Curcumin induces ER stress-mediated apoptosis through selective generation of reactive oxygen species in cervical cancer cells

• Published in: Molecular carcinogenesis 2016-05, Vol.55 (5), p.918-928
• Main Authors: Kim, Boyun, Kim, Hee Seung, Jung, Eun-Ji, Lee, Jung Yun, K. Tsang, Benjamin, Lim, Jeong Mook, Song, Yong Sang
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; BAX protein; Bcl protein; Bcl-2 protein; Cancer therapies; Cell death; Cell Line, Tumor; Cell proliferation; Cell Survival - drug effects; Cellular stress response; Cervical cancer; Cervix; Curcumin; Curcumin - pharmacology; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Epithelial cells; ER stress; Female; Gene Expression Regulation, Neoplastic - drug effects; HeLa Cells; Herbal medicine; Humans; Leukocytes (mononuclear); Oxidative stress; Peripheral blood mononuclear cells; Protein folding; Proteins; Reactive oxygen species; Reactive Oxygen Species - metabolism; ROS; Side effects; unfolded protein response; Unfolded Protein Response - drug effects; Uterine Cervical Neoplasms - metabolism
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.22332

Prolonged accumulation of misfolded or unfolded proteins caused by cellular stress, including oxidative stress, induces endoplasmic reticulum stress, which then activates an unfolded protein response (UPR). ER stress is usually maintained at higher levels in cancer cells as compared to normal cells due to altered metabolism in cancer. Here, we investigated whether curcumin is ER stress‐mediated apoptosis in cervical cancer cells, and ROS increased by curcumin are involved in the process as an upstream contributor. Curcumin inhibited proliferation of cervical cancer cells (C33A, CaSki, HeLa, and ME180) and induced apoptotic cell death. Curcumin activated ER‐resident UPR sensors, such as PERK, IRE‐1α, and ATF6, and their downstream‐signaling proteins in cervical cancer cells, but not in normal epithelial cells and peripheral blood mononuclear cells (PBMCs). CHOP, a key factor involved in ER stress‐mediated apoptosis, was also activated by curcumin. CHOP decreased the ratio of anti‐apoptotic protein Bcl‐2 to pro‐apoptotic protein Bax expression, and subsequently increased the apoptotic population of cervical cancer cells. Furthermore, curcumin elevated levels of intracellular reactive oxygen species (ROS) in cervical cancer cells, but not in normal epithelial cells. Scavenging ROS resulted in inhibition of ER stress and partially restored cell viability in curcumin‐treated cancer cells. Collectively, these observations show that curcumin promotes ER stress‐mediated apoptosis in cervical cancer cells through increase of cell type‐specific ROS generation. Therefore, modulation of these differential responses to curcumin between normal and cervical cancer cells could be an effective therapeutic strategy without adverse effects on normal cells. © 2015 Wiley Periodicals, Inc.