title: Chemical chaperones reduce ionizing radiation-induced endoplasmic reticulum stress and cell death in IEC-6 cells.
abstract: Radiotherapy, which is one of the most effective approaches to the treatment of various cancers, plays an important role in malignant cell eradication in the pelvic area and abdomen. However, it also generates some degree of intestinal injury. Apoptosis in the intestinal epithelium is the primary pathological factor that initiates radiation-induced intestinal injury, but the mechanism by which ionizing radiation (IR) induces apoptosis in the intestinal epithelium is not clearly understood. Recently, IR has been shown to induce endoplasmic reticulum (ER) stress, thereby activating the unfolded protein response (UPR) signaling pathway in intestinal epithelial cells. However, the consequences of the IR-induced activation of the UPR signaling pathway on radiosensitivity in intestinal epithelial cells remain to be determined. In this study, we investigated the role of ER stress responses in IR-induced intestinal epithelial cell death. We show that chemical ER stress inducers, such as tunicamycin or thapsigargin, enhanced IR-induced caspase 3 activation and DNA fragmentation in intestinal epithelial cells. Knockdown of Xbp1 or Atf6 with small interfering RNA inhibited IR-induced caspase 3 activation. Treatment with chemical chaperones prevented ER stress and subsequent apoptosis in IR-exposed intestinal epithelial cells. Our results suggest a pro-apoptotic role of ER stress in IR-exposed intestinal epithelial cells. Furthermore, inhibiting ER stress may be an effective strategy to prevent IR-induced intestinal injury.
authors: Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
authors: Eun Sang
authors: ES
authors: Lee
authors: Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
authors: Hae-June
authors: HJ
authors: Lee
authors: Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
authors: Yoon-Jin
authors: YJ
authors: Lee
authors: Division of Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
authors: Jae-Hoon
authors: JH
authors: Jeong
authors: Division of Life Sciences, Korea University, Seoul 136-701, Republic of Korea.
authors: Seongman
authors: S
authors: Kang
authors: Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea. Electronic address: yblim@kirams.re.kr.
authors: Young-Bin
authors: YB
authors: Lim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects* / Q000528:radiation effects; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000528:radiation effects; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D010654:Phenylbutyrates / Q000494:pharmacology*; D051381:Rats; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D019284:Thapsigargin / Q000494:pharmacology*; D014415:Tunicamycin / Q000494:pharmacology*; D056811:Unfolded Protein Response
chemical_list: D010654:Phenylbutyrates; D014415:Tunicamycin; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D019284:Thapsigargin; C075773:4-phenylbutyric acid; D053148:Caspase 3
keywords: Chemical chaperone; Endoplasmic reticulum stress; Ionizing radiation; Unfolded protein response