authors.lastname: Santra
authors.affiliation: National Centre for Cell Science, Ganeshkhind, Pune 411007, Maharashtra, India. Electronic address: rsrikanth@nccs.res.in.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Rapole
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D040901:Proteomics
chemical_list: D009363:Neoplasm Proteins; D005047:Etoposide
keywords: Chemoresistance; DIGE; Etoposide; Lung cancer; NSCLC; iTRAQ