Format

Send to

Choose Destination
Q Rev Biophys. 2015 Nov;48(4):453-64. doi: 10.1017/S0033583515000104.

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

Author information

1
Division of Chemistry and Chemical Engineering,California Institute of Technology,Pasadena,CA 91125,USA.

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.

KEYWORDS:

DNA-binding small molecule; Py-Im Polyamide; damage-associated molecular patterns; immunogenic cell death; necrotic cell death; telomere sequence

PMID:
26537405
PMCID:
PMC4743504
DOI:
10.1017/S0033583515000104
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Cambridge University Press Icon for PubMed Central
Loading ...
Support Center