ATF2 contributes to cisplatin resistance in non-small cell lung cancer and celastrol induces cisplatin resensitization through inhibition of JNK/ATF2 pathway

作者：Lo Iacono Marco^*; Monica Valentina; Vavala Tiziana; Gisabella Mara; Saviozzi Silvia; Bracco Enrico; Novello Silvia; Papotti Mauro; Scagliotti Giorgio Vittorio

来源：International Journal of Cancer, 2015, 136(11): 2598-2609.

DOI：10.1002/ijc.29302

• ATF2
• celastrol
• cisplatin resistance
• non-small cell lung cancer

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, Log(2)(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.
What's new? While platinum-based chemotherapy currently represents the standard of care for non-small cell lung cancer (NSCLC), patients show rapid onset of resistance. Here, the authors demonstrate a possible involvement of ATF2--a transcription factor involved in stress and DNA damage--in NSCLC platinum-resistance, thus identifying a putative target for the restoration of platinum sensitivity. They further show that celastrol--a plant extract used in traditional Chinese medicine as an anti-inflammatory agent--was able to reduce ATF2 activity and restore cisplatin efficacy in resistant cell lines through the functional inhibition of ATF2/cJUN.

• 出版日期2015-6-1