title: A Synthetic Cell-Penetrating Dominant-Negative ATF5 Peptide Exerts Anticancer Activity against a Broad Spectrum of Treatment-Resistant Cancers.
abstract: OBJECTIVE
  Despite significant progress in cancer research, many tumor entities still have an unfavorable prognosis. Activating transcription factor 5 (ATF5) is upregulated in various malignancies and promotes apoptotic resistance. We evaluated the efficacy and mechanisms of the first described synthetic cell-penetrating inhibitor of ATF5 function, CP-d/n-ATF5-S1.
  
  
  METHODS
  Preclinical drug testing was performed in various treatment-resistant cancer cells and in vivo xenograft models.
  
  
  RESULTS
  CP-d/n-ATF5-S1 reduced the transcript levels of several known direct ATF5 targets. It depleted endogenous ATF5 and induced apoptosis across a broad panel of treatment-refractory cancer cell lines, sparing non-neoplastic cells. CP-d/n-ATF5-S1 promoted tumor cell apoptotic susceptibility in part by reducing expression of the deubiquitinase Usp9X and led to diminished levels of antiapoptotic Bcl-2 family members Mcl-1 and Bcl-2. In line with this, CP-d/n-ATF5-S1 synergistically enhanced tumor cell apoptosis induced by the BH3-mimetic ABT263 and the death ligand TRAIL. In vivo, CP-d/n-ATF5-S1 attenuated tumor growth as a single compound in glioblastoma, melanoma, prostate cancer, and triple receptor-negative breast cancer xenograft models. Finally, the combination treatment of CP-d/n-ATF5-S1 and ABT263 significantly reduced tumor growth in vivo more efficiently than each reagent on its own.
  
  
  CONCLUSIONS
  Our data support the idea that CP-d/n-ATF5-S1, administered as a single reagent or in combination with other drugs, holds promise as an innovative, safe, and efficient antineoplastic agent against treatment-resistant cancers. Clin Cancer Res; 22(18); 4698-711. ©2016 AACR.
authors.affiliation: Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York.
authors.forename: Georg
authors.initials: G
authors.lastname: Karpel-Massler
authors.affiliation: Department of Dermatology, Columbia University Medical Center, New York, New York.
authors.forename: Basil A
authors.initials: BA
authors.lastname: Horst
authors.affiliation: Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York.
authors.forename: Chang
authors.initials: C
authors.lastname: Shu
authors.affiliation: Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York.
authors.forename: Lily
authors.initials: L
authors.lastname: Chau
authors.affiliation: Department of Neurosurgery, Columbia University Medical Center, New York, New York.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsujiuchi
authors.affiliation: Department of Neurosurgery, Columbia University Medical Center, New York, New York.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
authors.affiliation: Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York.
authors.forename: Peter
authors.initials: P
authors.lastname: Canoll
authors.affiliation: Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York.
authors.forename: Lloyd A
authors.initials: LA
authors.lastname: Greene
authors.affiliation: Department of Molecular Biosciences, University of California, Davis School of Veterinary Medicine, Davis, California. ms4169@cumc.columbia.edu msiegelin@gmail.com jmangelastro@ucdavis.com.
authors.forename: James M
authors.initials: JM
authors.lastname: Angelastro
authors.affiliation: Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York. ms4169@cumc.columbia.edu msiegelin@gmail.com jmangelastro@ucdavis.com.
authors.forename: Markus D
authors.initials: MD
authors.lastname: Siegelin
mesh_terms: D051696:Activating Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015415:Biomarkers; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D057846:Cell-Penetrating Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C507532:ATF5 protein, human; D051696:Activating Transcription Factors; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D015415:Biomarkers; D057846:Cell-Penetrating Peptides; D010455:Peptides; D013449:Sulfonamides; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D020169:Caspases; C528561:navitoclax