• 作者： Yu-Ke Fu, Bi-Juan Wang, Jen-Chih Tseng, Shih-Han Huang, Ching-Yu Lin, Ying-Yu Kuo, Tzyh-Chyuan Hour & Chih-Pin Chuu
• 作者服務機構： 1.Biotechnology Center, National Chung Hsing University, Taichung City, Taiwan 2.Department of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan 3.Department of Life Sciences, National Central University, Taoyuan City, Taiwan 4.Graduate Program for Aging and Graduate Institute of Basic Research Sciences, China Medical University, Taichung, Taiwan 5.Institute of Cellular and System Medicine, National Health Research Institutes, No. 35, Keyan Road, Zhunan Town, 35053, Miaoli County, Taiwan
• 中文摘要：
• 英文摘要：
  Background
  Docetaxel has been approved by USFDA as a first-line treatment for castration-resistant prostate cancer (CRPC) patients. Patients receiving androgen deprivation therapy along with docetaxel result in superior survival, lower serum prostate specific antigen (PSA) level, and better quality of life. However, a significant proportion of these patients ultimately develop resistance to docetaxel within months. Caffeic acid phenethyl ester (CAPE), one of the main bioactive components extracted from the propolis, has been reported to be effective for repressing the tumor growth, the migration and invasion of prostate cancer (PCa) cells, as well as the downstream signaling and stability of androgen receptor (AR). We hence determined if combination treatment of docetaxel with CAPE can suppress the proliferation and the survival of docetaxel-resistant PCa cells.
  
  Methods
  We established docetaxel-resistant PC/DX25 and DU/DX50 CRPC cell lines from PC-3 and DU-145 human PCa cells, respectively. Proliferation assay, MTT assay, flow cytometry with Annexin V staining, Comet Assay, and nude mice xenograft model were applied to determine the effects of combination treatment on cell proliferation and survival of the docetaxel-resistant PCa cells. Micro-Western Array (MWA) and qRT-PCR were used to investigate the molecular mechanism lying underneath.
  
  Results
  Combination treatment effectively suppressed the proliferation, survival and tumor growth of docetaxel-resistant PCa cells both in vitro and in nude mice. Comet assay and flow cytometry indicated that combination treatment induced apoptosis in docetaxel-resistant PCa cells. MWA and Western blotting assay revealed that combination treatment suppressed protein expression of Bcl-2, AKT2, c-Myc, apoptosis and caspase activation inhibitor (AVEN), pyruvate kinase M2 (PKM2) but increased protein expression of Bax, caspase 3, cytochrome c, glucose-6-phosphate dehydrogenase (G6PD) and acylglycerol kinase (AGK). Overexpression of Bcl-2 in the docetaxel-resistant PCa cells enhanced cell proliferation of docetaxel-resistant PCa cells under combination treatment. Analysis with qRT-PCR suggested that combination treatment decreased cholesterol biosynthesis genes DHCR24 (24-dehydrocholesterol reductase) and LSS (lanosterol synthase) but increased genes involved in glycolysis and TCA cycle.
  
  Conclusions
  Combination treatment of docetaxel with CAPE effectively suppressed the proliferation and survival of docetaxel-resistant PCa cells via inhibition of Bcl-2 and c-Myc as well as induction of metabolism interference. Combination treatment can be beneficial for patients with docetaxel-resistant PCa.
• 中文關鍵字：
• 英文關鍵字： Prostate cancer, Docetaxel, Cafeic acid phenethyl ester, Apoptosis, Bcl-2, DHCR24