title: Caffeic acid phenethyl ester induced cell cycle arrest and growth inhibition in androgen-independent prostate cancer cells via regulation of Skp2, p53, p21Cip1 and p27Kip1.
abstract: Prostate cancer (PCa) patients receiving the androgen ablation therapy ultimately develop recurrent castration-resistant prostate cancer (CRPC) within 1-3 years. Treatment with caffeic acid phenethyl ester (CAPE) suppressed cell survival and proliferation via induction of G1 or G2/M cell cycle arrest in LNCaP 104-R1, DU-145, 22Rv1, and C4-2 CRPC cells. CAPE treatment also inhibited soft agar colony formation and retarded nude mice xenograft growth of LNCaP 104-R1 cells. We identified that CAPE treatment significantly reduced protein abundance of Skp2, Cdk2, Cdk4, Cdk7, Rb, phospho-Rb S807/811, cyclin A, cyclin D1, cyclin H, E2F1, c-Myc, SGK, phospho-p70S6kinase T421/S424, phospho-mTOR Ser2481, phospho-GSK3α Ser21, but induced p21Cip1, p27Kip1, ATF4, cyclin E, p53, TRIB3, phospho-p53 (Ser6, Ser33, Ser46, Ser392), phospho-p38 MAPK Thr180/Tyr182, Chk1, Chk2, phospho-ATM S1981, phospho-ATR S428, and phospho-p90RSK Ser380. CAPE treatment decreased Skp2 and Akt1 protein expression in LNCaP 104-R1 tumors as compared to control group. Overexpression of Skp2, or siRNA knockdown of p21Cip1, p27Kip1, or p53 blocked suppressive effect of CAPE treatment. Co-treatment of CAPE with PI3K inhibitor LY294002 or Bcl-2 inhibitor ABT737 showed synergistic suppressive effects. Our finding suggested that CAPE treatment induced cell cycle arrest and growth inhibition in CRPC cells via regulation of Skp2, p53, p21Cip1, and p27Kip1.
authors: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan, ROC.
authors: Hui-Ping
authors: HP
authors: Lin
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan, ROC.
authors: Ching-Yu
authors: CY
authors: Lin
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan, ROC.|Department of Life Sciences, National Central University, Taoyuan, Taiwan, ROC.
authors: Chieh
authors: C
authors: Huo
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan, ROC.|Institute of Biotechnology, National Tsing Hua University, Hsinchu City, Taiwan, ROC.
authors: Ping-Hsuan
authors: PH
authors: Hsiao
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan, ROC.
authors: Liang-Cheng
authors: LC
authors: Su
authors: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan, ROC.
authors: Shih Sheng
authors: SS
authors: Jiang
authors: Department of Medical Education and Research, China Medical University Beigan Hospital, Yunlin, Taiwan, ROC.|Department of Medical Education and Research, China Medical University-An Nan Hospital, Tainan, Taiwan, ROC.
authors: Tzu-Min
authors: TM
authors: Chan
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan, ROC.
authors: Chung-Ho
authors: CH
authors: Chang
authors: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan, ROC.
authors: Li-Tzong
authors: LT
authors: Chen
authors: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan, ROC.|Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli County, Taiwan, ROC.
authors: Hsing-Jien
authors: HJ
authors: Kung
authors: Institute of Biotechnology, National Tsing Hua University, Hsinchu City, Taiwan, ROC.
authors: Horng-Dar
authors: HD
authors: Wang
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan, ROC.|Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, ROC.|Graduate Program for Aging, China Medical University, Taichung, Taiwan, ROC.|Biotechnology Center, National Chung Hsing University, Taichung, Taiwan, ROC.|Ph.D. Program in Environmental and Occupational Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan, ROC.
authors: Chih-Pin
authors: CP
authors: Chuu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002109:Caffeic Acids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D002109:Caffeic Acids; D050759:Cyclin-Dependent Kinase Inhibitor p21; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D044786:S-Phase Kinase-Associated Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27; D058539:Phosphatidylinositol 3-Kinase; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol
keywords: Skp2; caffeic acid phenethyl ester; cell cycle arrest; p53; prostate cancer