αNAC inhibition of the FADD-JNK axis plays anti-apoptotic role in multiple cancer cells.

Abstract

Nascent polypeptide-associated complex α (αNAC) is reportedly overexpressed in several types of cancers and regulates cell apoptosis under hypoxic conditions in HeLa cells. The aim of our study was to investigate the apoptotic function of αNAC in cancer progression. First, we observed the cellular effects of αNAC depletion. Mouse αNAC was used to restore the protein level and verify the effect. An Annexin V assay, a caspase activity reporter assay, an apoptotic molecular marker, and a colony formation assay were used as markers to investigate the mechanisms of cell death caused by αNAC depletion. The Cancer 10-pathway reporter assay was used to screen downstream pathways. PCR site-directed deletion based on the functional domains of αNAC was used to construct deletion mutants. Those functional domain deletion mutants were used to recover the apoptotic phenotype caused by αNAC depletion. Finally, the role of αNAC in TNF-related apoptosis-inducing ligand (TRAIL) treatment was investigated in vitro. We found that depletion of αNAC in multiple types of cancer cells induce typical apoptotic cell death. This anti-apoptotic function is mediated by the FADD/c-Jun N-terminal kinase pathway. Intact αNAC is required for the direct binding of FADD as well as its anti-apoptosis function. Either αNAC depletion or the deletion of the ubiquitin-associated domain of αNAC sensitizes L929 cancer cells to mTRAIL treatment. Our study revealed a αNAC anti-apoptotic function in multiple types of cancer cells and suggested its potential in cancer therapy.

• Authors: W Zeng, J Zhang, M Qi, C Peng, J Su, X Chen, Z Yuan
• Journal: Cell death & disease (Cell Death Dis) Vol. 5 Pg. e1282 (Jun 05 2014) ISSN: 2041-4889 [Electronic] England
• PMID: 24901053 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• FADD protein, human
• Fadd protein, mouse
• Fas-Associated Death Domain Protein
• Molecular Chaperones
• TNF-Related Apoptosis-Inducing Ligand
• Tnfsf10 protein, mouse
• nascent-polypeptide-associated complex
• MAP Kinase Kinase 4

Topics

• Animals
• Apoptosis
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Cell Hypoxia (drug effects, genetics)
• Fas-Associated Death Domain Protein (genetics, metabolism)
• HeLa Cells
• Humans
• MAP Kinase Kinase 4 (genetics, metabolism)
• Mice
• Molecular Chaperones (genetics, metabolism)
• Mutation
• Signal Transduction
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)