Research Papers:

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

Szu-Jung Chen _, Pei-Wen Lin, Hsin-Ping Lin, Sheng-Shyang Huang, Feng-Jie Lai, Hamm-Ming Sheu, Li-Jin Hsu and Nan-Shan Chang

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Oncotarget. 2015; 6:8007-8018. https://doi.org/10.18632/oncotarget.3153

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Szu-Jung Chen1,*, Pei-Wen Lin1,*, Hsin-Ping Lin1, Shenq-Shyang Huang1, Feng-Jie Lai2,*, Hamm-Ming Sheu3, Li-Jin Hsu4,5, Nan-Shan Chang1,5,6,7,8

1Institute of Molecular Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan, ROC

2Department of Dermatology, Chi-Mei Medical Center, Tainan, Taiwan, ROC

3Department of Dermatology, National Cheng Kung University College of Medicine, Tainan, Taiwan, ROC

4Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University Medical College, Tainan, Taiwan, ROC

5Center of Infectious Disease and Signaling Research, National Cheng Kung University Medical College, Tainan, Taiwan, ROC

6Advanced Optoelectronic Technology Center, National Cheng Kung University, Tainan, Taiwan, ROC

7Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, NY, USA

8Department 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: [email protected]

Keywords: WWOX, TRAF2, p53, UV, cold shock

Received: October 04, 2014     Accepted: January 16, 2015     Published: February 10, 2015


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.

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