FARNESYLTRANSFERAE INHIBITOR ON PROSTATE AND BREAST CANCER

University Of California Los Angeles, Los Angeles CA

Investigators

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Abstract

DESCRIPTION (provided by applicant): Farnesyltransferase inhibitor (FTI) belongs to a new class of anti-cancer drugs. However, its mechanism of action has not been elucidated. We have previously shown that FTI causes dramatic effects on human cancer cells especially prostate and breast cancer cells. Using a prostate cancer cell cline LNCaP, we showed that FTI causes accumulation of G0/G1 phase cells accompanied by hypophosphorylation of retinoblastoma protein (pRb). In addition, FTI induces apoptosis of LNCaP cells when they are exposed to low serum condition. The apoptosis involves activation of caspase-3. Further characterization of the effects of FTI on cell cycle progression and apoptosis led to the realization that RhoB and RhoD play important roles in the FTI effects. Together with the work by Dr. Prendergast on RhoB, our results highlight the significance of farnesylated Rho proteins (such as RhoB, D, and E) in the FTI action. In this application, we propose first to evaluate effects of FTI on the prenylation and cellular localization of RhoB, D and E. We will then mutate these Rho to a form that can bypass farnesylation, and ask whether expression of the mutant Rho renders cells resistant to FTI. This will be compared with gene expression changes observed after modulation of RhoB, D, E activities using a variety of mutants. Changes detected with both FTI and Rho mutants will be further characterized. Third, we will utilize tumor zenograft system to address two questions: (i) Is the growth of tumor derived from cells expressing the farnesylation bypass Rho mutant resistant to the FTI treatment? (ii) Does FTI cause gene expression changes in xenograft tumors similar to those seen with the human tumor cells treated with FTI? These studies may reveal critical roles farnesylated Rho proteins play in the action of FTI on prostate and breast cancer cells.