title: Autophagy protects against oxaliplatin-induced cell death via ER stress and ROS in Caco-2 cells.
abstract: Oxaliplatin is included in a number of effective combination regimens used as first and subsequent lines of therapy for metastatic colorectal cancer. Accumulating evidence indicates that autophagy plays a significant role in response to cancer therapy. However, the role of autophagy in oxaliplatin-induced cell death remains to be clarified. In this study, we showed that oxaliplatin induced cell death and autophagy in Caco-2 colorectal cancer cells. The suppression of autophagy using either pharmacologic inhibitors (3-methyladenine, bafilomycin A1) or RNA interference in essential autophagy genes (ATG5 or Beclin1) enhanced the cell death and reactive oxygen species (ROS) production induced by oxaliplatin in Caco-2 cells. Blocking oxaliplatin-induced ROS production by using ROS scavengers (NAC or Tiron) decreased autophagy. Furthermore, numerous dilated endoplasmic reticula (ER) were present in oxaliplatin-treated Caco-2 cells, and blocking ER stress by RNA interference against candidate of metastasis-1 (P8) and C/EBP-homologous protein (CHOP) decreased autophagy and ROS production. Taken together, these data indicate that oxaliplatin activates autophagy as a cytoprotective response via ER stress and ROS in human colorectal cancer cells.
authors.affiliation: Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.forename: Bin
authors.initials: B
authors.lastname: Tang
authors.forename: Pei-Wu
authors.initials: PW
authors.lastname: Yu
authors.forename: Bo
authors.initials: B
authors.lastname: Tang
authors.forename: Ying-Xue
authors.initials: YX
authors.lastname: Hao
authors.forename: Xiao
authors.initials: X
authors.lastname: Lei
authors.forename: Hua-Xing
authors.initials: HX
authors.lastname: Luo
authors.forename: Dong-Zhu
authors.initials: DZ
authors.lastname: Zeng
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D018938:Caco-2 Cells; D015179:Colorectal Neoplasms / Q000473:pathology / Q000648:ultrastructure; D019610:Cytoprotection / Q000187:drug effects*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D009944:Organoplatinum Compounds; D017382:Reactive Oxygen Species; D000077150:Oxaliplatin