Caffeic acid phenethyl ester induced cell cycle arrest and growth inhibition in androgen-independent prostate cancer cells via regulation of Skp2, p53, p21<sup>Cip1</sup> and p27<sup>Kip1</sup>

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

43 Scopus citations

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 p21<sup>Cip1</sup>, p27<sup>Kip1</sup>, 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 p21<sup>Cip1</sup>, p27<sup>Kip1</sup>, 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, p21<sup>Cip1</sup>, and p27<sup>Kip1</sup>.

Original languageEnglish (US)
Pages (from-to)6684-6707
Number of pages24
JournalOncotarget
Volume6
Issue number9
StatePublished - 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, p21<sup>Cip1</sup> and p27<sup>Kip1</sup> Oncotarget, 6(9), 6684-6707.