歐洲紫杉醇是主要用來治療轉移性攝護腺癌的抗癌藥物。然而大部分的病人在接受歐 洲紫杉醇治療時會產生抗藥性。先前的研究指出肝 X 受體(LXR)與其激活物 T0901317 在許多癌症中具有抗癌的活性，包含攝護腺癌。因此我們探討 T0901317 是否可以抑制 對於歐洲紫杉醇具有抗性的攝護腺癌細胞株的增生與存活。結果顯示 T0901317 可以抑 制抗藥性及非抗藥性癌細胞的增生，同時抑制細胞週期。流式細胞儀的結果也發現 T0901317 會減少抗藥性癌細胞在 G2/M 的分佈，而在 S phase 的細胞群增加，推測細胞 週期停止在 S-G2/M 檢查點。我們也發現 T0901317 會抑制抗藥性細胞株的轉移能力。 RT-PCR 的結果顯示 T0901317 會抑制抗藥性細胞株中與膽固醇合成、膽固醇移轉、脂 質合成以及脂肪酸合成相關的基因表現。而西方墨點法的結果也發現 T0901317 會降低 Skp2、c-Myc、AKT、STAT-3、JAK2 的蛋白質表現及增加 P27 及 P53 的蛋白質表現。 過量表現 c-Myc 可以看到由 T0901317 所造成的細胞抑制有回復的現象。綜合以上結 果，我們發現 T0901317 可以藉由降低 c-Myc 的表現來抑制抗藥性攝護腺癌細胞的增生 與存活。而肝 X 受體的活化在未來或許可以做為治療歐洲紫杉醇抗藥性攝護腺癌的治 療標的。;Taxane-based treatment, mainly docetaxel is a standard therapy for metastatic castrationresistant prostate cancer (CRPC) patients. Yet, the majority of patients acquire resistance to docetaxel during the treatment. T0901317 is a potent agonist for Liver X receptors (LXRs), LXRs belong to the nuclear superfamily. Previous research has demonstrated anti-cancer activity of LXR agonists on numerous cancer cell lines including prostate cancer (PCa) cells. We examined the effects of T0901317 on the proliferation and survival of docetaxel resistant PCa cells. Treatment with T0901317 suppressed the proliferation and caused cell cycle in PC3 and DU-145 cells and docetaxel-resistant PC/DX25 and DU/DX50 cells which were derived from PC-3 and DU-145, respectively. Flow cytometry analysis showed that T0901317 treatment reduced the percentage of cell population of PC/DX25 cells in G2/M phase and increased cell population in S phase, suggesting that T0901317 induced cell cycle arrest at the S-G2/M checkpoint. T0901317 also decreased the migration of docetaxel PC/DX25 cells. RTPCR revealed that treatment with T0901317 affected the expression of genes regulating cholesterol and fatty acid metabolism in docetaxel resistant PC-3 cells, including the genes involved in cholesterol biosynthesis, cholesterol efflux, lipogenesis and fatty acid synthase. Western blotting assay showed that T0901317 treatment down-regulated the protein expression of SKP2, c-Myc, AKT, STAT-3, JAK2 and increased the abundance of P27 protein. Overexpression of c-Myc rescued the suppression of cell proliferation of PC/DX25 cells under T0901317 treatment. In conclusion, T0901317 treatment suppressed the proliferation and survival of docetaxel-resistant PCa cells by inhibiting c-Myc. Activation of LXR can be a potential therapeutic approach for PCa patient resistant to docetaxel therapy.
