Thiazolidenediones induce tumour-cell apoptosis through the Akt-GSK3ß pathway

What is known and Objective: Prostate cancer is a major health threat for men. Thiazolidenediones (TZDs) are synthetic ligands of the peroxisome proliferator-activated receptor gamma (PPAR gamma), and previous studies have shown that TZDs induce apoptosis of prostate cancer cells independently of PPAR gamma activation. However, the exact mechanism of these effects remains unknown. Our objective was to investigate the effects of TZDs on apoptosis and on the serine/threonine kinase pathway, Akt, and glycogen synthase kinase 3 beta (GSK3 beta). Methods: LNCaP cells, a type of prostate cancer cells (derived from left supraclavicular lymph node of human prostrate carcinoma), were cultured in DMEM medium, and cell viability was evaluated with a colorimetric assay using MTT level. The total and phosphorylated protein level of Akt and GSK3 beta were detected by Western blotting. Results and Discussion: The apoptosis-inducing effect of TZDs on prostate cancer cells involves the inhibition of Akt phosphorylation. Furthermore, TZDs induce inactivation of GSK3 beta, a multifunctional kinase that mediates essential events promoting prostate cancer development and acquisition of androgen independence. In addition, the GSK3 beta inhibitor lithium chloride sensitizes prostate cancer cells to TZDs cytotoxicity. What is new and Conclusion: Our data suggest that modulation of Akt-GSK3 beta pathway is involved in the cell death pathway engaged by TZDs in prostate cancer cells. This reveals another possible mechanism of TZDs on apoptosis in prostate cancer. Inhibition of the Akt-GSK3 beta cascade may be a useful approach in prostate cancer.