Research Papers:

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

Hui-Ping Lin, Ching-Yu Lin, Chieh Huo, Ping-Hsuan Hsiao, Liang-Cheng Su, Shih Sheng Jiang, Tzu-Min Chan, Chung-Ho Chang, Li-Tzong Chen, Hsing-Jien Kung, Horng-Dar Wang and Chih-Pin Chuu _

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Oncotarget. 2015; 6:6684-6707. https://doi.org/10.18632/oncotarget.3246

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Hui-Ping Lin1,*, Ching-Yu Lin2,*, Chieh Huo2,3,*, Ping-Hsuan Hsiao2,4,*, Liang-Cheng Su2, Shih Sheng Jiang1, Tzu-Min Chan5,6, Chung-Ho Chang2, Li-Tzong Chen1, Hsing-Jien Kung1,7, Horng-Dar Wang4, Chih-Pin Chuu2,8,9,10,11

1National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan, ROC

2Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan, ROC

3Department of Life Sciences, National Central University, Taoyuan, Taiwan, ROC

4Institute of Biotechnology, National Tsing Hua University, Hsinchu City, Taiwan, ROC

5Department of Medical Education and Research, China Medical University Beigan Hospital, Yunlin, Taiwan, ROC

6Department of Medical Education and Research, China Medical University-An Nan Hospital, Tainan, Taiwan, ROC

7Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli County, Taiwan, ROC

8Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, ROC

9Graduate Program for Aging, China Medical University, Taichung, Taiwan, ROC

10Biotechnology Center, National Chung Hsing University, Taichung, Taiwan, ROC

11Ph.D. Program in Environmental and Occupational Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan, ROC

*These authors have contributed equally to this work

Correspondence to:

Chih-Pin Chuu, e-mail: [email protected]

Keywords: Prostate cancer, caffeic acid phenethyl ester, cell cycle arrest, Skp2, p53

Received: September 18, 2014     Accepted: January 30, 2015     Published: February 16, 2015


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.

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