國家衛生研究院 NHRI:Item 3990099045/9183
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    题名: Enhanced antitumor activity of rapamycin and genipin, a UCP-2 inhibitor, in lung cancer
    作者: Su, WP;Chang, JY;Liaw, H;Kuo, CC;Su, WC
    贡献者: Institute of Biotechnology and Pharmaceutical Research;National Institute of Cancer Research
    摘要: Background: 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. Methods: We combined the treatment of genipin and rapamycin in human lung cancer A549, H460 and CL1-0 cells. Then we treated the cancer cells with rapamycin, everolimus and BGT226 (a dual PI3K/mTOR inhibitor), and detected p62 and NrF2 activation, the downstream antioxidant signaling and UCP-2 expression and mRNA level. The NrF2 activation was confirmed by luciferase assay. Their relationship was verified by intracellular ROS measurement, and mitochondrial membrane potential. We used seahorse to examine the change in mitochondrial function of lung cancer cells after rapamycin treatment. Finally, we validated our results in animal model. Results: Combined with genipin and rapamycin have a synergistic effect with more cellular apoptosis in A549, H460 and CL1-0 cells. It's said that NrF2 may affect UCP-2 expression. We found NrF2 was activated in lung cancer A549, H460 and CL1-0 cells treated with rapamycin. Another mTOR inhibitor, everolimus and dual PI3K/mTOR inhibitor, BGT226, also induced NrF2 nuclear translocation in these lung cancer cells. Ishimura R et al. reported p62 activates NrF2 through P62 Ser351-phosphorylation under oxidant stress. 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 enhanced UCP-2 expression, leading to decreased mitochondrial membrane potential and mild increased oxygen consumption rate. Finally in A549 subcutaneous tumor from nude mice, combined genipin and everolimus demonstrated the greatest antitumor activity. Conclusions: Inhibition UCP-2 by genipin enhances anticancer effect of rapamycin in lung cancer.
    日期: 2015-05
    關聯: Journal of Clinical Oncology. 2015 May;33(15, Suppl.):e13595.
    Link to: http://meeting.ascopubs.org/cgi/content/abstract/33/15_suppl/e13595
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0732-183X&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000358036902586
    显示于类别:[郭靜娟] 會議論文/會議摘要
    [張俊彥] 會議論文/會議摘要

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