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.
Highlights
Prostate cancer is the second most frequently diagnosed cancer of men and the fifth most common cancer overall in the world
Our study suggested that Caffeic acid phenethyl ester (CAPE) treatment can efficiently induced G1 or G2/M cell cycle arrest, cellular and growth inhibition in castration-resistant prostate cancer (CRPC) cells via inhibition of Skp2 as well as induction of p21Cip1, p27Kip1, and p53 in CRPC cell lines
We compared the sensitivity of LNCaP 104-R1 cells to CAPE treatment with the four other CRPC cell lines
Summary
Prostate cancer is the second most frequently diagnosed cancer of men and the fifth most common cancer overall in the world. We have established LNCaP sublines mimic the progression of PCa. An androgen-dependent clonal subline of the LNCaP human prostate cancer cell line called LNCaP 104-S was subjected to long-term androgen deprivation in order to model changes which occur in the PCa cells in patient undergoing androgen-ablation therapy. We discovered that CAPE treatment inhibited cell growth and induced G1 cell cycle arrest by suppressing c-Myc and Akt-related protein signaling networks in LNCaP 104-S and PC-3 cells [18,19,20]. The protein expression profile and response to treatment of chemotherapy drugs or kinase inhibitors was quite different between LNCaP 104R1 and LNCaP 104-S cells [21]. We used MWA to determine the changes of signaling protein profile in LNCaP 104R1 cells being treated with CAPE. Our finding implied that CAPE treatment might be a potential therapy for patients with CRPC
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