MiR-494 is regulated by ERK1/2 and modulates TRAIL-induced apoptosis in non-small-cell lung cancer through BIM down-regulation.

Abstract

MicroRNAs (miRNAs) have an important role in the development of chemosensitivity or chemoresistance in different types of cancer. Activation of the ERK1/2 pathway is a major determinant of diverse cellular processes and cancer development and is responsible for the transcription of several important miRNAs. Here we show a link between the ERK1/2 pathway and BIM expression through miR-494. We blocked ERK1/2 nuclear activity through the overexpression of an ERK1/2 natural interactor, the protein PED/PEA15, and we performed a microRNA expression profile. miR-494 was the most down-regulated microRNA after ERK1/2 inactivation. Moreover, we found that miR-494 induced Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) resistance in non-small-cell lung cancer (NSCLC) through the down-modulation of BIM. Elucidation of this undiscovered ERK1/2 pathway that regulates apoptosis and cell proliferation through miR-494 in NSCLC will greatly enhance our understanding of the mechanisms responsible for TRAIL resistance and will provide an additional arm for the development of anticancer therapies.

• Authors: Giulia Romano, Mario Acunzo, Michela Garofalo, Gianpiero Di Leva, Luciano Cascione, Ciro Zanca, Brad Bolon, Gerolama Condorelli, Carlo M Croce
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 41 Pg. 16570-5 (Oct 09 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 23012423 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• BCL2L11 protein, human
• Bcl-2-Like Protein 11
• Bcl2l11 protein, mouse
• MIRN494 microRNA, human
• Membrane Proteins
• MicroRNAs
• Proto-Oncogene Proteins
• TNF-Related Apoptosis-Inducing Ligand
• MAPK1 protein, human
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Animals
• Apoptosis (drug effects, genetics)
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Bcl-2-Like Protein 11
• Blotting, Western
• Carcinoma, Non-Small-Cell Lung (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation
• Down-Regulation
• Gene Expression Profiling
• HEK293 Cells
• Humans
• Lung Neoplasms (genetics, metabolism, pathology)
• MAP Kinase Signaling System (genetics)
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Nude
• MicroRNAs (genetics)
• Mitogen-Activated Protein Kinase 1 (genetics, metabolism)
• Mitogen-Activated Protein Kinase 3 (genetics, metabolism)
• Proto-Oncogene Proteins (genetics, metabolism)
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• Tumor Burden (genetics)
• Xenograft Model Antitumor Assays