Cyclopentenone-prostaglandin derivatives, including the peroxisome-proliferator activated receptor γ (PPARγ) ligand 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), inhibit tumor cell growth in vitro and in vivo. As 15d-PGJ2 was found to stimulate the expression of vascular endothelial growth factor (VEGF) in endothelial cells, we investigated whether 15d-PGJ2 induces this angiogenic factor in the human androgen-independent PC 3 prostate and the 5637 urinary bladder carcinoma cell line. In PC 3 cells, 15d-PGJ2 caused a dose-dependent increase in VEGF mRNA expression, as determined by RT-PCR. Stimulation started after 6 h, and after 72 h, VEGF mRNA expression reached a maximum of 3.3±0.3 U, 4.4±0.3 U and 6.1±0.1 U with 1, 5 and 10 μM 15d-PGJ2, respectively. Between 12-72 h, VEGF protein production was stimulated by up to 2-fold with 5 and 10 μM 15d-PGJ2 as assessed by ELISA in PC 3 cell-conditioned medium. In 5637 cells, 15d-PGJ2 did not alter VEGF mRNA expression for up to 72 h. Thereafter, VEGF mRNA expression was transiently increased from 2.3±0.8 U in control cells to 4.6±0.5 U in 1 μM and 5.9±0.6 U in 5 μM 15d-PGJ2-treated cells. VEGF protein production was only moderately stimulated (1.7-fold). 10 μM 15d-PGJ2 had no effect on VEGF mRNA expression in 5637 cells, but effectively reduced viability in both cell lines. 15d-PGJ2 also increased PPARγ mRNA expression in both cell lines. While in PC 3 cells, stimulation of PPARγ mRNA expression occurred after 72 h, in 5637 cells, a transient stimulation took place after 6 h (4-fold). We demonstrated that 15d-PGJ2 induces VEGF in PC 3 and 5637 cancer cells. This might be important if PG-analogues are considered as antitumor agents.

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