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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 HP, Lin CY, Huo C, Hsiao PH, Su LC, Jiang SS, Chan TM, Chang CH, Chen LT, Kung HJ, Wang HD, Chuu CP - Oncotarget (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan, ROC.

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.

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Over-expression of p27Kip1, p21Cip1, and p53 blocked the suppressive effect of CAPE on proliferation of LNCaP 104-R1 cellsLNCaP 104-R1 cells overexpressing p27Kip1(A), p21Cip1(B), or p53 (C) and their plasmid control cells were treated with increasing concentrations of CAPE for 96 hr and analyzed by 96-well proliferation assay for cell proliferation. Overexpression of p27Kip1, p21Cip1, and p53 proteins was confirmed by Western blotting. Protein abundance of β-actin was used as loading control.
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Figure 11: Over-expression of p27Kip1, p21Cip1, and p53 blocked the suppressive effect of CAPE on proliferation of LNCaP 104-R1 cellsLNCaP 104-R1 cells overexpressing p27Kip1(A), p21Cip1(B), or p53 (C) and their plasmid control cells were treated with increasing concentrations of CAPE for 96 hr and analyzed by 96-well proliferation assay for cell proliferation. Overexpression of p27Kip1, p21Cip1, and p53 proteins was confirmed by Western blotting. Protein abundance of β-actin was used as loading control.

Mentions: Besides Skp2, CAPE treatment induced protein expression of p27Kip1, p21Cip1, and p53 in all CRPC cell lines. We therefore determined if siRNA knockdown of p27Kip1, p21Cip1, or p53 may rescue the growth inhibition of LNCaP 104-R1 cells induced by CAPE treatment. Indeed, siRNA knockdown of p27Kip1 (Figure 11A), p21Cip1 (Figure 11B), or p53 (Figure 11C) rescued the cell proliferation of LNCaP 104-R1 cells being treated with increasing concentration of CAPE, confirming their essential role in regulating cell cycle arrest induced by CAPE treatment.


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 HP, Lin CY, Huo C, Hsiao PH, Su LC, Jiang SS, Chan TM, Chang CH, Chen LT, Kung HJ, Wang HD, Chuu CP - Oncotarget (2015)

Over-expression of p27Kip1, p21Cip1, and p53 blocked the suppressive effect of CAPE on proliferation of LNCaP 104-R1 cellsLNCaP 104-R1 cells overexpressing p27Kip1(A), p21Cip1(B), or p53 (C) and their plasmid control cells were treated with increasing concentrations of CAPE for 96 hr and analyzed by 96-well proliferation assay for cell proliferation. Overexpression of p27Kip1, p21Cip1, and p53 proteins was confirmed by Western blotting. Protein abundance of β-actin was used as loading control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466643&req=5

Figure 11: Over-expression of p27Kip1, p21Cip1, and p53 blocked the suppressive effect of CAPE on proliferation of LNCaP 104-R1 cellsLNCaP 104-R1 cells overexpressing p27Kip1(A), p21Cip1(B), or p53 (C) and their plasmid control cells were treated with increasing concentrations of CAPE for 96 hr and analyzed by 96-well proliferation assay for cell proliferation. Overexpression of p27Kip1, p21Cip1, and p53 proteins was confirmed by Western blotting. Protein abundance of β-actin was used as loading control.
Mentions: Besides Skp2, CAPE treatment induced protein expression of p27Kip1, p21Cip1, and p53 in all CRPC cell lines. We therefore determined if siRNA knockdown of p27Kip1, p21Cip1, or p53 may rescue the growth inhibition of LNCaP 104-R1 cells induced by CAPE treatment. Indeed, siRNA knockdown of p27Kip1 (Figure 11A), p21Cip1 (Figure 11B), or p53 (Figure 11C) rescued the cell proliferation of LNCaP 104-R1 cells being treated with increasing concentration of CAPE, confirming their essential role in regulating cell cycle arrest induced by CAPE treatment.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan, ROC.

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.

Show MeSH
Related in: MedlinePlus