Transcriptional regulation of pro-apoptotic Par-4 by NF-kappaB/p65 and its function in controlling cell kinetics during early events in endometrial tumourigenesis.

Prostatic apoptosis response-4 (Par-4) was first identified in prostatic cancer cells that were induced to undergo apoptosis. Recently, Par-4 has been suggested to be a tumour suppressor gene that plays a role in the development of endometrial carcinomas (ECs), but the exact mechanism remains to be clarified. Here we examined gene activation signalling cascades and influence on cell kinetics during endometrial tumourigenesis. In normal endometrium, constitutively high levels of Par-4 expression were observed in epithelial cells through the menstrual cycle, in contrast to the transient up-regulation in stromal components in the menstrual stage, correlated positively with the phospho-p65 (pp65) status and apoptosis. In contrast, most ECs exhibited significant down-regulation as compared to normal endometrium, with positive links only to pp65 expression. In EC cell lines, transfection of the NF-kappaB subunit p65 led to transactivation of Par-4 through specific binding to its promoter region, in contrast to the suppression by active Akt, suggesting that the balance between the two signals may be important to determine Par-4 expression levels. In addition, transient overexpression of Par-4 resulted in the induction of not only apoptosis but also senescence, through changes in the expression of bcl-2 and p21$;{{\rm WAF1}}$, respectively. Together, these findings suggest that a signalling cascade involving sequential activation of NF-kappaB/p65 and Par-4 may participate in relatively early events of endometrial tumourigenesis, leading to modulation of cell kinetics including apoptosis and cell cycle progression.