Download A role of Noxa, a BH3-only protein, in tumor cell killing and its

A role of Noxa, a BH3-only protein, in tumor cell killing and its application
Tae-Hyoung Kim, PhD
Associate Professor, Chosun University School of Medicine
Noxa was originally identified as an adult T-cell leukemia-derived phorbol-12myristate-13 acetate (PMA)-responsive protein. Later studies showed that Noxacan
be transcriptionally induced by p53, leading to cell death by mitochondrial damages
including cytochrome c release.However, the mechanism by which Noxa causes
mitochondrial damage remains largely unknown. We have demonstrated that Noxa
induces cytochrome c release in a Bak-independent manner, and Noxa contains a
novel MTD domain for mitochondrial translocation. Also, we showed that
mitochondrial fragmentation is associated with Noxa-induced cell death, and MTD of
Noxa is responsible for Noxa-induced mitochondrial fragmentation. Interestingly, we
found that MTD peptide conjugated with cell penetration tag R8 causes necrotic-like
cell death in a BH3-independent manner, suggesting that MTD may be a novel killing
domain. To understand the physiological significance of Noxa-induced cell death, we
searched novel inducers of Noxa expression, and found that LPS and Interferons
(IFNs) can upregulateNoxa expression. This upregulation of Noxa is mediated by
interferon-regulatory factors, which are known as signal transducers of Toll-like
receptors in response to LPS. LPS and IFNs have shown to play a crucial role in
tumor surveillance. Using knock-down expression system of Noxa in CT26 cells that
can form tumor in BalB/c mice, we reveal that Noxaupregulation in tumor cells is a
necessary event to eliminate tumor cells in vivo.
We are also trying to develop a peptide-based anti-cancer agent using MTD-killing
activity and TU17:MTD can eliminate the tumor tissue transplanted with CT26
adenocarcinoma cells in BalB/c mice.