A sequence-specific DNA binding small molecule triggers the release of immunogenic signals and phagocytosis in a model of B-cell lymphoma

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,...

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Bibliographic Details
Published in:Quarterly reviews of biophysics 2015-11, Vol.48 (4), p.453-464
Main Authors: Kang, JeenJoo S., Dervan, Peter B.
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - chemistry
Animals
Apoptosis
Binding
Binding sites
Biophysics
Calreticulin - metabolism
Cancer
Cell death
Deoxyribonucleic acid
Discovery
DNA
DNA - chemistry
Enzyme-Linked Immunosorbent Assay
Gene sequencing
HMGB1 Protein - metabolism
Humans
Imidazoles - chemistry
Immune system
Immunoblotting
Inflammation
K562 Cells
Luminescence
Lymphoma
Lymphoma, B-Cell - metabolism
Macrophages - cytology
Macrophages - metabolism
Necrosis - pathology
Neoplasms - metabolism
Neoplasms - pathology
Nylons - chemistry
Phagocytosis
Polyamide resins
Pyrroles - chemistry
Signal Transduction
Telomere - chemistry
Up-Regulation
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Summary: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.
ISSN:0033-5835
1469-8994
DOI:10.1017/S0033583515000104