title: A sequence-specific DNA binding small molecule triggers the release of immunogenic signals and phagocytosis in a model of B-cell lymphoma.
abstract: Means to cause an immunogenic cell death could lead to significant insight into how cancer escapes immune control. In this study, we screened a library of five pyrrole-imidazole polyamides coding for different DNA sequences in a model of B-cell lymphoma for the upregulation of surface calreticulin, a pro-phagocytosis signal implicated in immunogenic cell death. We found that hairpin polyamide 1 triggers the release of the damage-associated molecular patterns calreticulin, ATP and HMGB1 in a slow necrotic-type cell death. Consistent with this signaling, we observed an increase in the rate of phagocytosis by macrophages after the cancer cells were exposed to polyamide 1. The DNA sequence preference of polyamide 1 is 5'-WGGGTW-3' (where W = A/T), indicated by the pairing rules and confirmed by the Bind-n-Seq method. The close correspondence of this sequence with the telomere-repeat sequence suggests a potential mechanism of action through ligand binding at the telomere. This study reveals a chemical means to trigger an inflammatory necrotic cell death in cancer cells.
authors.affiliation: Division of Chemistry and Chemical Engineering,California Institute of Technology,Pasadena,CA 91125,USA.
authors.forename: JeenJoo S
authors.initials: JS
authors.lastname: Kang
authors.affiliation: Division of Chemistry and Chemical Engineering,California Institute of Technology,Pasadena,CA 91125,USA.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dervan
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D037282:Calreticulin / Q000378:metabolism; D004247:DNA / Q000737:chemistry*; D004797:Enzyme-Linked Immunosorbent Assay; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D015151:Immunoblotting; D007249:Inflammation; D020014:K562 Cells; D049449:Luminescence; D016393:Lymphoma, B-Cell / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D009336:Necrosis / Q000473:pathology; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D009757:Nylons / Q000737:chemistry; D010587:Phagocytosis; D011758:Pyrroles / Q000737:chemistry; D015398:Signal Transduction; D016615:Telomere / Q000737:chemistry; D015854:Up-Regulation
chemical_list: D037282:Calreticulin; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D000255:Adenosine Triphosphate; D004247:DNA
keywords: DNA-binding small molecule; Py-Im Polyamide; damage-associated molecular patterns; immunogenic cell death; necrotic cell death; telomere sequence