α NAC inhibition of the FADD-JNK axis plays anti-apoptotic role in multiple cancer cells
CELL DEATH & DISEASE(2014)
Abstract
Nascent polypeptide-associated complex α ( α NAC) 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 α NAC in cancer progression. First, we observed the cellular effects of α NAC depletion. Mouse α NAC 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 α NAC depletion. The Cancer 10-pathway reporter assay was used to screen downstream pathways. PCR site-directed deletion based on the functional domains of α NAC was used to construct deletion mutants. Those functional domain deletion mutants were used to recover the apoptotic phenotype caused by α NAC depletion. Finally, the role of α NAC in TNF-related apoptosis-inducing ligand (TRAIL) treatment was investigated in vitro . We found that depletion of α NAC 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 α NAC is required for the direct binding of FADD as well as its anti-apoptosis function. Either α NAC depletion or the deletion of the ubiquitin-associated domain of α NAC sensitizes L929 cancer cells to mTRAIL treatment. Our study revealed a α NAC anti-apoptotic function in multiple types of cancer cells and suggested its potential in cancer therapy.
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Key words
cancer, immunity, neurodegeneration, apoptosis, cell death, cell growth, Stem Cell, Signaling, Autophagy, Wallerian Degeneration, Cornification, Keratinization, Toxicity, Transcription
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