Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2015 Jun 30;112(26):E3355-64. doi: 10.1073/pnas.1504630112. Epub 2015 Jun 15.

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

Author information

1
Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210;
2
Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210; Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
3
Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210; Department of Experimental Oncology and Molecular Medicine, Start Up Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale per lo Studio e la Cura dei Tumori, 20133 Milan, Italy;
4
Department of Morphology and Embryology, Human Anatomy Section, University of Ferrara, 44100 Ferrara, Italy;
5
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712;
6
Department of Life Systems, Sookmyung Women's University, Seoul 140-742, Republic of Korea;
7
Transcriptional Networks in Lung Cancer Group, Cancer Research United Kingdom Manchester Institute, University of Manchester, Manchester M20 4BX, United Kingdom michela.garofalo@cruk.manchester.ac.uk carlo.croce@osumc.edu.
8
Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210; michela.garofalo@cruk.manchester.ac.uk carlo.croce@osumc.edu.

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.

KEYWORDS:

acquired TRAIL-resistance; lung cancer; microRNAs

PMID:
26080425
PMCID:
PMC4491797
DOI:
10.1073/pnas.1504630112
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center