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, Chih Pin Chuu

Research output: Contribution to journalArticle

44 Citations (Scopus)

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-GSK3a 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.

Original languageEnglish
Pages (from-to)6684-6707
Number of pages24
JournalOncotarget
Volume6
Issue number9
Publication statusPublished - Jan 1 2015
Externally publishedYes

Keywords

  • Caffeic acid phenethyl ester
  • Cell cycle arrest
  • P53
  • Prostate cancer
  • Skp2

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Lin, H. P., Lin, C. Y., Huo, C., Hsiao, P. H., Su, L. C., Jiang, S. S., Chan, T. M., Chang, C. H., Chen, L. T., Kung, H. J., Wang, H. D., & Chuu, C. P. (2015). 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, 6(9), 6684-6707.