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

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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

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Cell Cycle Checkpoints
Androgens
Prostatic Neoplasms
Growth
Castration
S-Phase Kinase-Associated Proteins
Therapeutics
Cyclin H
G2 Phase Cell Cycle Checkpoints
Cyclin A
Cyclin E
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
caffeic acid phenethyl ester
Cyclin D1
p38 Mitogen-Activated Protein Kinases
Phosphatidylinositol 3-Kinases
Heterografts
Nude Mice
Small Interfering RNA
Agar

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

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

In: Oncotarget, Vol. 6, No. 9, 01.01.2015, p. 6684-6707.

Research output: Contribution to journalArticle

Lin, HP, Lin, CY, Huo, C, Hsiao, PH, Su, LC, Jiang, SS, Chan, TM, Chang, CH, Chen, LT, Kung, HJ, Wang, HD & Chuu, CP 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, vol. 6, no. 9, pp. 6684-6707.
Lin, Hui Ping ; Lin, Ching Yu ; Huo, Chieh ; Hsiao, Ping Hsuan ; Su, Liang Cheng ; Jiang, Shih Sheng ; Chan, Tzu Min ; Chang, Chung Ho ; Chen, Li Tzong ; Kung, Hsing Jien ; Wang, Horng Dar ; Chuu, Chih Pin. / 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. In: Oncotarget. 2015 ; Vol. 6, No. 9. pp. 6684-6707.
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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.",
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AU - Su, Liang Cheng

AU - Jiang, Shih Sheng

AU - Chan, Tzu Min

AU - Chang, Chung Ho

AU - Chen, Li Tzong

AU - Kung, Hsing Jien

AU - Wang, Horng Dar

AU - Chuu, Chih Pin

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