A set of NF-kappa B-regulated microRNAs induces acquired TRAIL resistance in Lung cancer

作者：Jeon Young Jun; Middleton Justin; Kim Taewan; Lagana Alessandro; Piovan Claudia; Secchiero Paola; Nuovo Gerard J; Cui Ri; Joshi Pooja; Romano Giulia; Di Leva Gianpiero; Lee Bum Kyu; Sun Hui Lung; Kim Yonghwan; Fadda Paolo; Alder Hansjuerg; Garofalo Michela^*; Croce Carlo M

来源：Proceedings of the National Academy of Sciences, 2015, 112(26): E3355-E3364.

DOI：10.1073/pnas.1504630112

• microRNAs
• acquired TRAIL-resistance
• lung cancer

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 tumorsuppressor 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.

• 出版日期2015-6-30