UV irradiation/cold shock-mediated apoptosis is switched to bubbling cell death at low temperatures

Abstract

// Szu-Jung Chen 1, * , Pei-Wen Lin 1, * , Hsin-Ping Lin 1 , Shenq-Shyang Huang 1 , Feng-Jie Lai 2, * , Hamm-Ming Sheu 3 , Li-Jin Hsu 4, 5 , Nan-Shan Chang 1, 5, 6, 7, 8 1 Institute of Molecular Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan, ROC 2 Department of Dermatology, Chi-Mei Medical Center, Tainan, Taiwan, ROC 3 Department of Dermatology, National Cheng Kung University College of Medicine, Tainan, Taiwan, ROC 4 Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University Medical College, Tainan, Taiwan, ROC 5 Center of Infectious Disease and Signaling Research, National Cheng Kung University Medical College, Tainan, Taiwan, ROC 6 Advanced Optoelectronic Technology Center, National Cheng Kung University, Tainan, Taiwan, ROC 7 Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, NY, USA 8 Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA * These authors have contributed equally to this work Correspondence to: Nan-Shan Chang, e-mail: changns@mail.ncku.edu.tw Keywords: WWOX, TRAF2, p53, UV, cold shock Received: October 04, 2014      Accepted: January 16, 2015      Published: February 10, 2015 ABSTRACT When COS7 fibroblasts and other cells were exposed to UVC irradiation and cold shock at 4°C for 5 min, rapid upregulation and nuclear accumulation of NOS2, p53, WWOX, and TRAF2 occurred in 10–30 min. By time-lapse microscopy, an enlarging gas bubble containing nitric oxide (NO) was formed in the nucleus in each cell that finally popped out to cause “bubbling death”. Bubbling occurred effectively at 4 and 22°C, whereas DNA fragmentation was markedly blocked at 4°C. When temperature was increased to 37°C, bubbling was retarded and DNA fragmentation occurred in 1 hr, suggesting that bubbling death is switched to apoptosis with increasing temperatures. Bubbling occurred prior to nuclear uptake of propidium iodide and DAPI stains. Arginine analog Nω-LAME inhibited NO synthase NOS2 and significantly suppressed the bubbling death. Unlike apoptosis, there were no caspase activation and flip-over of membrane phosphatidylserine (PS) during bubbling death. Bubbling death was significantly retarded in Wwox knockout MEF cells, as well as in cells overexpressing TRAF2 and dominant-negative p53. Together, UV/cold shock induces bubbling death at 4°C and the event is switched to apoptosis at 37°C. Presumably, proapoptotic WWOX and p53 block the protective TRAF2 to execute the bubbling death.