期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：26
页码：E3355-E3364
DOI：10.1073/pnas.1504630112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceTRAIL (TNF-related apoptosis-inducing ligand) is a promising antitumor agent effective in a very small subset of lung cancer patients with low toxicity. However, the majority of lung tumors are TRAIL-resistant and very little is known about how tumor cells acquire resistance to TRAIL. Here, we show that continuous exposure to subtoxic concentrations of TRAIL induces NF-{kappa}B-dependent up-regulation of miR-21, miR-30c, and miR-100, which by silencing caspase-8, caspase-3, TRAF7, and FoxO3a further strengthens the NF-{kappa}B signaling, inducing acquired TRAIL resistance. Our findings imply that combinatory therapies of NF-{kappa}B inhibitors and TRAIL might be a useful therapy to improve the response of lung cancer to TRAIL. TRAIL (TNF-related apoptosis-inducing ligand) is a promising anticancer agent that can be potentially used as an alternative or complementary therapy because of its specific antitumor activity. However, TRAIL can also stimulate the proliferation of cancer cells through the activation of NF-{kappa}B, but the exact mechanism is still poorly understood. In this study, we show that chronic exposure to subtoxic concentrations of TRAIL results in acquired resistance. This resistance is associated with the increase in miR-21, miR-30c, and miR-100 expression, which target tumor-suppressor genes fundamental in the response to TRAIL. Importantly, down-regulation of caspase-8 by miR-21 blocks receptor interacting protein-1 cleavage and induces the activation of NF-{kappa}B, which regulates these miRNAs. Thus, TRAIL activates a positive feedback loop that sustains the acquired resistance and causes an aggressive phenotype. Finally, we prove that combinatory treatment of NF-{kappa}B inhibitors and TRAIL is able to revert resistance and reduce tumor growth, with important consequences for the clinical practice.
关键词：microRNAs ; acquired TRAIL-resistance ; lung cancer
