The majority of newly diagnosed prostate cancer is organ confined and thus amenable to surgical intervention. Approximately one third of the patients will be diagnosed with or will develop advanced disease. Changes in cellular metabolism are associated with the ability of prostate tumor cells to escape reliance on the prostate microenvironment. Alterations in the fatty acid synthesis pathway is a common feature in prostate cancer. The key regulatory enzyme of de novo lipogenesis is fatty acid synthase (FAS). FAS converts carbohydrates to fatty acids. Expression and activity of FAS is low in most tissues due to availability of dietary fat but is elevated in many cancers including prostate cancer. While FAS in prostate cells is androgen responsive, it persists or is reactivated in tumors after androgen ablation. High FAS results in enhanced production of phospholipids and triglycerides, theroretically for increased membrane production and activation of new signaling pathways associated with growth and survival. The molecular role dysregulated fatty acid synthesis plays during prostate cancer progression is not understood. In the TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) model, animals develop progressive stages of prostate cancer with time ranging from early stage prostatic intraepithelial neoplasia (PIN) to late stage poorly differentiated adenocarcinoma with metastatic lesions. During prostate disease progression in TRAMP, FAS levels are elevated, recapitulating upregulation of FAS in human prostate cancer. We will use TRAMP and xenograft models in the following specific aims:
Specific Aim 1. To identify key molecular mechanisms in the fatty acid synthesis pathway involved in upregulatlon of pathway molecules and signaling cascades in human prostate cancer cell lines and transgenic mouse model (TRAMP).
Specific Aim 2. To define the alterations in FAS regulation during metastatic relapse in an autochthonous model of prostate cancer and determine the molecular effects of FAS antimetabolite treatment during disease progression.
Specific Aim 3. To determine the effects of FAS antimetabolites on inhibition of the development and metastatic spread of androgen-dependent and -independent prostate cancer in TRAMP animals, characterize the molecular effects of FAS pathway inhibition on androgen-dependent and -independent disease and determine whether FAS levels correlate with disease outcome.
| D'Antonio, Jason M; Ma, Changqing; Monzon, Federico A et al. (2008) Longitudinal analysis of androgen deprivation of prostate cancer cells identifies pathways to androgen independence. Prostate 68:698-714 |
| Shah, Uzma S; Dhir, Rajiv; Gollin, Susanne M et al. (2006) Fatty acid synthase gene overexpression and copy number gain in prostate adenocarcinoma. Hum Pathol 37:401-9 |
