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

  • Oncotarget. 2015 Mar 30;6(9):6684-707. doi: 10.18632/oncotarget.3246.
Hui-Ping Lin  1 ,  Ching-Yu Lin  2 ,  Chieh Huo  2  3 ,  Ping-Hsuan Hsiao  2  4 ,  Liang-Cheng Su  2 ,  Shih Sheng Jiang  1 ,  Tzu-Min Chan  5  6 ,  Chung-Ho Chang  2 ,  Li-Tzong Chen  1 ,  Hsing-Jien Kung  1  7 ,  Horng-Dar Wang  4 ,  Chih-Pin Chuu  2  8  9  10  11
Affiliations
  • 1. National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan, ROC.
  • 2. Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan, ROC.
  • 3. Department of Life Sciences, National Central University, Taoyuan, Taiwan, ROC.
  • 4. Institute of Biotechnology, National Tsing Hua University, Hsinchu City, Taiwan, ROC.
  • 5. Department of Medical Education and Research, China Medical University Beigan Hospital, Yunlin, Taiwan, ROC.
  • 6. Department of Medical Education and Research, China Medical University-An Nan Hospital, Tainan, Taiwan, ROC.
  • 7. Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli County, Taiwan, ROC.
  • 8. Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, ROC.
  • 9. Graduate Program for Aging, China Medical University, Taichung, Taiwan, ROC.
  • 10. Biotechnology Center, National Chung Hsing University, Taichung, Taiwan, ROC.
  • 11. Ph.D. Program in Environmental and Occupational Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan, ROC.
PMID: 25788262 DOI: 10.18632/oncotarget.3246
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.

Keywords
Skp2; caffeic acid phenethyl ester; cell cycle arrest; p53; prostate cancer.
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