ABSTRACT
This corrects the article DOI: 10.1038/cdd.2010.65.
ABSTRACT
Non-small cell lung cancer (NSCLC) accounts for â¼80% of all lung cancers. Although some advances in lung cancer therapy have been made, patient survival is still quite poor. Two microRNAs, miR-221 and miR-222, upregulated by the MET proto-oncogene, have been already described to enhance cell survival and to induce TNF-related apoptosis-inducing ligand (TRAIL) resistance in NSCLC cell lines, through the downregulation of p27(kip1), PTEN and TIMP3. Here, we further investigated this pathway and showed that miR-130a, expressed at low level in lung cancer cell lines, by targeting MET was able to reduce TRAIL resistance in NSCLC cells through the c-Jun-mediated downregulation of miR-221 and miR-222. Moreover, we found that miR-130a reduced migratory capacity of NSCLC. A better understanding of MET-miR-221 and 222 axis regulation in drug resistance is the key in developing new strategies in NSCLC therapy.
Subject(s)
MicroRNAs/genetics , Proto-Oncogene Proteins c-met/genetics , TNF-Related Apoptosis-Inducing Ligand/pharmacology , 3' Untranslated Regions/genetics , Apoptosis/drug effects , Apoptosis/genetics , Binding Sites/genetics , Blotting, Western , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Movement/drug effects , Cell Movement/genetics , Cell Survival/drug effects , Cell Survival/genetics , Cysteine Proteinase Inhibitors/pharmacology , Down-Regulation , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic , Humans , JNK Mitogen-Activated Protein Kinases/genetics , JNK Mitogen-Activated Protein Kinases/metabolism , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mutation , Oligopeptides/pharmacology , Proto-Oncogene Mas , Proto-Oncogene Proteins c-met/metabolism , RNA Interference , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Akt is a serine-threonine kinase that has an important role in transducing survival signals. Akt also regulates a number of proteins involved in the apoptotic process. To find new Akt interactors, we performed a two-hybrid screening in yeast using full-length Akt cDNA as bait and a human cDNA heart library as prey. Among 200 clones obtained, two of them were identified as coding for the c-FLIP(L) protein. c-FLIP(L) is an endogenous inhibitor of death receptor-induced apoptosis through the caspase-8 pathway. Using co-immunoprecipitation experiments of either transfected or endogenous proteins, we confirmed the interaction between Akt and c-FLIP(L). Furthermore, we observed that c-FLIP(L) overexpression interferes with Gsk3-ß phosphorylation levels. Moreover, through its effects on Gsk3ß, c-FLIP(L) overexpression in cancer cells induced resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). This effect was mediated by the regulation of p27(Kip1) and caspase-3 expression. These results indicate the existence of a new mechanism of resistance to TRAIL in cancer cells, and unexpected functions of c-FLIP(L).
