Journal
ONCOTARGET
Volume 6, Issue 9, Pages 6684-6707Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3246
Keywords
Prostate cancer; caffeic acid phenethyl ester; cell cycle arrest; Skp2; p53
Categories
Funding
- National Health Research Institutes [CS-103-PP-14]
- Ministry of Health and Welfare [CA-103-SP-01]
- (Ministry of Science and Technology) in Taiwan [MOST 103-2325-B-400-001, MOST 103-2321-B-400-016]
- National Core Facility Program for Biotechnology from Taiwan [NSC 102-2319-B-400-001]
- MOST, (Taiwan) [103-2325-B-400-002]
- Micro-Western Array
- Cell sorting core facility of NHRI
- [MOST 103-2633-B-400-002]
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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(Cip1), p27(Kip1), 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(Cip1), p27(Kip1), 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(Cip1), and p27(Kip1).
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