KRIBB11 Exerts Anticancer Effects on A172 Glioblastoma Cells via the Cdh1/SKP2/p27 and HSF1/p53/p21 Pathways.

Background/aim: KRIBB11, a heat shock factor1 (HSF1) inhibitor, sensitizes cancer cells to several anticancer drugs. We have previously demonstrated that KRIBB11 alone induced the apoptosis of A172 glioblastoma cells. However, the molecular basis of its anticancer activity remains unclear. Hence, we aimed to examine the alterations in cell cycle regulators and the relevance of HSF1 activity following KRIBB11 treatment in A172 cells.

Materials and methods: The expression levels of p21, p27, and p53 were determined using western blotting or real-time PCR. Alterations in p27 levels were induced using small interfering RNA and retroviral transfection. SKP2 degradation was analyzed through a cycloheximide chase assay.

Results: p21 and p27 exhibited opposite expression profiles in A172 cells following KRIBB11 treatment, with p21 accumulating and p27 decreasing, respectively. Further experiments revealed that p21 induction could be attributed to HSF1-dependent p53 accumulation, which is responsible for cell cycle arrest and apoptosis. In contrast, p27 reduction was not reproduced by HSF1 silencing; however, further suppression of p27 accelerated poly (ADP-ribose) polymerase cleavage by KRIBB11 treatment, which was partially reversed by p27 overexpression. Thus, the reduction in p27 levels by KRIBB11 appeared favorable for apoptosis, suggesting that p27 functions as an oncogene in A172 cells. Subsequently, we demonstrated that the decrease in p27 levels following KRIBB11 exposure was mediated by the accumulation of the SKP2 protein, accompanied by a reduction in Cdh1 ubiquitin ligase.

Conclusion: KRIBB11 induces apoptotic cell death in A172 cells through two axes: HSF1-dependent p53/p21 accumulation and Cdh1/SKP2-dependent reduction of p27.