title: ATF2 contributes to cisplatin resistance in non-small cell lung cancer and celastrol induces cisplatin resensitization through inhibition of JNK/ATF2 pathway.
abstract: ATF2 is a transcription factor involved in stress and DNA damage. A correlation between ATF2 JNK-mediated activation and resistance to damaging agents has already been reported. The purpose of the present study was to investigate whether ATF2 may have a role in acquired resistance to cisplatin in non-small cell lung cancer (NSCLC). mRNA and protein analysis on matched cancer and corresponding normal tissues from surgically resected NSCLC have been performed. Furthermore, in NSCLC cell lines, ATF2 expression levels were evaluated and correlated to platinum (CDDP) resistance. Celastrol-mediated ATF2/cJUN activity was measured. High expression levels of both ATF2 transcript and proteins were observed in lung cancer specimens (p << 0.01, Log2 (FC) = +4.7). CDDP-resistant NSCLC cell lines expressed high levels of ATF2 protein. By contrast, Celastrol-mediated ATF2/cJUN functional inhibition restored the response to CDDP. Moreover, ATF2 protein activation correlates with worse outcome in advanced CDDP-treated patients. For the first time, it has been shown NSCLC ATF2 upregulation at both mRNA/protein levels in NSCLC. In addition, we reported that in NSCLC cell lines a correlation between ATF2 protein expression and CDDP resistance occurs. Altogether, our results indicate a potential increase in CDDP sensitivity, on Celastrol-mediated ATF2/cJUN inhibition. These data suggest a possible involvement of ATF2 in NSCLC CDDP-resistance.
authors.affiliation: Department of Oncology, University of Turin, S. Luigi Hospital, Regione Gonzole 10, Orbassano, Turin, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Lo Iacono
authors.forename: Valentina
authors.initials: V
authors.lastname: Monica
authors.forename: Tiziana
authors.initials: T
authors.lastname: Vavalà
authors.forename: Mara
authors.initials: M
authors.lastname: Gisabella
authors.forename: Silvia
authors.initials: S
authors.lastname: Saviozzi
authors.forename: Enrico
authors.initials: E
authors.lastname: Bracco
authors.forename: Silvia
authors.initials: S
authors.lastname: Novello
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
authors.forename: Giorgio Vittorio
authors.initials: GV
authors.lastname: Scagliotti
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D053978:Pentacyclic Triterpenes; D011379:Prognosis; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; C050414:celastrol; D002945:Cisplatin
keywords: ATF2; celastrol; cisplatin resistance; non-small cell lung cancer