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) administration and calorie restriction (CR) exert their chemopreventive effects in p53-deficient (p53-/-) mice. Using immunohistochemical detection we found that treatment with both DHEA and CR resulted in decreased expression of the PCNA proliferation marker in the thymus. In addition, treatment 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 understand 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 the thymus than wild-type (p53+/+) mice. Treatment of p53-/- animals 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 expression. The present study provides molecular evidence that DHEA and CR may modulate tumorigenesis through alterations in the apoptotic and/or proliferative pathways.
Wang
T T
TT
Laboratory of Nutritional and Molecular Regulation, NCI-Frederick Cancer Research and Development Center, NIH, MD 21702-1201, USA.
Hursting
S D
SD
Perkins
S N
SN
Phang
J M
JM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D002149:Energy Intake / Q000502:physiology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D018809:Proliferating Cell Nuclear Antigen; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D003687:Dehydroepiandrosterone