title: Unraveling the mechanism of cell death induced by chemical fibrils.
abstract: We previously discovered a small-molecule inducer of cell death, named 1541, that noncovalently self-assembles into chemical fibrils ('chemi-fibrils') and activates procaspase-3 in vitro. We report here that 1541-induced cell death is caused by the fibrillar rather than the soluble form of the drug. A short hairpin RNA screen reveals that knockdown of genes involved in endocytosis, vesicle trafficking and lysosomal acidification causes partial 1541 resistance. We confirm the role of these pathways using pharmacological inhibitors. Microscopy shows that the fluorescent chemi-fibrils accumulate in punctae inside cells that partially colocalize with lysosomes. Notably, the chemi-fibrils bind and induce liposome leakage in vitro, suggesting they may do the same in cells. The chemi-fibrils induce extensive proteolysis including caspase substrates, yet modulatory profiling reveals that chemi-fibrils form a distinct class from existing inducers of cell death. The chemi-fibrils share similarities with proteinaceous fibrils and may provide insight into their mechanism of cellular toxicity.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, California, USA.
authors.forename: Olivier
authors.identifier: 0000000170687299
authors.initials: O
authors.lastname: Julien
authors.affiliation: 1] Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, California, USA. [2] Howard Hughes Medical Institute, University of California-San Francisco, San Francisco, California, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Kampmann
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, California, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Bassik
authors.affiliation: Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, California, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Zorn
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California-San Francisco, San Francisco, California, USA.
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Venditto
authors.affiliation: Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, California, USA.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Shimbo
authors.affiliation: Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, California, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Agard
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York, USA.
authors.forename: Kenichi
authors.identifier: 0000000185409785
authors.initials: K
authors.lastname: Shimada
authors.affiliation: Department of Chemistry, University of California-San Diego, San Diego, California, USA.
authors.forename: Arnold L
authors.initials: AL
authors.lastname: Rheingold
authors.affiliation: 1] Department of Biological Sciences, Columbia University, New York, New York, USA. [2] Department of Chemistry, Columbia University, New York, New York, USA. [3] Howard Hughes Medical Institute, Columbia University, New York, New York, USA.
authors.forename: Brent R
authors.initials: BR
authors.lastname: Stockwell
authors.affiliation: 1] Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, California, USA. [2] Howard Hughes Medical Institute, University of California-San Francisco, San Francisco, California, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Weissman
authors.affiliation: 1] Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, California, USA. [2] Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, California, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Wells
mesh_terms: D000595:Amino Acid Sequence; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020014:K562 Cells; D008247:Lysosomes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D001549:Benzamides; D003374:Coumarins; D053148:Caspase 3