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Expression of TIP-1 confers radioresistance of malignant glioma cells
Miaojun Han1, Hailun Wang, Hua-Tang Zhang
1Department of Radiation Oncology, Vanderbilt University, Nashville, Tennessee, United States of America.
Background:
Malignant gliomas represent one group of tumors that poorly respond to ionizing radiation (IR) alone or combined with chemotherapeutic agents because of the intrinsic or acquired resistance. In this study, TIP-1 was identified as one novel protein that confers resistance of glioma cells to IR.
Methodology/Principal Findings:
Meta-analysis indicated that high TIP-1 expression levels correlate with the poor prognosis of human malignant gliomas after radiotherapy. Studies with established human glioma cell lines demonstrated that TIP-1 depletion with specific shRNAs sensitized the cells to IR, whereas an ectopic expression of TIP-1 protected the glioma cells from the IR-induced DNA damage and cell death. Biochemical studies indicated that TIP-1 protein promoted p53 ubiquitination and resulted in a reduced p53 protein level. Furthermore, p53 and its ubiquitination are required for the TIP-1 regulated cellular response to IR. A yeast two-hybrid screening identified that TIP-1, through its single PDZ domain, binds to the carboxyl terminus of LZAP that has been studied as one tumor suppressor functioning through ARF binding and p53 activation. It was revealed that the presence of TIP-1 enhances the protein association between LZAP and ARF and modulates the functionality of ARF/HDM2 toward multi-ubiquitination of p53, while depleting TIP-1 rescued p53 from polyubiquitination and degradation in the irradiated glioma cells. Studies with a mouse xenograft model indicated that depleting TIP-1 within D54 cells improved the tumor growth control with IR.
Conclusions/Significance:
This study provided the first evidence showing that TIP-1 modulates p53 protein stability and is involved in the radioresistance of malignant gliomas, suggesting that antagonizing TIP-1 might be one novel approach to sensitize malignant gliomas to radiotherapy.
Insights
Tumor suppressor TIP-1 (Tumor suppressor interacting protein 1) confers radioresistance in malignant gliomas by promoting p53 degradation. Targeting TIP-1 may enhance radiotherapy effectiveness for these challenging brain tumors.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Malignant gliomas exhibit resistance to radiotherapy.
- Identifying novel proteins involved in this resistance is crucial for improving treatment outcomes.
Purpose of the Study:
- To investigate the role of TIP-1 (Tumor suppressor interacting protein 1) in glioma radioresistance.
- To elucidate the underlying molecular mechanisms of TIP-1's function in response to ionizing radiation.
Main Methods:
- Meta-analysis of TIP-1 expression and patient prognosis.
- In vitro studies using glioma cell lines with TIP-1 depletion or overexpression.
- Biochemical assays to examine p53 ubiquitination and protein levels.
- Yeast two-hybrid screening to identify interacting proteins.
- In vivo studies using a mouse xenograft model.
Main Results:
- High TIP-1 expression correlates with poor prognosis in malignant gliomas post-radiotherapy.
- TIP-1 depletion sensitizes glioma cells to ionizing radiation (IR).
- TIP-1 protects cells from IR-induced DNA damage and cell death by promoting p53 ubiquitination and degradation.
- TIP-1 interacts with LZAP, modulating ARF/HDM2 activity and p53 ubiquitination.
- TIP-1 depletion in a xenograft model improved tumor growth control with IR.
Conclusions:
- TIP-1 plays a significant role in malignant glioma radioresistance by affecting p53 stability.
- Antagonizing TIP-1 presents a potential novel strategy to enhance radiotherapy efficacy for gliomas.
