Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), an essential component of the inflammasome complex, is frequently silenced by epigenetic methylation in many tumor cells. Here, we demonstrate that restoration of ASC expression in human colorectal cancer DLD-1 cells, in which ASC is silenced by aberrant methylation, potentiated cell death mediated by DNA damaging agent. Contrarily, ASC knockdown in HT-29 cells rendered cells less susceptible to etoposide toxicity. The increased susceptibility of ASC-expressing DLD-1 cells to genotoxic stress was independent of inflammasome or caspase activation, but partially dependent on mitochondrial ROS production and JNK activation. Thus, our data suggest that ASC expression in cancer cells is an important factor in determining their susceptibility to chemotherapy.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent because its cytotoxicity is selective for tumor cells. Despite promising outcomes in clinical trials using this ligand, sustained clinical responses have been impeded because cancer cells acquire resistance to TRAIL-based therapies. Ginseng, a well-known food product consumed globally, has been reported to reduce fatigue and possess antioxidant and antitumor activities. We explored the sensitizing influence of a formulated red ginseng extract (RGE) on TRAIL-derived cell death in hepatocellular carcinoma (HCC) cell lines and the underlying molecular mechanisms responsible for TRAIL sensitization. We found that the RGE promoted TRAIL-derived apoptosis in HepG2, Huh-7 and Hep3B cell lines. We also found that death receptor 5 expression was induced by the RGE and mediated by C/EBP homologous protein (CHOP). shRNA-induced downregulation of CHOP expression effectively suppressed cell death induced by combined treatment with the RGE and TRAIL in the HepG2 cell line, indicating that RGE-related upregulation of the CHOP protein plays an important role in sensitizing TRAIL-derived apoptosis. In summary, we showed that the RGE sensitized human HCC cell lines to TRAIL-derived cell death and could be utilized as a dietary supplement in combination with cancer treatment.

TNF Receptor-Associated Death Domain (TRADD) is an essential mediator of TNF receptor-1-mediated TNF signaling and is responsible for recruitment of other effector proteins. Recruitment of these adaptor proteins leads to the activation of MAP kinases and NF-kB, as well as cell death. it is well known that aspect of ROS biological effects is their regulatory roles on cell death to function as direct activator cell death or as second messengers in the cell death processes. ROS may initiate cell death processes through affecting various signaling cascade. Several studies on the oxidative stress-induced cell death has shown that some of the key TNF signaling molecules serve as the molecular targets of ROS in cell death. However, there is no report concerning whether TRADD has a function in oxidative stress-induced cell death. The availability of TRADD deficiency mice let us investigate the physiological functions of TRADD on oxidative stress-induce cell death. In this study, we found that TRADD deficiency renders cells more susceptible to oxidative stress-induced cell death through the persistent activation of JNK. Citation Format: Ki-Bang Koo, Da-gyum Lee, Ji-Yoon Oh, Yun-Sun Lee, You-Sun Kim. Deletion of TRADD sensitizes oxidative stress-induced necrotic cell death. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2950. doi:10.1158/1538-7445.AM2013-2950