Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Cell protective role of c-Myc against cellular insults

YD Yoo PhD 1, JK Park MS 1, J Kim MS 2, YM Chung MS 1, S Kang PhD 2, Y Kim PhD 3

1 Laboratory of Experimental Therapeutics, Korea Cancer Center Hospital;, 2 Korea University;, 3 Dept Life Science, Sogang University; Seoul, Korea,

[Introduction] c-Myc has an important role in the various cellular functions including cell proliferation, transformation, and apoptosis. c-Myc is induced upon not only the addition of growth factors but a variety of apoptotic stimuli, including cytokines, hypoxia, DNA damage, and chemotherapeutic agents. Although c-Myc induction by some cellular insults has been understood to induce apoptosis, recent reports demonstrated that inhibition of c-Myc expression enhanced cisplatin-induced cell death rather than blocking apoptosis in vitro and in vivo. [Results] In this study, therefore, we examined a possible role of c-Myc in the protection against various cellular insults and investigated a signaling pathway involved in c-Myc induction by cisplatin. c-Myc expression was induced by many cellular insults including cisplatin, adriamycin, paclitaxel, 5-FU, H-2O-2, and radiation. Enhanced expression of c-Myc protected cell death rather than cell proliferation and apoptosis through induction of ornithine decarboxylase (ODC). Because there are many functions of c-Myc in cells, we made a stable transfectant of ODC, a transcriptional target of c-Myc, to investigate the cell protective role of c-Myc among various functions. Enhanced expression of ODC prevented cell death induced by cellular insults such as cisplatin, H-2O-2, and radiation. NF-kappaB shows a dual function, anti-apoptotic activity in the TNF-alpha-induced apoptosis and pro-apoptotic activity in the p53-induced apoptosis. In this study, NF-kappaB responded cellular stresses such as cisplatin, H-2O-2, and radiation, resulting in inhibition the cisplatin-induced apoptosis. NF-kappaB is a central regulator of stress responses, is induced by over 150 stimuli, and regulates transcription of over 150 target genes. [Conclusion] Our results showed that cisplatin induced NF-kappaB activation, and the activated NF-kappaB subsequently induces expression of c-Myc, resulting in blocking apoptosis through ODC expression. Our present data strongly suggest that c-Myc has a function promoting cell survival from cellular insults, resulted from NF-kappaB activation in response to them.

KEY WORDS: c-Myc, ODC NF-kappaB, cisplatin, apoptosis, stress response, cell death, chemotherapeutic drug, radiation, hydrogen peroxide.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on chemotherapy.