title: hBfl-1/hNOXA Interaction Studies Provide New Insights on the Role of Bfl-1 in Cancer Cell Resistance and for the Design of Novel Anticancer Agents.
abstract: Upregulation of antiapoptotic Bcl-2 proteins in certain tumors confers cancer cell resistance to chemotherapy or radiations. Members of the antiapoptotic Bcl-2 proteins, including Bcl-2, Mcl-1, Bcl-xL, Bcl-w, and Bfl-1, inhibit apoptosis by selectively binding to conserved α-helical regions, named BH3 domains, of pro-apoptotic proteins such as Bim, tBid, Bad, or NOXA. Five antiapoptotic proteins have been identified that interact with various selectivity with BH3 containing pro-apoptotic counterparts. Cancer cells present various and variable levels of these proteins, making the design of effective apoptosis based therapeutics challenging. Recently, BH3 profiling was introduced as a method to classify cancer cells based on their ability to resist apoptosis following exposure to selected BH3 peptides. However, these studies were based on binding affinities measured with model BH3 peptides and Bcl-2-proteins taken from mouse sequences. While the majority of these interactions are conserved between mice and humans, we found surprisingly that human NOXA binds to human Bfl-1 potently and covalently via conserved Cys residues, with over 2 orders of magnitude increased affinity over hMcl-1. Our data suggest that some assumptions of the original BH3 profiling need to be revisited and that perhaps further targeting efforts should be redirected toward Bfl-1, for which no suitable specific inhibitors or pharmacological tools have been reported. In this regard, we also describe the initial design and characterizations of novel covalent BH3-based agents that potently target Bfl-1. These molecules could provide a novel platform on which to design effective Bfl-1 targeting therapeutics.
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California, Riverside , 900 University Avenue, Riverside, California 92521, United States.
authors.forename: Elisa
authors.initials: E
authors.lastname: Barile
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California, Riverside , 900 University Avenue, Riverside, California 92521, United States.
authors.forename: Guya D
authors.initials: GD
authors.lastname: Marconi
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California, Riverside , 900 University Avenue, Riverside, California 92521, United States.
authors.forename: Surya K
authors.initials: SK
authors.lastname: De
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California, Riverside , 900 University Avenue, Riverside, California 92521, United States.
authors.forename: Carlo
authors.initials: C
authors.lastname: Baggio
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California, Riverside , 900 University Avenue, Riverside, California 92521, United States.
authors.forename: Luca
authors.initials: L
authors.lastname: Gambini
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California, Riverside , 900 University Avenue, Riverside, California 92521, United States.
authors.forename: Ahmed F
authors.initials: AF
authors.lastname: Salem
authors.affiliation: Moores Cancer Center, University of California, San Diego , La Jolla, California 92093, United States.|CLL Research Consortium, and Department of Medicine, University of California, San Diego , La Jolla, California 92093, United States.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Kashyap
authors.affiliation: Moores Cancer Center, University of California, San Diego , La Jolla, California 92093, United States.|CLL Research Consortium, and Department of Medicine, University of California, San Diego , La Jolla, California 92093, United States.
authors.forename: Januario E
authors.initials: JE
authors.lastname: Castro
authors.affiliation: Moores Cancer Center, University of California, San Diego , La Jolla, California 92093, United States.|CLL Research Consortium, and Department of Medicine, University of California, San Diego , La Jolla, California 92093, United States.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California, Riverside , 900 University Avenue, Riverside, California 92521, United States.
authors.forename: Maurizio
authors.identifier: 0000-0001-5179-470X
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015778:Minor Histocompatibility Antigens / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C096816:BCL2-related protein A1; D015778:Minor Histocompatibility Antigens; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2