Dz13, a c-jun DNAzyme, is a potent inducer of caspase-2 activation.
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.
Dass
Crispin R
CR
Department of Orthopaedics, St. Vincent's Hospital Melbourne, Fitzroy, VIC, Australia. cris.dass@yahoo.com
Galloway
Stuart J
SJ
Choong
Peter F M
PF
D000818:Animals; D001483:Base Sequence; D053143:Caspase 2 / Q000378:metabolism*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D017931:DNA Primers; D021881:DNA, Catalytic / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D021881:DNA, Catalytic; C485475:Dz13 DNAzyme; D053143:Caspase 2