A set of NF-κB–regulated microRNAs induces acquired TRAIL resistance in lung cancer

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; Croce, C

Abstract

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.

Citation

Jeon, Y., Middleton, J., Kim, T., Laguna, A., Piovan, C., Secchiero, P., …Croce, C. (2015). A set of NF-κB–regulated microRNAs induces acquired TRAIL resistance in lung cancer. Proceedings of the National Academy of Sciences, 112(26), E3355-E3364. https://doi.org/10.1073/pnas.1504630112

• Journal Article Type: Article
• Acceptance Date: May 28, 2015
• Online Publication Date: Jun 15, 2015
• Publication Date: Jun 15, 2015
• Deposit Date: Jul 26, 2016
• Journal: Proceedings of the National Academy of Sciences of the United States of America (PNAS)
• Publisher: National Academy of Sciences
• Volume: 112
• Issue: 26
• Pages: E3355-E3364
• DOI: https://doi.org/10.1073/pnas.1504630112
• Publisher URL: http://dx.doi.org/10.1073/pnas.1504630112
• Related Public URLs: http://www.pnas.org/
• Additional Information: Funders : NIH;Kimmel Cancer Foundation