| Summary: | 碩士 === 中原大學 === 生物科技研究所 === 106 === Prostate cancer is the second leading cause of cancer death in men in the United States. Polymethoxyflavonoids (PMFs), such as tangeretin and nobeliten, which exclusively exist in citrus fruit peels have been demonstrated to exhibit various bioactivities. In this study, we investigated the inhibitory effect of eight derives of tangeretin (PMFs 1-4) and nobelitin (PMFs 5-8) against human prostate cancer LNCaP and PC-3 cells. The results showed that 4’,5-didemethyltangeretin (PMF1) significantly inhibited the growth of LNCaP and PC-3 cells (IC50 14.3 and 13.5 µM, respectively) while PMF1 at 15 µM didn’t affect the growth of human normal prostate RWPE-1 cells. PMF1 also suppressed the anchorage-independent growth of LNCaP and PC-3 cells. PMF1 increased Bad expression and decreased procaspases3, pro-PARP, and Bcl-2 expressions, there by inducing apoptosis in LNCaP cells. PMF1 downregulated DNA methyltransferase (DNMT) 3b and histone deacetylases (HDACs) 1, 2, and 4/5/9 in LNCaP cells. PMF1 also induced cell cycle arrest in PC-3 cells in which PMF1 decreased protein expressions of CDK1, DNMTs 1 and 3b, and HDACs 2 and 4/5/9. Furthermore, PMF1 increased tumor suppressor gene p21 mRNA and protein levels in both LNCaP and PC-3 cells. Methylation-specific PCR results revealed that PMF1 decreased methylated p21 promoter level in LNCaP cells. We further demonstrated that PMF1 supressed DNA methyltransferase (M.SssI) activity in vitro, PMF1 had ability to bind to DNMTs 1, 2 and 3a ex vivo in LNCaP cells. Additionally, PMF1 inhibited the anchorage-independent growth of isolated LNCaP cancer stem-like cells (CSLCs) with high CD166 mRNA expression. These results suggested that PMF1 might effectively inhibit the growth of human prostate cancer cells through epigenetic upregulation of p21 pathway and cancer stem cells.
Key words : apoptosis, cancer stem-like cells, cell cycle, epigenetics, polymethoxyflavones (PMFs), prostate cancer
|
|---|
