Abstract 4036: Curcumin induces ER stress-mediated apoptosis through cell type-specific interruption of redox balance in cervical cancer cells.

Abstract

Abstract Prolonged accumulation of misfolded or unfolded proteins prompts a cellular stress condition known as ER stress which activates unfolded protein response (UPR). The ER stress is usually sustained at higher level in cancers than in normal cells due to altered metabolism of the cancer. Recent studies have shown that curcumin, a major yellow pigment of tumeric derived from Curcuma longa plant, triggers apoptosis through induction of ER stress in several cancer cells. Here, we found that ER stress was induced by interruption of redox balance when cervical cancer cells were exposed to curcumin. We used four cervical cancer cell lines, C33A, CaSki, HeLa and ME180. Curcumin inhibited proliferation of cervical cancer cells in a dose- and time-dependent manner and induced apoptotic cell death (increase of AnnexinV-positive and SubG1 fraction). Additionally, proteolytic activation of caspase-9 and -3 and PARP cleavage were shown in cervical cancer cells. We next evaluated activation of unfolded protein response (UPR) in response to curcumin. Three ER-resident sensors (PERK, IRE1α and ATF6) and their down-signaling proteins (XBP1, ATF4 and eIF2α) were activated in all cervical cancer cells (C33A, CaSki, HeLa and ME180), but not in normal cervical epithelial cell. Also, one of UPR down-signaling proteins CHOP/GADD153, which is a transcription factor inducing ER stress-mediated apoptosis, was up-regulated by curcumin. CHOP/GADD153 decreased anti-apoptotic protein Bcl2 and subsequently promoted apoptosis of cervical cancer cells exposed to curcumin. Furthermore, curcumin led to elevation of intracellular ROS in CaSki and ME180 cells, but not in C33A, HeLa and normal cervical epithelial cell. Pretreatment of N-acetyl-cysteine (ROS scavenger) resulted in inhibition of ER stress and cell death at least in part. Taken together, these results show that curcumin promotes ER stress-mediated apoptosis through cell type-specific ROS generation in cervical cancer cells. Citation Format: Boyun Kim, Eun-Ji Jung, Yong Sang Song. Curcumin induces ER stress-mediated apoptosis through cell type-specific interruption of redox balance in cervical cancer cells. [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 4036. doi:10.1158/1538-7445.AM2013-4036