title: 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.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, People's Republic of China.
authors.forename: W
authors.initials: W
authors.lastname: Zeng
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Plastic Surgery, Xiangya Hospital, Central South University, Changsha, People's Republic of China.
authors.forename: M
authors.initials: M
authors.lastname: Qi
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, People's Republic of China.
authors.forename: C
authors.initials: C
authors.lastname: Peng
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, People's Republic of China.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.affiliation: 1] Department of Dermatology, Xiangya Hospital, Central South University, Changsha, People's Republic of China [2] Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology
chemical_list: D051017:Apoptosis Regulatory Proteins; C505533:FADD protein, human; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D018832:Molecular Chaperones; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; C096099:nascent-polypeptide-associated complex; D048670:MAP Kinase Kinase 4