Abstract 1308: Enhanced antitumor activity of rapamycin and genipin, a UCP-2 inhibitor, in lung cancer

mTOR is constitutively activated in lung cancer. Deletion of TOR1 increases expression of OXPHOS proteins, and mitochondrial uncoupling proteins 2 (UCP-2) expression promotes chemoresistance. Therefore, we evaluated whether adding genipin, a UCP-2 inhibitor, to rapamycin has better antitumor effect in lung cancer. Combined with genipin and rapamycin have a synergistic effect with more cellular apoptosis in A549, H460 and CL1-0 cells. The similar phenomenon was found in the combination treatment with genipin and everolimus or BGT226 (a dual PI3K/mTOR inhibitor) in this three lung cancer cells. It is said that NrF2 may affect UCP-2 expression, and we found NrF2 was activated in lung cancer A549, H460 and CL1-0 cells treated with rapamycin. Everolimus and dual PI3K/mTOR inhibitor, BGT226, also induced NrF2 nuclear translocation in these lung cancer cells. It is said that under oxidant stress, p62 activates NrF2 through P62 Ser351-phosphorylation. We found that rapamycin induced ROS generation, p62 serine phosphorylation and NrF2 downstream mRNA and protein expression, including UCP-2. ROS inhibitor, NAC, and down-regulation of p62 by siRNA suppressed rapamycin-induced UCP-2 expression. Overexpression of p62 by cDNA transfection enhanced NrF2 activation and then UCP-2 expression in lung cancer cells. Moreover, rapamycin-induced increased UCP-2 expression, leading decreased mitochondrial membrane potential and mild increased oxygen consumption rate. Finally in A549 subcutaneous tumor mode in SCID mice, combined genipin and everolimus also demonstrated the greatest antitumor activity. Therefore, inhibition UCP-2 by genipin enhances anticancer effect of rapamycin in lung cancer. Citation Format: Wen-Pin Su, Jang-Yang Chang, Ching-Chuan Kuo, Wu-Chou Su. Enhanced antitumor activity of rapamycin and genipin, a UCP-2 inhibitor, in lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1308.