EFFECTS OF DEHYDROEPIANDROSTERONE AND CALORIE RESTRICTION ON THE BCL-2 BAX-MEDIATED APOPTOTIC PATHWAY IN P53-DEFICIENT MICE/

Modulation of apoptosis through altered expression of Bcl-2 and/or Bax may be a mechanism by which dehydroepiandrosterone (DHEA) administrat ion and calorie restriction (CR) exert their chemopreventive effects i n p53-deficient (p53(-/-)) mice. Using immunohistochemical detection w e found that treatment with both DHEA and CR resulted in decreased exp ression of the PCNA proliferation marker in the thymus. In addition, t reatment with DHEA also increased the rate of apoptosis in the thymus, resulting in marked thymic atrophy. Thus, both DHEA and CR appear to shift cell number homeostasis by favoring apoptosis. To further unders tand the molecular mechanisms by which DHEA and CR exert their effects , we examined two components of the apoptotic pathway, Bcl-2 and Bax. We found that p53(-/-) mice have much higher levels of Bcl-2 mRNA in t he thymus than wild-type (p53(+/+)) mice. Treatment of p53(-/-) animal s with DHEA resulted in decreased Bcl-2 but not Bax mRNA levels in the thymus. In contrast, CR did not change either Bcl-2 or Bax mRNA expre ssion. The present study provides molecular evidence that DHEA and CR may modulate tumorigenesis through alterations in the apoptotic and/or proliferative pathways. Published by Elsevier Science Ireland Ltd.