| Epidemiological studies indicated that alpha-tocopherol (alpha-vitamin E) has a protective effect against prostate cancer. The goal of this thesis was to characterize functions of tocopherol associated protein (TAP) in prostate cancer and to investigate mechanisms by which alpha-vitamin E analogs inhibit prostate cancer cell growth.; We revealed that TAP mediated vitamin E uptake and facilitated vitamin E antiproliferative activity in prostate cancer cells. However, TAP can inhibit prostate cancer cell growth through a non-vitamin E manner in vitro and in vivo. This conclusion is supported by the evidence that overexpression of TAP inhibited prostate cancer cell growth while knockdown of TAP by RNAi strategy could help the cells gain growth advantage. The mechanistic studies suggested that the tumor suppression function of TAP was via disrupting PI3K/Akt signaling. Moreover, TAP mRNA and protein expression levels were reduced or lost in human prostate cancer tissues compared to benign prostate tissues. Therefore, TAP may represent a new prognostic marker for prostate cancer progression.; alpha-Vitamin E succinate (VES) is one of the potent vitamin E analogs in terms of anti-tumor effects. In addition to inhibiting androgen receptor expression, we found VES inhibited prostate cancer cell growth through (1) cell cycle arrest and (2) reduction of telomerase activity. Moreover, the efficacy of alpha-vitamin E/VES was correlated with its cellular bioavailability in prostate cancer cells. Taken together, these results suggest that VES utilizes multiple mechanisms to control prostate cancer cell growth.; Furthermore, we developed a new nonhydrolyzable ether analog of VES. This new analog potently inhibited prostate cancer cell growth. Oral intake of new analog, but not VES, reduced the tumor burden in the xenograft animal model. Therefore, this new analog might be suitable as an agent for prostate cancer prevention.; In summary, this thesis reveals and characterizes the functions of TAP via both vitamin E-dependent and -independent tumor suppression, and provides a systemic study of VES-mediated inhibition of prostate cancer. The accomplishments of this thesis provide better understanding of the biological relevance of TAP and alpha-vitamin E in prostate cancer, and molecular basis for developing new strategies for prevention and therapy of prostate cancer. |
