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in IEC-6 cells
1 Department of Physiology, The University of Tennessee Health Science Center, Memphis, Tennessee, USA
* To whom correspondence should be addressed. E-mail: rray{at}physio1.utmem.edu.
Intracellular polyamine homeostasis is important for the regulation of cell proliferation and apoptosis and is necessary for the balanced growth of cells and tissues. Polyamines have been shown to play a role in the regulation of apoptosis in many cell types including IEC-6 cells, but the mechanism is not clear. In this study we analyzed the mechanism by which polyamines regulate the process of apoptosis in response to tumor necrosis factor-
(TNF-). TNF- or cycloheximide (CHX) alone did not induce apoptosis in IEC-6 cells. Significant apoptosis was observed when CHX was given along with TNF- as indicated by a significant increase in the detachment of cells, caspase-3 activity and DNA fragmentation. Polyamine depletion by treatment with -difluoromethylornithine (DFMO) significantly reduced the level of apoptosis as judged by DNA fragmentation as well as the caspase-3 activity of attached cells. Apoptosis in IEC-6 cells was accompanied by the activation of upstream caspases-6, -8, and -9 and N-terminal c-jun kinase (JNK). Inhibition of JNK activation prevented caspase-9 activation. Polyamine depletion prevented the activation of JNK and of caspases-6, -8, -9 and 3. SP-600125, a specific inhibitor of JNK activation prevented cytochrome C release from mitochondria, JNK activation, DNA fragmentation and caspase-9 activation in response to TNF-/CHX. In conclusion, we have shown that polyamine depletion delays and decreases TNF--induced apoptosis in IEC-6 cells, that apoptosis is accompanied by the release of cytochrome C, the activation of JNK, and of upstream caspases as well as caspase-3. Polyamine depletion prevented JNK activation, which may confer protection against apoptosis by modulation of upstream caspase-9 activation.
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