Functional Mechanisms of Vitamin E in Prostate Cancer

Currently, a new clinical trial, SELECT,20,21 has been initiated in the US, and an earlier epidemiological study also indicated that daily supplements of Vitamin E could reduce the incidence and mortality of prostate cancer.2 However, the functional mechanisms remain largely unclear. We summarize the functional mechanisms of vitamin E as follows.

Vitamin E and Its Analogs Induce Proapoptotic Properties in Prostate Cancer Cells a-Vitamin E (a-tocopherol) has been shown by researchers to have proapoptotic properties in human prostate cancer LNCaP cells. Their data showed that vitamin E administration resulted in reduced DNA synthesis and enhanced DNA fragmentation, as well as a general inhibition of cell proliferation.22

Another study by Gunawardena and colleagues, showed that a-tocopherol stimulated apoptosis in three different human prostate cancer cell lines: DU-145 (androgen-unresponsive), LNCaP (androgen-responsive), and ALVA-101 (moderately androgen-responsive). The group cited nucleosome fragmentation as evidence of apoptosis following a-tocopherol treatment in these different prostate cancer cell lines.23

Furthermore, results from other researchers indicated that the apoptosis-triggering properties of VES may be due to its modulation of Fas signaling. Fas belongs to the tumor necrosis factor receptor and nerve growth factor receptor superfamily, and contains a cytoplasmic death domain that can initiate an apoptotic cascade. Using two prostate cancer cell lines (LNCaP and PC-3) and the normal prostate epithelial cells (PrEC) the investigators showed that VES induced apoptosis only in cancer cells. They also showed that VES administration enhanced Fas ligand expression and increased Fas levels in the membrane, both of which are important events in Fas-induced apoptosis.24

Vitamin E and Its Analogs Inhibit Cell Cycle Progression

VES has been shown to inhibit the proliferation of prostate cancer cell lines through the inhibition of cell cycle. Our group has found that VES effectively inhibits prostate cancer LNCaP cell growth by causing cell cycle arrest in the G1 phase with a reduction of cells in S phase. VES decreases the expression of several cell cycle regulatory proteins such as cyclin D1, D3, E, cdk2, and cdk4, but not cdk6.25 In addition, Ni et al. also found that VES can inhibit the phosphorylation of retinoblastoma (Rb), and consequently inhibit the E2F activity.25 Another group, Venkasteswaran et al., has observed similar inhibitory effects of VES. Their data shows VES-induced

G1 arrest in LNCaP and G2/M arrest in PC-3 prostate cancer cells. Their data also showed a G1 phase arrest, and the mechanism credited for the increased amounts of p27 by VES.26

In addition to a-tocopherol, 7-tocopherol is another isoform of vitamin E that has demonstrated anticancer properties. A study by Gysin and colleagues showed that 7-tocopherol inhibits cell proliferation more significantly than a-tocopherol in DU-145 and LNCaP cells. They also showed that the mechanisms of 7-tocopherol are through inhibition of DNA synthesis, defects of cell cycle with decreased S-phase cell population, and down-regulation of cyclin D1 and cyclin E levels. Based on their results, 7-tocopherol is more potent than a-tocopherol in those two cell lines.27 However, the absorption efficiency of 7-tocopherol is lower than that of a-tocopherol in human.14

VES Inhibits the Expressions of PSA and the Androgen Receptor (AR)

A functional AR is essential for the development and progression of prostate cancer.28-30 In prostate, AR can bind to the promoter of and regulate the expression of prostate-specific antigen (PSA), the most popular detection marker for prostate cancer. Results from our earlier report suggested that VES, at a non-toxic concentration and in vivo achievable level, could selectively inhibit the expression of both AR and PSA, but not retinoid X receptor a (RXRa) and peroxisome proliferators-activated receptor a (PPARa), in prostate cancer LNCaP cells. Results from further investigation indicated that VES can affect the translational efficiency of AR. Overall, the results suggested that VES-mediated inhibition of prostate cancer cell growth can be partly due to the inhibition of AR function.31

VES Inhibits Activity of MMP9 Secreted From Prostate Cancer Cells

Most of the tumors of prostate cancer patients become incurable once their cancers progress to metastatic stage. Metastasis of cancer cells employs complicated processes including degradation of extracellular matrix, migration, homing and angiogenesis. Our group has found that

VES can affect the invasiveness of prostate cancer PC-3 and DU-145 cells. Results from mechanism investigation suggested that VES could affect the matrix metalloproteinase-9 (MMP-9) activity, but not the tissue inhibitor of metalloproteinases (TIMPs). The inhibition of MMP-9 activity and cancer metastasis through matrigel could be observed with 24 h treatment of VES. This time frame is shorter then the event of VES mediated disturbance of the cell cycle distribution and cell growth, which takes action upon longer VES treatment. Thus, the inhibition of MMP-9 activity could be an event independent of VES-mediated cell growth inhibition and cell cycle progression of prostate cancer cells.32

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