咖啡酸苯乙酯透過調控磷酸化進而抑制雄激素受體之活性與穩定

簡易檢索 / 詳目顯示

回結果列表

研究生：	郭盈妤 Kuo, Ying-Yu
論文名稱：	咖啡酸苯乙酯透過調控磷酸化進而抑制雄激素受體之活性與穩定 Caffeic Acid Phenethyl Ester suppresses androgen receptor signaling and stability via regulation of phosphorylation
指導教授：	張壯榮 Chang, Chuang-Rung 褚志斌 Chuu, Chih-Pin
口試委員:	張偉嶠 Chang, Wei-Chiao 汪宏達 Wang, Horng-Dar 張凱雄 Chang, Kai-Hsiung
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生物科技研究所 Biotechnology
論文出版年：	2019
畢業學年度：	108
語文別：	英文
論文頁數：	89
中文關鍵詞：	雄激素受體、咖啡酸苯乙酯、攝護腺癌
外文關鍵詞：	androgen receptor, caffeic acid phenethyl ester, prostate cancer
相關次數：	點閱：1 下載：0
分享至:	分享至facebook 分享至twitter

查詢本校圖書館目錄查詢臺灣博碩士論文知識加值系統勘誤回報

由雄激素受體所主導的訊息傳遞在攝護腺癌的發育、惡化及轉移過程中扮演重要角色。雄激素受體經雄激素活化後進入細胞核內，啟動下游基因--攝護腺特異性抗原--的表現，藉以調控細胞的增生與凋亡。雄激素受體亦參與在雄激素依賴型攝護腺癌惡化成雄激素非依賴型攝護腺癌的過程，使得攝護腺癌在治療上更加困難。雄激素受體的mRNA經選擇性剪接後產生缺少配體結合區的雄激素變異體7號，在過去的研究指出此類變異體的表現量為所有變異體中最高，同時與攝護腺癌復發、惡化以及抗藥性具有高度相關性。蜂膠內的主成份之一--咖啡酸苯乙酯—是NF-𝑘B的抑制劑，過去也被發現具有抗癌的效果。然而，咖啡酸苯乙酯是否影響雄激素受體的訊息傳遞仍不清楚。我們發現隨著咖啡酸苯乙酯的濃度提升，可以有效的抑制雄激素受體、雄激素變異體7號及其下游基因的蛋白質表現。利用放線菌酮的處理，發現咖啡酸苯乙酯會加速雄激素受體及其變異體7號的蛋白質降解。我們進一步發現，咖啡酸苯乙酯藉由抑制CDK1及AKT1的活性，減少雄激素受體81號位點及213號位點的磷酸化程度，進而達到加速雄激素受體降解的目的。另外，在細胞內過量表現CDK1或AKT可以趨緩咖啡酸苯乙酯造成的雄激素受體蛋白質降解，降低細胞內CDK1的表現則會加劇由咖啡酸苯乙酯造成的蛋白質不穩定程度。在人類皮下腫瘤小鼠疾病模式的實驗中，我們也證實咖啡酸苯乙酯對於腫瘤細胞在小鼠體內的生長速度有明顯的抑制效果，同時雄激素受體、雄激素受體變異體7號以及CDK1的表現量也顯著的被抑制。因此我們認為咖啡酸苯乙酯可以直接且有效的抑制雄激素受體及其變異體，使得未來在治療攝護腺癌和雄激素受體相關疾病上出現一道新曙光。

Androgen receptor signaling plays important roles in the development, progression, and metastasis of prostate cancer (PCa). Androgen receptor (AR) binds to testosterone and activates one of its target genes, PSA, to regulate cell proliferation, cell death, and most importantly, evolution from androgen-dependent state to androgen-resistant PCa. AR splice variant-7 (AR- V7), one of the most abundant ARV, is constitutively activated and highly associated with recurrence and drug-resistance of PCa. Caffeic acid phenethyl ester (CAPE) is the main component of honey bee propolis. CAPE was an NF-!B inhibitor and also exhibited anti- carcinogenic property. However, the molecular mechanism of AR signaling affected by CAPE was unclear. We wondered if CAPE affects the signaling and stability of AR in PCa cells. CAPE treatment dose-dependently reduced protein levels of AR and AR-V7, as well as their target genes, PSA and UBE2C, respectively. Cycloheximide treatment revealed that androgen stabilized AR or AR-V7 protein, and stability of AR or AR-V7 was diminished by CAPE. CAPE treatment suppressed the phosphorylation of Ser81 and Ser213 on AR or AR-V7, which regulates the stability of AR. CDK1 and AKT are the kinases phosphorylating Ser81 and Ser213 on AR, respectively. CAPE treatment significantly reduced the protein level and activity of CDK1 and AKT in PCa cells. Overexpression of CDK1 or AKT rescued the protein levels and phosphorylation on Ser81 residue of AR and AR-V7 under CAPE treatment. Knockdown of CDK1 reduced the phosphorylation of Ser81 on AR-V7. Xenograft studies demonstrated that CAPE significantly inhibits tumor growth and reduced expression level of AR, AR-V7, and CDK1. Our results suggested that CAPE treatment reduced phosphorylation of AR and AR-V7, thus decreased their stability. Our findings implied the possibility of using CAPE as a treatment for advanced PCa and AR-related diseases.

Chapter I: Introduction    1
1.    Prostate Cancer    1
2.    Androgen Receptor    1
3.    Androgen Receptor Variants    3
4.    Propolis and Caffeic Acid Phenethyl Ester    5
Chapter II: Materials and Methods    8
1.    Cell culture, Chemicals and Plasmids    8
2.    Dual luciferase assay    9
3.    Immunoblot analysis    9
4.    Real-time polymerase chain reactions    9
5.    Immunofluorescence    10
6.    Nuclear and cytosolic extraction    10
7.    Cell proliferation assay    10
8.    Transfection    11
9.    Tumor xenograft studies    11
10.    Immunohistochemistry    12
11.    AR competitor assay    12
12.    Data analysis and sample size    13
Chapter III: Results    14
Part. A: CAPE suppresses androgen receptor signaling and stability via inhibition of phosphorylation on Ser81 and Ser213    14
1.    CAPE inhibits AR transcriptional activity    14
2.    CAPE suppresses AR protein level but not mRNA    15
3.    CAPE reduces the abundance of AR protein in cytoplasm and nucleus    15
4.    CAPE accelerates AR protein degradation by inhibiting CDK1 activity, AKT activity and the phosphorylation of AR    16
Part. B: CAPE suppresses androgen receptor variant-7 signaling via inhibition of phosphorylation on Ser81    18
1.    CAPE suppressed cell proliferation ability, AR-V7, and AR signaling axis    18
2.    CAPE reduces the abundance of AR-V7 protein in nucleus    19
3.    CAPE suppresses both AR mRNA and protein level    19
4.    CAPE reduced AR-V7 protein abundance by inhibiting CDK1 activity    20
5.    CAPE inhibits tumor growth and simultaneously downregulates AR-V7 and CDK1 expression in prostate tumor xenograft in mice    22
Chapter IV: Discussions    24
Chapter V: Perspectives    27
Chapter VI: Figures    30
Figure 1. Androgen receptor signaling pathway.    29
Figure 2. Enzalutamide, a next-generation hormone agent, has been approved for treatment of mCRPC    31
Figure 3. Abiraterone acetate (AA), an inhibitor of CYP17A1, was used for mCRPC treatment by impeding androgen biosynthesis    33
Figure 4. Human androgen receptor gene and the structural organization.    35
Figure 5. ICR/RMH patient cohorts utilized for this study    37
Figure 6. Transcript levels of full-length androgen receptor mRNA and AR-V7 detected in circulating tumor cells from patients with castration-resistant prostate cancer.    39
Figure 7. CAPE is a well-known NF-𝑘B inhibitor.    41
Figure 8. CAPE treatment suppressed transcriptional activity of androgen receptor (AR).    43
Figure 9. CAPE treatment suppressed protein level of AR and PSA but not mRNA of AR.    45
Figure 10. The distribution of AR in LNCaP 104-S and 104-R1 cells treated with or without androgen and CAPE.    47
Figure 11. CAPE treatment suppressed AR protein level by accelerating the degradation of AR.    49
Figure 12. CAPE treatment suppressed phosphorylation of AR on Ser81 and expression level of CDK1..    51
Figure 13. Phosphorylation of AR Ser 213 and AKT signaling pathway were suppressed by CAPE treatment    53
Figure 14. CAPE treatment suppressed protein level of AR, CDK1 and AKT of LNCaP 104-R1 xenografts in nude mice    55
Figure 15. The hydrophobicity of three compounds (DHT, CAPE and bicalutamide) was analyzed by Druglikeness software.    57
Figure 16. The nuclear receptor ligand score of three compounds (DHT, CAPE and bicalutamide) was analyzed by sophisticated Bayesian statistics    59
Figure 17. The binding ability of AR-ligand binding domain with DHT, CAPE and Bicalutamide was determined by AR competitor assay    61
Figure 18. AR-V7 protein level suppressed by CAPE treatment in time- and dose- dependent manners in 22RV1 cell line.    63
Figure 19. CAPE treatment suppressed protein levels of AR-V7 and the downstream protein, UBE2C    65
Figure 20. The distribution of AR-V7 and CDK1 in 22RV1 and VCaP cells treated with or without CAPE    67
Figure 21. AR-V7 protein level was suppressed by CAPE due to both acceleration of protein degradation and reduction of mRNA transcript..    69
Figure 22. CAPE treatment suppressed phosphorylation of AR-V7 on Ser81 and expression level of CDK1    71
Figure 23.Phosphorylation of AR-V7 Ser 81 and CDK1 signaling pathway were suppressed by CAPE treatment.    73
Figure 24. Reduced expression of AR-V7 and CDK1 by CAPE was associated with significant xenograft tumor growth inhibition    75
Figure 25. Putative model of anti-androgen effect of CAPE    77
Chapter VII: Appendix    78
Appendix 1. Primer sequences that were used for qRT-PCR detection    78
Appendix 2. The list of antibodies that were used    79
Chapter VIII: References    80
Chapter IX: Resume    89

                                

1 Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2019. CA Cancer J Clin 69, 7-34, doi:10.3322/caac.21551 (2019).
2 Huggins, C., Stevens, R. E., Hodge, C. V. Studies on prostatic cancer II. The effects of castration on advanced carcinoma of the prostate gland. Arch Surg. 43, 209-223 (1941).
3 Gilligan, T. & Kantoff, P. W. Chemotherapy for prostate cancer. Urology 60, 94-100, doi:10.1016/s0090-4295(02)01583-2 (2002).
4 Chuu, C. P. et al. Androgens as therapy for androgen receptor-positive castration-resistant prostate cancer. J. Biomed. Sci. 18, 63, doi:10.1186/1423-0127-18-63 (2011).
5 Hellerstedt, B. A. & Pienta, K. J. The Current State of Hormonal Therapy for Prostate Cancer. CA Cancer J. Clin. 52, 154-179, doi:10.3322/canjclin.52.3.154 (2002).
6 Feldman, B. J. & Feldman, D. The development of androgen-independent prostate cancer. Nat. Rev. Cancer 1, 34-45, doi:10.1038/35094009 (2001).
7 Chang, C. S., Kokontis, J. & Liao, S. T. Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science 240, 324-326 (1988).
8 MacLean, H. E., Warne, G. L. & Zajac, J. D. Localization of functional domains in the androgen receptor. J. Steroid Biochem. Mol. Biol. 62, 233-242, doi:10.1016/s0960-0760(97)00049-6 (1997).
9 Wang, Q. et al. A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth. Mol. Cell 27, 380-392, doi:10.1016/j.molcel.2007.05.041 (2007).
10 Wang, Q. et al. Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 138, 245-256, doi:10.1016/j.cell.2009.04.056 (2009).
11 Xu, Y., Chen, S. Y., Ross, K. N. & Balk, S. P. Androgens induce prostate cancer cell proliferation through mammalian target of rapamycin activation and post-transcriptional increases in cyclin D proteins. Cancer Res. 66, 7783-7792, doi:10.1158/0008-5472.CAN-05-4472 (2006).
12 Quigley, C. A. et al. Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr. Rev. 16, 271-321, doi:10.1210/edrv-16-3-271 (1995).
13 Ricke, E. A. et al. Androgen hormone action in prostatic carcinogenesis: stromal androgen receptors mediate prostate cancer progression, malignant transformation and metastasis. Carcinogenesis 33, 1391-1398, doi:10.1093/carcin/bgs153 (2012).
14 Lin, C. Y. et al. Elevation of androgen receptor promotes prostate cancer metastasis by induction of epithelial-mesenchymal transition and reduction of KAT5. Cancer Sci. 109, 3564-3574, doi:10.1111/cas.13776 (2018).
15 SadiMV, W., BarrackER. Immunohistochemicalstudy of androgen receptors in metastatic prostate cancer. Cancer 67 (1991).
16 Heinlein, C. A. & Chang, C. Androgen receptor in prostate cancer. Endocr. Rev. 25, 276-308, doi:10.1210/er.2002-0032 (2004).
17 Visakorpi, T. et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat. Genet. 9, 401-406, doi:10.1038/ng0495-401 (1995).
18 Wayne D. Tilley, G. B. & Theresa E. Hickey, a. J. M. B. Mutations in the Androgen Receptor Gene Are Associated with Progression of Human Prostate Cancer to Androgen Independence. Clin. Cancer Res., 277-285 (1996).
19 Chen, C. D. et al. Molecular determinants of resistance to antiandrogen therapy. Nat. Med. 10, 33-39, doi:10.1038/nm972 (2004).
20 Zegarra-Moro, O. L., Schmidt, L. J., Huang, H. & Tindall, D. J. Disruption of androgen receptor function inhibits proliferation of androgen-refractory prostate cancer cells. Cancer Res. 62, 1008-1013 (2002).
21 Edwards, J., Krishna, N. S., Grigor, K. M. & Bartlett, J. M. Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer. Br. J. Cancer 89, 552-556, doi:10.1038/sj.bjc.6601127 (2003).
22 Tran, C. et al. Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer. Science 324, 787-790, doi:10.1126/science.1168175 (2009).
23 O'Donnell, A. et al. Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. Br. J. Cancer 90, 2317-2325, doi:10.1038/sj.bjc.6601879 (2004).
24 Scher, H. I. et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy. N. Engl. J. Med. 367, 1187-1197, doi:10.1056/NEJMoa1207506 (2012).
25 de Bono, J. S. et al. Abiraterone and Increased Survival in Metastatic Prostate Cancer. N. Engl. J. Med. 364, 1995-2005, doi:10.1056/NEJMoa1014618 (2011).
26 Scher, H. I. et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. The Lancet 375, 1437-1446, doi:10.1016/s0140-6736(10)60172-9 (2010).
27 Haidar, S., Ehmer, P. B., Barassin, S., Batzl-Hartmann, C. & Hartmann, R. W. Effects of novel 17α-hydroxylase/C17, 20-lyase (P450 17, CYP 17) inhibitors on androgen biosynthesis in vitro and in vivo. J. Steroid Biochem. Mol. Biol. 84, 555-562, doi:10.1016/s0960-0760(03)00070-0 (2003).
28 Antonarakis, E. S., Armstrong, A. J., Dehm, S. M. & Luo, J. Androgen receptor variant-driven prostate cancer: clinical implications and therapeutic targeting. Prostate Cancer Prostatic Dis. 19, 231-241, doi:10.1038/pcan.2016.17 (2016).
29 Ahrens-Fath I, P. O., Geserick C, et al. Androgen receptor function is modulated by the tissue-specific AR45 variant. FEBS J. 272 (2005).
30 Lu, C. & Luo, J. Decoding the androgen receptor splice variants. Transl. Androl. Urol. 2, 178-186, doi:10.3978/j.issn.2223-4683.2013.09.08 (2013).
31 Dehm, S. M., Schmidt, L. J., Heemers, H. V., Vessella, R. L. & Tindall, D. J. Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res. 68, 5469-5477, doi:10.1158/0008-5472.CAN-08-0594 (2008).
32 Guo, Z. et al. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res. 69, 2305-2313, doi:10.1158/0008-5472.CAN-08-3795 (2009).
33 Hu, R. et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 69, 16-22, doi:10.1158/0008-5472.CAN-08-2764 (2009).
34 Marcias, G. et al. Identification of novel truncated androgen receptor (AR) mutants including unreported pre-mRNA splicing variants in the 22Rv1 hormone-refractory prostate cancer (PCa) cell line. Hum. Mutat. 31, 74-80, doi:10.1002/humu.21138 (2010).
35 Sun, S. et al. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J. Clin. Invest. 120, 2715-2730, doi:10.1172/JCI41824 (2010).
36 Brand, L. J. & Dehm, S. M. Androgen receptor gene rearrangements: new perspectives on prostate cancer progression. Curr. Drug. Targets. 14, 441-449, doi:10.2174/1389450111314040005 (2013).
37 Xu, D. et al. Androgen Receptor Splice Variants Dimerize to Transactivate Target Genes. Cancer Res. 75, 3663-3671, doi:10.1158/0008-5472.CAN-15-0381 (2015).
38 Sun, F. et al. Androgen receptor splice variant AR3 promotes prostate cancer via modulating expression of autocrine/paracrine factors. J. Biol. Chem. 289, 1529-1539, doi:10.1074/jbc.M113.492140 (2014).
39 Antonarakis, E. S. et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N. Engl. J. Med. 371, 1028-1038, doi:10.1056/NEJMoa1315815 (2014).
40 Qu, F. et al. Association of AR-V7 and Prostate-Specific Antigen RNA Levels in Blood with Efficacy of Abiraterone Acetate and Enzalutamide Treatment in Men with Prostate Cancer. Clin. Cancer Res. 23, 726-734, doi:10.1158/1078-0432.CCR-16-1070 (2017).
41 S, V. K. Propolis in dentistry and oral cancer management. N. Am. J. Med. Sci. 6, 250-259, doi:10.4103/1947-2714.134369 (2014).
42 Grunberger, D. et al. Preferential cytotoxicity on tumor cells by caffeic acid phenethyl ester isolated from propolis. Experientia 44, 230-232, doi:10.1007/bf01941717 (1988).
43 Okutan, H., Ozcelik, N., Yilmaz, H. R. & Uz, E. Effects of caffeic acid phenethyl ester on lipid peroxidation and antioxidant enzymes in diabetic rat heart. Clin. Biochem. 38, 191-196, doi:10.1016/j.clinbiochem.2004.10.003 (2005).
44 Bhimani, R. S., Troll, W., Grunberger, D. & Frenkel, K. Inhibition of oxidative stress in HeLa cells by chemopreventive agents. Cancer Res. 53, 4528-4533 (1993).
45 Natarajan, K., Singh, S., Burke, T. R., Jr., Grunberger, D. & Aggarwal, B. B. Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B. Proc. Natl. Acad. Sci. USA 93, 9090-9095, doi:10.1073/pnas.93.17.9090 (1996).
46 Nomura, M., Kaji, A., Ma, W., Miyamoto, K. & Dong, Z. Suppression of cell transformation and induction of apoptosis by caffeic acid phenethyl ester. Mol. Carcinog. 31, 83-89 (2001).
47 Wu, J. et al. Caffeic acid phenethyl ester (CAPE), derived from a honeybee product propolis, exhibits a diversity of anti-tumor effects in pre-clinical models of human breast cancer. Cancer Lett. 308, 43-53, doi:10.1016/j.canlet.2011.04.012 (2011).
48 Watabe, M., Hishikawa, K., Takayanagi, A., Shimizu, N. & Nakaki, T. Caffeic acid phenethyl ester induces apoptosis by inhibition of NF kappa B and activation of Fas in human breast cancer MCF-7 cells. J. Biol. Chem. 279, 6017-6026, doi:10.1074/jbc.M306040200 (2004).
49 Lin, H. P., Jiang, S. S. & Chuu, C. P. Caffeic acid phenethyl ester causes p21 induction, Akt signaling reduction, and growth inhibition in PC-3 human prostate cancer cells. PLoS One 7, e31286, doi:10.1371/journal.pone.0031286 (2012).
50 Chuu, C. P. et al. Caffeic acid phenethyl ester suppresses the proliferation of human prostate cancer cells through inhibition of p70S6K and Akt signaling networks. Cancer Prev. Res. (Phila) 5, 788-797, doi:10.1158/1940-6207.CAPR-12-0004-T (2012).
51 Lin, H. P. et al. Caffeic Acid phenethyl ester as a potential treatment for advanced prostate cancer targeting akt signaling. Int. J. Mol. Sci. 14, 5264-5283, doi:10.3390/ijms14035264 (2013).
52 Chen, M. F., Wu, C. T., Chen, Y. J., Keng, P. C. & Chen, W. C. Cell killing and radiosensitization by caffeic acid phenethyl ester (CAPE) in lung cancer cells. J. Radiat. Res. 45, 253-260, doi:10.1269/jrr.45.253 (2004).
53 Lin, H. P., Kuo, L. K. & Chuu, C. P. Combined treatment of curcumin and small molecule inhibitors suppresses proliferation of A549 and H1299 human non-small-cell lung cancer cells. Phytother. Res. 26, 122-126, doi:10.1002/ptr.3523 (2012).
54 Lee, Y. T. et al. Cytotoxicity of phenolic acid phenethyl esters on oral cancer cells. Cancer Lett. 223, 19-25, doi:10.1016/j.canlet.2004.09.048 (2005).
55 Onori, P. et al. Caffeic acid phenethyl ester decreases cholangiocarcinoma growth by inhibition of NF-kappaB and induction of apoptosis. Int. J. Cancer 125, 565-576, doi:10.1002/ijc.24271 (2009).
56 Hung, M. W., Shiao, M. S., Tsai, L. C., Chang, G. G. & Chang, T. C. Apoptotic effect of caffeic acid phenethyl ester and its ester and amide analogues in human cervical cancer ME180 cells. Anticancer Res. 23, 4773-4780 (2003).
57 Usia, T. et al. Constituents of Chinese propolis and their antiproliferative activities. J. Nat. Prod. 65, 673-676, doi:10.1021/np010486c (2002).
58 Chen, Y. J., Shiao, M. S., Hsu, M. L., Tsai, T. H. & Wang, S. Y. Effect of caffeic acid phenethyl ester, an antioxidant from propolis, on inducing apoptosis in human leukemic HL-60 cells. J. Agric. Food Chem. 49, 5615-5619, doi:10.1021/jf0107252 (2001).
59 Jin, U. H. et al. Caffeic acid phenethyl ester induces mitochondria-mediated apoptosis in human myeloid leukemia U937 cells. Mol. Cell Biochem. 310, 43-48, doi:10.1007/s11010-007-9663-7 (2008).
60 Lee, Y. J. et al. Involvement of tumor suppressor protein p53 and p38 MAPK in caffeic acid phenethyl ester-induced apoptosis of C6 glioma cells. Biochem. Pharmacol. 66, 2281-2289, doi:10.1016/j.bcp.2003.07.014 (2003).
61 Su, Z. Z., Lin, J., Grunberger, D. & Fisher, P. B. Growth suppression and toxicity induced by caffeic acid phenethyl ester (CAPE) in type 5 adenovirus-transformed rat embryo cells correlate directly with transformation progression. Cancer Res. 54, 1865-1870 (1994).
62 Lin, Y. H. et al. Antiproliferation and radiosensitization of caffeic acid phenethyl ester on human medulloblastoma cells. Cancer Chemother. Pharmacol. 57, 525-532, doi:10.1007/s00280-005-0066-8 (2006).
63 He, Y. J. et al. Inhibitory effect of caffeic acid phenethyl ester on the growth of SW480 colorectal tumor cells involves beta-catenin associated signaling pathway down-regulation. World J. Gastroenterol. 12, 4981-4985, doi:10.3748/wjg.v12.i31.4981 (2006).
64 Kuo, H. C. et al. Inhibitory effect of caffeic acid phenethyl ester on the growth of C6 glioma cells in vitro and in vivo. Cancer Lett. 234, 199-208, doi:10.1016/j.canlet.2005.03.046 (2006).
65 Wang, D. et al. Effect of caffeic acid phenethyl ester on proliferation and apoptosis of colorectal cancer cells in vitro. World J. Gastroenterol. 11, 4008-4012, doi:10.3748/wjg.v11.i26.4008 (2005).
66 Xiang, D. et al. Caffeic acid phenethyl ester induces growth arrest and apoptosis of colon cancer cells via the beta-catenin/T-cell factor signaling. Anticancer Drugs 17, 753-762, doi:10.1097/01.cad.0000224441.01082.bb (2006).
67 Shigeoka, Y. et al. Sulindac sulfide and caffeic acid phenethyl ester suppress the motility of lung adenocarcinoma cells promoted by transforming growth factor-beta through Akt inhibition. J. Cancer Res. Clin Oncol 130, 146-152, doi:10.1007/s00432-003-0520-0 (2004).
68 Weyant, M. J., Carothers, A. M., Bertagnolli, M. E. & Bertagnolli, M. M. Colon cancer chemopreventive drugs modulate integrin-mediated signaling pathways. Clin. Cancer Res. 6, 949-956 (2000).
69 Mahmoud, N. N. et al. Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis. Carcinogenesis 21, 921-927, doi:10.1093/carcin/21.5.921 (2000).
70 Nagaoka, T. et al. Inhibitory effects of caffeic acid phenethyl ester analogues on experimental lung metastasis of murine colon 26-L5 carcinoma cells. Biol. Pharm. Bull. 26, 638-641, doi:10.1248/bpb.26.638 (2003).
71 Borrelli, F. et al. Effect of a propolis extract and caffeic acid phenethyl ester on formation of aberrant crypt foci and tumors in the rat colon. Fitoterapia 73 Suppl 1, S38-43 (2002).
72 Carrasco-Legleu, C. E. et al. A single dose of caffeic acid phenethyl ester prevents initiation in a medium-term rat hepatocarcinogenesis model. World J. Gastroenterol. 12, 6779-6785, doi:10.3748/wjg.v12.i42.6779 (2006).
73 Carrasco-Legleu, C. E. et al. Chemoprotective effect of caffeic acid phenethyl ester on promotion in a medium-term rat hepatocarcinogenesis assay. Int. J. Cancer 108, 488-492, doi:10.1002/ijc.11595 (2004).
74 Kudugunti, S. K., Vad, N. M., Ekogbo, E. & Moridani, M. Y. Efficacy of caffeic acid phenethyl ester (CAPE) in skin B16-F0 melanoma tumor bearing C57BL/6 mice. Invest. New Drugs 29, 52-62, doi:10.1007/s10637-009-9334-5 (2011).
75 Liao, H. F. et al. Inhibitory effect of caffeic acid phenethyl ester on angiogenesis, tumor invasion, and metastasis. J. Agric. Food Chem. 51, 7907-7912, doi:10.1021/jf034729d (2003).
76 Orsolic, N., Knezevic, A. H., Sver, L., Terzic, S. & Basic, I. Immunomodulatory and antimetastatic action of propolis and related polyphenolic compounds. J. Ethnopharmacol 94, 307-315, doi:10.1016/j.jep.2004.06.006 (2004).
77 Chung, T. W. et al. Novel and therapeutic effect of caffeic acid and caffeic acid phenyl ester on hepatocarcinoma cells: complete regression of hepatoma growth and metastasis by dual mechanism. FASEB J. 18, 1670-1681, doi:10.1096/fj.04-2126com (2004).
78 Wang, X. et al. Pharmacokinetics of caffeic acid phenethyl ester and its catechol-ring fluorinated derivative following intravenous administration to rats. Biopharm. Drug Dispos. 30, 221-228, doi:10.1002/bdd.657 (2009).
79 Omene, C. O., Wu, J. & Frenkel, K. Caffeic Acid Phenethyl Ester (CAPE) derived from propolis, a honeybee product, inhibits growth of breast cancer stem cells. Invest. New Drugs 30, 1279-1288, doi:10.1007/s10637-011-9667-8 (2012).
80 Akyol, S. et al. The potential usage of caffeic acid phenethyl ester (CAPE) against chemotherapy-induced and radiotherapy-induced toxicity. Cell Biochem. Funct. 30, 438-443, doi:10.1002/cbf.2817 (2012).
81 Yagmurca, M. et al. Caffeic acid phenethyl ester as a protective agent against doxorubicin nephrotoxicity in rats. Clin. Chim. Acta. 348, 27-34, doi:10.1016/j.cccn.2004.03.035 (2004).
82 Fadillioglu, E. et al. Protective effects of caffeic acid phenethyl ester on doxorubicin-induced cardiotoxicity in rats. J. Appl. Toxicol. 24, 47-52, doi:10.1002/jat.945 (2004).
83 Irmak, M. K. et al. Effects of caffeic acid phenethyl ester and alpha-tocopherol on reperfusion injury in rat brain. Cell Biochem. Funct. 21, 283-289, doi:10.1002/cbf.1024 (2003).
84 Iraz, M. et al. Protective effect of caffeic acid phenethyl ester (CAPE) administration on cisplatin-induced oxidative damage to liver in rat. Cell Biochem. Funct. 24, 357-361, doi:10.1002/cbf.1232 (2006).
85 Yilmaz, H. R. et al. The activities of liver adenosine deaminase, xanthine oxidase, catalase, superoxide dismutase enzymes and the levels of malondialdehyde and nitric oxide after cisplatin toxicity in rats: protective effect of caffeic acid phenethyl ester. Toxicol. Ind. Health 21, 67-73, doi:10.1191/0748233705th216oa (2005).
86 Oktem, F. et al. Methotrexate-induced renal oxidative stress in rats: the role of a novel antioxidant caffeic acid phenethyl ester. Toxicol. Ind. Health 22, 241-247, doi:10.1191/0748233706th265oa (2006).
87 Ozyurt, H. et al. Inhibitory effect of caffeic acid phenethyl ester on bleomycine-induced lung fibrosis in rats. Clin. Chim. Acta. 339, 65-75, doi:10.1016/j.cccn.2003.09.015 (2004).
88 Albukhari, A. A., Gashlan, H. M., El-Beshbishy, H. A., Nagy, A. A. & Abdel-Naim, A. B. Caffeic acid phenethyl ester protects against tamoxifen-induced hepatotoxicity in rats. Food Chem. Toxicol. 47, 1689-1695, doi:10.1016/j.fct.2009.04.021 (2009).
89 Yildiz, O. G., Soyuer, S., Saraymen, R. & Eroglu, C. Protective effects of caffeic acid phenethyl ester on radiation induced lung injury in rats. Clin. Invest. Med. 31, E242-247 (2008).
90 Chen, Y. J., Liao, H. F., Tsai, T. H., Wang, S. Y. & Shiao, M. S. Caffeic acid phenethyl ester preferentially sensitizes CT26 colorectal adenocarcinoma to ionizing radiation without affecting bone marrow radioresponse. Int. J. Radiat. Oncol. Biol. Phys. 63, 1252-1261, doi:10.1016/j.ijrobp.2005.08.001 (2005).
91 Kokontis, J., Takakura, K., Hay, N. & Liao, S. Increased androgen receptor activity and altered c-myc expression in prostate cancer cells after long-term androgen deprivation. Cancer Res. 54, 1566-1573 (1994).
92 Horwitz, K. B., Koseki, Y. & McGuire, W. L. Estrogen control of progesterone receptor in human breast cancer: role of estradiol and antiestrogen. Endocrinology 103, 1742-1751, doi:10.1210/endo-103-5-1742 (1978).
93 Koryakina, Y., Knudsen, K. E. & Gioeli, D. Cell-cycle-dependent regulation of androgen receptor function. Endocr. Relat. Cancer 22, 249-264, doi:10.1530/ERC-14-0549 (2015).
94 Solomon, M. J., Lee, T. & Kirschner, M. W. Role of phosphorylation in p34cdc2 activation: identification of an activating kinase. Mol. Biol. Cell 3, 13-27, doi:10.1091/mbc.3.1.13 (1992).
95 Kokontis, J. M. et al. Role of androgen receptor in the progression of human prostate tumor cells to androgen independence and insensitivity. Prostate 65, 287-298, doi:10.1002/pros.20285 (2005).
96 Cato, L. et al. ARv7 Represses Tumor-Suppressor Genes in Castration-Resistant Prostate Cancer. Cancer Cell 35, 401-413 e406, doi:10.1016/j.ccell.2019.01.008 (2019).
97 Kuo, Y. Y. et al. Caffeic acid phenethyl ester suppresses androgen receptor signaling and stability via inhibition of phosphorylation on Ser81 and Ser213. Cell Commun. Signal. 17, 100, doi:10.1186/s12964-019-0404-9 (2019).
98 Yoshiaki Okamoto, T. O., Kou Miyazaki, Mineyoshi Aoyama, Masaru Miyazaki, and Akira Nakagawara. UbcH10 Is the Cancer-related E2 Ubiquitin-conjugating Enzyme. Cancer Res. 15, 7 (2003).
99 Guo, Z. et al. Regulation of androgen receptor activity by tyrosine phosphorylation. Cancer Cell 10, 309-319, doi:10.1016/j.ccr.2006.08.021 (2006).
100 Gioeli, D. et al. Stress kinase signaling regulates androgen receptor phosphorylation, transcription, and localization. Mol. Endocrinol. 20, 503-515, doi:10.1210/me.2005-0351 (2006).
101 Gioeli, D. et al. Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites. J. Biol. Chem 277, 29304-29314, doi:10.1074/jbc.M204131200 (2002).
102 Taneja, S. S. et al. Cell-specific regulation of androgen receptor phosphorylation in vivo. J. Biol. Chem. 280, 40916-40924, doi:10.1074/jbc.M508442200 (2005).
103 Wen, Y. et al. HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway. Cancer Res. 60, 6841-6845 (2000).
104 Chen, S., Xu, Y., Yuan, X., Bubley, G. J. & Balk, S. P. Androgen receptor phosphorylation and stabilization in prostate cancer by cyclin-dependent kinase 1. Proc. Natl. Acad. Sci. USA 103, 15969-15974, doi:10.1073/pnas.0604193103 (2006).
105 Hsu, F. N. et al. Regulation of androgen receptor and prostate cancer growth by cyclin-dependent kinase 5. J. Biol. Chem. 286, 33141-33149, doi:10.1074/jbc.M111.252080 (2011).

簡易檢索 / 詳目顯示

相關論文