Cervical cancer is the second leading cause of cancer deaths in women worldwide. Infection with high risk types of human papiliomavirus (HPV) such as HPV16 has been causally linked to cervical cancer. New medications are needed to both prevent and treat this disease. The overall goal of this application is to determine whether cyclooxygenase-2 (COX-2) represents a bona fide therapeutic target for preventing or treating cervical cancer. Several lines of evidence suggest that COX-2 is important in carcinogenesis. COX-2 deficiency protects against intestinal and skin tumor formation in animals. Moreover, selective COX-2 inhibitors suppress the formation, growth and metastasis of experimental tumors. We have discovered that levels of COX-2 are elevated in human cervical intraepithelial neoplasia and cancers. This raises the possibility that selective COX-2 inhibitors will be useful for preventing or treating cervical cancer.
One aim of this proposal, therefore, is to determine whether pharmacological inhibition or genetic ablation of COX-2 inhibits cervical carcinogenesis in an animal model of cervical cancer. Additionally, we will determine whether a selective COX-2 inhibitor suppresses the growth of experimental cervical cancer and attempt to elucidate the underlying mechanism.
The second aim will be to elucidate the mechanisms that account for increased expression of COX-2 and microsomal prostaglandin E synthase (mPGES) in cervical cancer. Emphasis will be placed on defining the mechanisms by which HPV16 E6 and E7 regulate the expression of both COX-2 and mPGES. Both human cell lines and tissues will be used to carry out the experiments proposed in aim two.
The third aim will be to decipher the mechanism by which prostaglandin E2 induces the expression of E6 and E7 in vitro. Additionally, we will determine whether celecoxib, a selective COX-2 inhibitor, reduces E6 and E7 expression by a COX-2 independent mechanism in addition to inhibiting PGE2 biosynthesis. Finally, we will attempt to translate these in vitro findings by investigating whether celecoxib down-regulates levels of HPV16 E6 and E7 in an in vivo model of human cervical cancer. The development of a safe and effective therapy to reduce E6/E7 levels could have significant public health implications. Taken together, the results of these studies should strengthen the rationale for evaluating the utility of selective COX-2 inhibitors in the prevention and treatment of cervical cancer.
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