Regulation of HIF-1 alpha Expression By PI3K/Akt Pathway Inhibitors in Breast Cancer Cell Lines

Aim: The aim of this study is to compare the effect of PI-103, which is a dual PI3K/mTOR inhibitor, on MDA-MB-231 human breast cancer cell line that has an intact PI3K/Akt pathway with MDA-MB-468 cells defected in this pathway (EGFR amplification and PTEN mutation) and also to compare the effect of PI-103, to Wortmannin, which is a PI3K inhibitor, by determining the regulatory role of this inhibition on HIF-1 alpha expression. Materials and Methods: Cultured MDA-MB-231 and MDA-MB-468 human breast cancer cell lines were incubated with PI3K/Akt signaling pathway inhibitors (Wortmannin and PI-103). Sensitivity of tumor cells to PI-103 was assessed by MTT assay. Signaling molecules p-Akt, total Akt, p-p70S6K expressions and effect of these inhibitors on HIF-1 alpha expression have been evaluated by western blotting. Results: Wortmannin (PI3K inhibitor), inhibited PI3K/Akt signaling in both cell lines and decreased HIF-1 alpha protein expression. PI-103, which is a dual PI3K-mTOR inhibitor, decreased HIF-1 alpha expression only in MDA-MB-231 cells despite of achieving effective inhibition of signaling in both cell lines. Although PTEN deficient MDA-MB-468 cells were found to be more sensitive to PI-103, this result had no marked effect on HIF-1 alpha expression. Conclusion: Our study shows for the first time that, PI-103 regulates HIF-1 alpha protein expression in breast cancer cells. Wortmannin was found to have much stronger effect of decreasing HIF-1 alpha protein level than PI-103. The decrease in cytoplasmic accumulation of HIF-1 alpha provided by signaling inhibitors is noteworthy with respect to the increasing impact of PI3K/Akt inhibitors in treatment strategies.