title: Curcumin induces ER stress-mediated apoptosis through selective generation of reactive oxygen species in cervical cancer cells.
abstract: 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.
authors.affiliation: WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea.
authors.forename: Boyun
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hee Seung
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun-Ji
authors.initials: EJ
authors.lastname: Jung
authors.affiliation: Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jung Yun
authors.initials: JY
authors.lastname: Lee
authors.affiliation: WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea.|Departments of Obstetrics & Gynecology and Cellular & Molecular Medicine, Interdisciplinary School of Health Sciences, University of Ottawa, and Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Benjamin
authors.initials: B
authors.lastname: K Tsang
authors.affiliation: WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea.
authors.forename: Jeong Mook
authors.initials: JM
authors.lastname: Lim
authors.affiliation: WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea.|Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Yong Sang
authors.initials: YS
authors.lastname: Song
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D003474:Curcumin
keywords: ER stress; ROS; cervical cancer; curcumin; unfolded protein response