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Carcinogenesis Advance Access published online on April 29, 2004
Carcinogenesis, doi:10.1093/carcin/bgh176
© 2004 by Oxford University Press
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Received January 19, 2004
Revised March 20, 2004
Accepted April 20, 2004

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Age-associated changes in the expression pattern of cyclooxygenase-2 and related apoptotic markers in the cancer susceptible region of rat prostate

Alaa F. Badawi 1*, Yingying Liu 1, Mazen B. Eldeen 1, Willard Morrow 2, Zaineb R. Razak 1, Marie Maradeo 1, Mostafa Z. Badr 3

1 Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA 19111
2 Department of Basic Medical Science, School of Medicine, University of Missouri - Kansas City, Kansas City, MO 64108
3 Division of Pharmacology, School of Pharmacy, University of Missouri - Kansas City, Kansas City, MO 64108

* To whom correspondence should be addressed. E-mail: af_badawi{at}fccc.edu.


  Abstract

Senescence-associated changes in the prostate are believed to play an important role in the genesis of prostate cancer. In order to provide further information on how aging increases the prostate susceptibility to cancer, we examined the pattern of COX-2 expression and the concomitant alterations in prostaglandin E2 (PGE2) synthesis in the prostate glands of 4, 10, 50 and 100 week-old Fischer 344 rats. This was carried out in the prostatic areas where hormone-induced tumors arise, namely the periurethral ducts of the dorsolateral prostate (DLP). Age-associated changes were also evaluated for pro- and anti-apoptotic factors linked to COX-2 signaling and known to be involved in the normal development of the prostate gland as well as in carcinogenesis. COX-2 expression was increased in the DLP in an age-dependent manner where senescent rats had >3-4 fold higher COX-2 mRNA and protein levels than their juvenile counterparts (P<0.05). The age-related changes in COX-2 were accompanied by a similar upregulation in the PGE2 synthesis. Evaluation of mediators of apoptotic signaling showed a significant (P<0.05) decline in the expression levels of the pro-apoptotic BAX (>6-fold) and PPAR{gamma} (>3-fold) and in caspase-3 activity (>2-fold) and an upregulation of the anti-apoptotic Bcl2 (>8-fold), PKC{alpha} (>2-fold) and pAkt (>4-fold) in the 100-week old rats vs. the 4-week old animals. There was ~15-fold age-dependent decrease in the pro-apoptotic ratio BAX:Bcl2 and increase in the anti-apoptotic variable PKC{alpha}*Bcl2/BAX in the senescent rats compared to the juvenile ones. These results suggest that increased COX-2 expression can be linked to the decline in the pro-apoptotic signaling in the prostate gland during aging. Subsequently, COX-2 inhibitors can be considered as a promising class of agents to attenuate the increased cell survival and, hence, protect against tumorigenesis in the aging prostate.

Key Words: Aging, Prostate, Cyclooxygenases, Peroxisome proliferator-activated receptors, Apoptosis


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