|Title||Identified the mechanism of apoptosis gene that is involved in the resistance to cancer treatment|
▲ Mechanism of control extrinsic apoptosis that links the TRAIL of DDIAS
- Identified the mechanism of deterring apoptosis by new lung cancer treatment target gene (DDIAS) which is involved in the resistance to cancer treatment
- Expected to overcome resistance to anti-cancer treatment and develop new treatment for lung cancer and liver cancer
Research conducted by the team lead by Dr. Won Mi-seon of the Personalized Genomic Medicine Research Center (corresponding author: Dr. Won Mi-seon, lead author: Dr. Lim Joo-young, Dr. Kim Bo-gyeong) of the Korea Research Institute of Bioscience & Biotechnology (KRIBB, President Chang Kyu-tae) was supported by the senior researcher support project/bio medicine project by the Ministry of Science, ICT and Future Planning and National Research Foundation of Korea and published on the online version of Oncogene, world’s renowned journal in biology field (Oncogene, IF 7.519, top 7.2%) as of Dec. 14 (Dec. 15, Korean Standard Time).
Apoptosis refers to the phenomenon where cells kills themselves under various stress conditions. Apoptosis prevents normal cells from being abnormal cells. In particular, cancer cells with genetic mutation grow continuously by resisting to apoptosis. Apoptosis is activated by various causes, which can be divided into extrinsic apoptosis that starts from ligand outside of cells and intrinsic apoptosis that starts inside cells.
The research team, which has developed proprietary technology by identifying DDIAS as cancer treatment target genes, presented new mechanism of extrinsic apoptosis through identification of DDIAS functions to deter extrinsic apoptosis. The research team reported that decrease in DDIAS amount does not affect normal cells but kills cancer cells through apoptosis route implying that DDIAS has a function of preventing apoptosis of cancer cells.
If receptor binding factors (TNFα, TRAIL, FasL) that induce external apoptosis combines with receptors (TNFR, DR4, Fas, etc.) fas-associated protein with death domain, which is a protein that connects receptors and procaspase-8 are bound to form death-inducing signaling complex (DISC) and apoptosis occurs with activation of procaspase-8.
The research team found that DDIAS is combined with FADD to prevent the formation of DISC. In addition, it was also found that DDIAS catalyzes the dissolution of procaspase-8, which is key protein for apoptosis indicating that there are double mechanism to prevent apoptosis of cancer cells.
The research team presented DDIAS as a way to overcome resistance to **TRAIL (Tumor necrosis factor-related apoptosis-inducing ligand) which is grabbing the attention as the next generation anti-cancer drugs.
** It is a cytokine released from cells activating extrinsic apoptosis by combining with death receptor or TRAIL receptor.
The research team observed that lung cancer and liver cancer cells are killed effectively when TRAIL and DDIAS inhibitor are applied simultaneously. It is confirmed that deterrence of DDIAS function increases the amount of procaspase-8 that induces apoptosis and DISC formation that induces apoptosis is catalyzed to activate extrinsic apoptosis by TRAIL.
Overcoming resistance to TRAIL has become the major issue to use TRAIL, which kills only cancer cells selectively clinically as cancer treatment. The research found that DDIAS makes resistance to TRAIL by preventing apoptosis induced by TRAIL.
Dr. Won Mi-seon, who is responsible for the research, said “the outcome of this research that shows the evidence that DDIAS plays an important role in extrinsic apoptosis has academic meaning but at the same time verifies the value of DDIAS as cancer treatment target”. “The research outcome presented the importance of utilizing DDIAS inhibitor to overcome resistance to TRAIL treatment and development of cancer treatment targeting DDIAS.”