Lipoxygenase, Angiogenicity, and Prostate Cancer Radioresistance

Radiotherapy is a prevalent modality for the treatment of prostate tumor. Although radiation is capable of eradicating localized prostate tumors, nearly 30% of patients treated with potentially curative doses relapse at the sites of irradiation. Therefore, there is an imperative need to improve the success rate of radiotherapy for PCa. This proposal is focused on a role of 12-lipoxygenase (LOX) in modulating radiation response of PCa cells. 12-LOX catalyzes the formation of 12(S)-hydroxyeicosatetraenoic acid (HETE). Our studies suggest an involvement of 12-LOX in radioresistance of PCa cells. It is our hypothesize that VEGF is an important intermediary for 12-LOX mediated radioresistance in PCa. We intend to define the role of 12-LOX in radioresponse in PCa. 12-LOX will be overexpressed in LNCaP and DU145 cells. Then we will study whether an increase in 12-LOX expression LNCaP and DU145 cells can enhance their resistance to radiotherapy. We also propose to study whether VEGF is required by 12-LOX to enhance PCa radioresistance through blockade of VEGF activity with a neutralizing antibody. Finally, we will evaluate whether BHPP, a 12-LOX inhibitor, can be used to sensitize prostate tumors to radiotherapy.
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