title: TRAP1 regulates proliferation, mitochondrial function, and has prognostic significance in NSCLC.
abstract: The TNF receptor-associated protein 1 (TRAP1) is a mitochondrial HSP that has been related to drug resistance and protection from apoptosis in colorectal and prostate cancer. Here, the effect of TRAP1 ablation on cell proliferation, survival, apoptosis, and mitochondrial function was determined in non-small cell lung cancer (NSCLC). In addition, the prognostic value of TRAP1 was evaluated in patients with NSCLC. These results demonstrate that TRAP1 knockdown reduces cell growth and clonogenic cell survival. Moreover, TRAP1 downregulation impairs mitochondrial functions such as ATP production and mitochondrial membrane potential as measured by TMRM (tetramethylrhodamine methylester) uptake, but it does not affect mitochondrial density or mitochondrial morphology. The effect of TRAP1 silencing on apoptosis, analyzed by flow cytometry and immunoblot expression (cleaved PARP, caspase-9, and caspase-3) was cell line and context dependent. Finally, the prognostic potential of TRAP1 expression in NSCLC was ascertained via immunohistochemical analysis which revealed that high TRAP1 expression was associated with increased risk of disease recurrence (univariate analysis, P = 0.008; multivariate analysis, HR: 2.554; 95% confidence interval, 1.085-6.012; P = 0.03). In conclusion, these results demonstrate that TRAP1 impacts the viability of NSCLC cells, and that its expression is prognostic in NSCLC.
  
  
  CONCLUSIONS
  TRAP1 controls NSCLC proliferation, apoptosis, and mitochondrial function, and its status has prognostic potential in NSCLC.
authors.affiliation: Authors' Affiliations: Oncology Division, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona; 2Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain; 3Nuffield Department of Clinical Laboratory Sciences; 4Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital; 5Department of Medical Oncology, University of Oxford, The Churchill Hospital, Oxford, United Kingdom; 6Department of Rheumatology and Immunology, Shandong Provincial Hospital, Shandong University, Jinan, China; and 7Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.
authors.forename: Jackeline
authors.initials: J
authors.lastname: Agorreta
authors.forename: Jianting
authors.initials: J
authors.lastname: Hu
authors.forename: Dongxia
authors.initials: D
authors.lastname: Liu
authors.forename: Domenico
authors.initials: D
authors.lastname: Delia
authors.forename: Helen
authors.initials: H
authors.lastname: Turley
authors.forename: David J P
authors.initials: DJ
authors.lastname: Ferguson
authors.forename: Francisco
authors.initials: F
authors.lastname: Iborra
authors.forename: María J
authors.initials: MJ
authors.lastname: Pajares
authors.forename: Marta
authors.initials: M
authors.lastname: Larrayoz
authors.forename: Isabel
authors.initials: I
authors.lastname: Zudaire
authors.forename: Ruben
authors.initials: R
authors.lastname: Pio
authors.forename: Luis M
authors.initials: LM
authors.lastname: Montuenga
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Kevin
authors.initials: K
authors.lastname: Gatter
authors.forename: Francesco
authors.initials: F
authors.lastname: Pezzella
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000368:Aged; D017209:Apoptosis / Q000502:physiology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D055785:Gene Knockdown Techniques; D018841:HSP90 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology
chemical_list: D018841:HSP90 Heat-Shock Proteins; D034741:RNA, Small Interfering; C092306:TRAP1 protein, human; D000255:Adenosine Triphosphate