Dz13, a c-jun DNAzyme, is a potent inducer of caspase-2 activation.

Abstract

Signaling pathways for caspase-2-mediated apoptosis are poorly defined. This is partially due to a lack of a reproducible stimulus to trigger caspase-2 activation. We present the oligonucleotide Dz13, a DNA enzyme that cleaves c-Jun mRNA and is capable of inhibiting various model tumors in mice, which potently induces caspase-2 resulting in apoptosis in a panel of tumor cell lines. Dz13-mediated cell death occurred even in the absence of known caspase-2 molecular partners in p53-induced protein with a death domain, RIP-associated Ich-1/CED homologous protein with death domain, or DNA-dependent protein kinase catalytic subunit, or other caspases in cell lines of breast cancer, prostate cancer, osteosarcoma, and liposarcoma. z-VDVAD-fmk, caspase-2(-/-) mouse embryonic fibroblasts and siRNA silencing of caspase-2 in tumor cells abrogated Dz13-mediated cell death. In an orthotopic tumor model, expression of caspase-2 increased as the tumor metastasized and caspase-2 expression was sporadic in patient tumor specimens. These findings provide hope that Dz13, and other agents that evoke activation of caspase-2, may be therapeutic clinically.

• Authors: Crispin R Dass, Stuart J Galloway, Peter F M Choong
• Journal: Oligonucleotides (Oligonucleotides) Vol. 20 Issue 3 Pg. 137-46 (Jun 2010) ISSN: 1557-8526 [Electronic] United States
• PMID: 20180631 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• DNA Primers
• DNA, Catalytic
• Dz13 DNAzyme
• Caspase 2

Topics

• Animals
• Base Sequence
• Caspase 2 (metabolism)
• Catalytic Domain
• Cell Line, Tumor
• DNA Primers
• DNA, Catalytic (chemistry, metabolism)
• Enzyme Activation
• Female
• Humans
• Immunohistochemistry
• In Situ Nick-End Labeling
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasms (enzymology, pathology)
• Reverse Transcriptase Polymerase Chain Reaction