Jeon, Y, Middleton, J, Kim, T, Laguna, A, Piovan, C, Secchiero, P, Nuovo, G, Cui, R, Joshi, P, Romano, G, Di Leva, Gianpiero, Lee, B, Sun, H, Kim, Y, Fadda, P, Alder, H, Garofalo, M and Croce, C 2015, 'A set of NF-κB–regulated microRNAs induces acquired TRAIL resistance in lung cancer' , Proceedings of the National Academy of Sciences of the United States of America (PNAS), 112 (26) , E3355-E3364.
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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-κB, 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-κB, 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-κB inhibitors and TRAIL is able to revert resistance and reduce tumor growth, with important consequences for the clinical practice.
|Schools:||Schools > School of Environment and Life Sciences > Biomedical Research Centre|
|Journal or Publication Title:||Proceedings of the National Academy of Sciences of the United States of America (PNAS)|
|Publisher:||National Academy of Sciences|
|Funders:||NIH, Kimmel Cancer Foundation|
|Depositing User:||G Di Leva|
|Date Deposited:||26 Jul 2016 07:40|
|Last Modified:||26 Jul 2016 07:40|
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