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KRIBB11 Exerts Anticancer Effects on A172 Glioblastoma Cells via the Cdh1/SKP2/p27 and HSF1/p53/p21 Pathways
Kyunghyun Yoo1,2, Hye Hyeon Yun1,2, Soon-Young Jung1,2
1Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
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.
Insights
KRIBB11 triggers glioblastoma cell death by activating heat shock factor 1 (HSF1) to increase p53/p21 and decreasing p27 via Cdh1/SKP2. This dual action promotes apoptosis in A172 cells.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- KRIBB11, a heat shock factor 1 (HSF1) inhibitor, is known to sensitize cancer cells to various anticancer drugs.
- Previous studies showed KRIBB11 induces apoptosis in A172 glioblastoma cells, but its molecular mechanisms were unclear.
- Understanding KRIBB11's anticancer activity is crucial for developing targeted glioblastoma therapies.
Purpose of the Study:
- To investigate the molecular mechanisms underlying KRIBB11-induced apoptosis in A172 glioblastoma cells.
- To examine the alterations in cell cycle regulators (p21, p27, p53) following KRIBB11 treatment.
- To determine the role of HSF1 activity in KRIBB11's anticancer effects.
Main Methods:
- Western blotting and real-time PCR were used to quantify p21, p27, and p53 expression levels.
- Small interfering RNA and retroviral transfection were employed to manipulate p27 levels.
- Cycloheximide chase assays were performed to analyze SKP2 degradation.
Main Results:
- KRIBB11 treatment led to increased p21 and decreased p27 expression in A172 cells.
- HSF1-dependent p53 accumulation mediated p21 induction, causing cell cycle arrest and apoptosis.
- KRIBB11-induced p27 reduction was linked to SKP2 accumulation and Cdh1 downregulation, favoring apoptosis.
Conclusions:
- KRIBB11 induces apoptotic cell death in A172 glioblastoma cells via two distinct molecular pathways.
- The first pathway involves HSF1-dependent accumulation of p53 and p21.
- The second pathway involves Cdh1/SKP2-dependent reduction of p27, which acts as an oncogene in these cells.
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